母体日粮蛋白水平对仔猪骨骼肌蛋白合成及myostatin转录调控的影响及其机制
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摘要
肌肉生长抑制素(Myostatin,MSTN)作为骨骼肌生长的负调控因子,自发现以来,对其研究主要集中在基因敲除或过表达对肌肉的影响及在体外对细胞增殖和分化的影响等方面。近来的研究表明,MSTN可以通过下调骨骼肌蛋白的合成来抑制肌肉的肥大,进而影响肌肉生长。然而,其调节蛋白合成的信号途径还不是很清楚。骨骼肌是营养程序化的敏感组织,妊娠和／或哺乳期间母体营养不良或蛋白限饲,均可影响肌纤维的可塑性,从而影响其表现型。我们前期的研究发现,母体日粮蛋白水平可以改变子代骨骼肌功能基因MyHC的表达,并且这种影响有阶段差异,即短期的效应和长期的效应。然而母体日粮蛋白水平是否影响骨骼肌的蛋白合成及MSTN的表达尚不清楚,其影响是否具有阶段差异也不清楚,对于造成这种差异的分子机理更是知之甚少。本研究以梅山猪为动物模型,研究母猪妊娠期和哺乳期饲喂不同蛋白水平的日粮对子代骨骼肌蛋白合成及MSTN转录调控的影响及其机制。
1母体日粮蛋白水平对子代血清中胰岛素和氨基酸水平及肌纤维横截面积的影响
本实验选用14头初产的小梅山母猪,体重在36.1±1.8kg范围内,随机分为标准蛋白组和低蛋白组。在妊娠期和哺乳期饲喂等能量但饲料粗蛋白含量不同的饲料。在妊娠和哺乳期间,标准蛋白组分别饲喂粗蛋白含量为12%和14%的日粮,而低蛋白组则分别饲喂粗蛋白含量6%和7%的日粮。在分娩后24小时内,每个处理组每窝调整为7-8只小猪进行实验,在仔猪出生后35天断奶,断奶后,两个处理组的仔猪均给以正常蛋白水平的日粮饲喂,直至8月龄出栏。分别在断奶(35天)和育肥(8月龄)进行样品采集。用BCA法测定断奶仔猪和育肥猪背最长肌的蛋白浓度,用经典HE染色法染色,测定断奶和育肥阶段背最长肌肌纤维横截面积,用放射免疫分析法检测血清中的胰岛素水平,用氨基酸自动分析仪检测血清中的游离氨基酸水平。结果显示：仔猪到35天断奶,低蛋白组的体重、肌肉重及肌肉蛋白含量均显著低于标准蛋白组(P<0.05),低蛋白组断奶阶段背最长肌肌纤维的横截面积显著低于标准蛋白组(P<0.05),低蛋白组断奶阶段血清中胰岛素水平下降,血清中游离氨基酸水平尤其是支链氨基酸水平极显著降低(P<0.01)；而到育肥阶段,无论是体重、肌肉重及肌肉蛋白含量还是血清中胰岛素水平、游离氨基酸水平,两组之间均无明显差异；而与标准蛋白日粮组相比,低蛋白组背最长肌肌纤维的横截面积有上升的趋势(P=0.057),说明母体日粮蛋白水平可能通过影响子代断奶阶段血清中胰岛素及氨基酸的水平来影响背最长肌的蛋白合成。
2母体日粮蛋白水平对子代背最长肌胰岛素和氨基酸-下游信号-通路及MSTN下游信号-通路的影响
通过以上研究发现,母体日粮蛋白水平影响到血清中胰岛素及氨基酸的水平,是否影响其下游信号,从而影响骨骼肌的蛋白合成?是否其它因素也参与影响骨骼肌的蛋白合成?我们运用Western blotting方法检测了胰岛素的下游信号胰岛素受体(Insulin receptor,IR)和Akt的蛋白表达,同时检测了氨基酸下游蛋白质合成关键因子——p70S6K和eIF4E的表达。用Real-time PCR检测了肌肉发育相关基因(MSTN、 MyoD、MEF2和Myogenin)及氨基酸下游相关基因的表达,结果发现,母体日粮蛋白水平并没有影响胰岛素的下游信号,但母体低蛋白日粮显著下调了子代断奶阶段氨基酸下游蛋白合成关键因子p70S6K和eIF4E的磷酸化水平(P<0.05),并显著下调了氨基酸下游信号eIF2a的表达(P<0.05)；同时我们还发现母体低蛋白日粮显著降低了断奶仔猪氨基酸信号下游关键基因ATF4、LAT1和CHOP的表达(P<0.05),然而对肌肉发育相关的基因除MSTN外,并无显著影响。MSTN是氨基酸敏感基因,并且对骨骼肌蛋白质的合成起重要的调节作用。母体低蛋白日粮,显著降低了子代断奶阶段背最长肌MSTN的mRNA水平(P<0.05),但显著上调了育肥阶段MSTN的mRNA水平(P<0.05)。于是,我们检测了MSTN的受体ACVR2B和ALK5的表达,并检测了其下游信号smad2/3、p38-MAPK、ERK和JNK及其磷酸化形式的表达。结果发现,低蛋白组断奶阶段背最长肌ACVR2B的：mRNA水平显著升高(P<0.05),ALK5的nRNA水平有升高的趋势(P=0.073);smad2和p38-MAPK的磷酸化水平显著升高；而育肥猪两组之间没有显著差异,提示母体日粮蛋白水平可能通过氨基酸和MSTN信号通路影响子代断奶阶段骨骼肌蛋白的合成。
3母猪日粮蛋白水-平影响子代背最长肌MSTN转录调节的分子机理
由以上的研究,我们发现母体日粮蛋白水平对MSTN的mRNA水平在断奶和育肥阶段的影响截然相反,为探索母体程序化作用的机制,我们运用Western blotting方法检测背最长肌MSTN转录因子(FOXO1、MyoD、CREB和C/EBPβ在核内的表达。结果显示,到断奶阶段,低蛋白组C/EBPβ (LAP*)在核中的表达显著降低(P<0.05)；提示C/EBPβ可能参与MSTN的转录调控。而到育肥期C/EBPβ的蛋白表达,两组之间均无显著差异。为了探讨C/EBPβ是否参与MSTN的转录调控,采用染色质免疫共沉淀(ChIP)方法检测了C/EBPβ在MSTN启动子区的结合情况。结果发现,断奶阶段,低蛋白组C/EBPβ与MSTN启动子区的3个预测的结合位点的结合情况显著降低(P<0.05),而育肥阶段,低蛋白组C/EBPβ与3个预测的结合位点中的2个的结合情况显著升高(P<0.05)；这与MSTN的mRNA水平变化一致,提示C/EBPβ参与MSTN的转录调控。为探索表遗传是否参与MSTN的转录调控,运用ChIP方法检测了MSTN启动子区的组蛋白修饰情况,结果显示,育肥阶段,低蛋白组组蛋白的乙酰化水平显著升高(P<0.05),组蛋白H3第9位赖氨酸的一甲基化(H3K9me1)水平显著降低(P<0.05),而组蛋白H3第27位赖氨酸的三甲基化(H3K27me3)水平显著升高(P<0.05),而断奶阶段两组之间组蛋白的修饰并无显著差异,提示组蛋白的修饰可能参与了育肥阶段MSTN的转录调控。Real-time PCR险测了以MSTN为靶的miRNA的表达,发现育肥阶段低蛋白组miR-500和miR-136的表达显著降低(P<0.05),miR-27a的表达有下降的趋势(P=0.057),而断奶阶段两组之间miRNA的表达并无显著变化,提示miRNA可能参与了育肥阶段MSTN的转录调控。以上结果提示：妊娠和哺乳期间母体日粮蛋白水平影响MSTN的转录调节,并且这一影响呈阶段特异性。断奶阶段MSTN的转录调节可能由C/EBPβ介导,而育肥阶段MSTN的转录不仅由C/EBPβ调节,而且表遗传因素——组蛋白修饰和miRNA也参与其调节。
Myostatin (MSTN) is a negative regulator of skeletal muscle growth factor. Since MSTN was discovered, the researches about it were focused on the effects of gene knockout or over-expression on muscle and effects on cell proliferation and differentiation in vitro. Recent studies have shown that, MSTN can reduce muscle hypertrophy by inhibition of skeletal muscle protein synthesis, thereby affect muscle growth. However, the signaling pathways of MSTN regulating protein synthesis are not clear. Skeletal muscle is susceptible to nutritional programming, demonstrating high plasticity of muscle fiber phenotype in response to maternal undernutrition or protein restriction during pregnancy and/or lactation. Our previous study found that maternal dietary protein levels can change MyHCIIb gene expression in skeletal muscle of offspring Meishan pigs, and the effects are stage-specific, namely short-term and long-term effects.However, it is not clear whether maternal dietary protein affect protein synthesis and the expression of MSTN in LD muscle, or the effects are stage-specific. Furthermore, the mechanisms underlying such stage-dependent regulation of gene expression in response to maternal nutrition have not been elucidated. Therefore, the present study was aimed to investigate the effects of maternal dietary protein during gestation and lactation on offspring skeletal muscle MSTN activity and transcriptional regulation in Meishan pigs and its mechanism.
1Effects of maternal dietary protein level on the levels of insulin and free amino acid in the plasma and cross-sectional area of muscle fiber of offspring at weaning and finishing stages
Meishan sows were fed traditionally on low-protein diets, whereas the standard commercial diets contain at least2folds higher crude protein. In this study,14primiparous purebred Meishan sows were fed on either low-protein (6%and7%) or standard-protein (12%and14%) diets, during gestation and lactation, respectively. Newborn pigs were counted and individually weighed at parturition. Litter size was adjusted to7to8pigs per litter at24h post farrowing in the same group. Newborn piglets were allowed free access to their mothers and weaned at35days (d) of age. After weaning, piglets were raised following the standard feeding regimen with the starter, grower and finisher diets recommended for the breed. Male pigs were killed at weaning (35days of age) and finishing (8months of age) stages, and the myofiber characteristics were observed.
The longissimus dorsi (LD) was taken for measuring the cross-sectional areas using HE staining, determination muscle protein concentration using bicinchonininc acid (BCA). The levels of insulin and free amino acids in plasma were measured by radioimmunoassay and amino acid auto-analyzer, respectively. The results showed that:Body weight, LD muscle weights and muscle protein concentrations were significantly lower(p<0.05) in LP piglets at weaning stage with decreased cross-sectional area muscle fiber (CSA)(p<0.05). The levels of insulin and free amino acid were decreased significantly in LP piglets at weaning stage (p<0.01).At finishing stage, none of body weight, muscle weight or muscle protein concentration was affected by maternal dietary protein, so did insulin or free amino acid in plasma. However, cross-sectional area of muscle fiber was showed a tendency of increase (p=0.057) in LP pigs. These results suggest that maternal dietary protein level may regulate the growth of skeletal muscle by affecting skeletal muscle protein synthesis in pigs at weaning stage.
2Effects of maternal dietary protein levels on the downstream signal of insulin and amino acid and MSTN downstream signal pathway in LD muscle of offspring at weaning and finishing stages
As mentioned above, maternal dietary protein levels changed the levels of insulin and free amino acids in plasma, and did it affect their downstream signal or not? We investigated insulin receptor (Insulin receptor, IR) and Akt protein expression of insulin downstream signaling and protein aynthesis key factors of amino acid downstream signaling using Western blotting. We detected the expression of genes (MSTN,MyoD, MEF2and Myogenin) related to muscle development and amino acid downstream signal genes using Real-time PCR.We found that maternal dietary protein levels did not affect downstream of insulin signaling, but maternal low dietary protein decreased protein aynthesis key factors p70S6K and eIF4E activity of amino acid downstream signal significantly (p<0.05),and reduced eIF2a expression of amino acid downstream signal in LD muscle of offspring at weaning stage. We also found that the expression of ATF4, LAT1and CHOP of amino acid downstream signal were decreased significantly in LP piglets at weaning stage (p<0.05),but the expression of muscle development related genes were not affected except MSTN.MSTN is susceptive to amino acid, and it played an important role in skeletal muscle protein syntheis. Maternal low dietary protein decreased MSTN mRNA levels significantly in LP piglets at weaning stage, but the MSTN mRNA level was increased in LP pigs significantly at finishing stage (P<0.05). Thus, we examined the expression of MSTN receptor (ACVR2B and ALK5) and the changes of its downstream signal smad2,3, p38-MAPK, ERK, JNK and their phosphorylation forms. The results showed that ACVR2B mRNA levels was significantly increased (p<0.05) and ALK5mRNA levels showed a trend of increase in LP piglets at weaning stage (p=0.073), the phosphorylation levels of smad2and p38-MAPK were significantly increased in LP piglets at weaning stage. Nevertheless, there were no significant differences between the two groups at finishing stages.Our results suggested that maternal dietary protein levels may affect muscle protein synthesis by amino acid and MSTN signaling pathways at weaning stage.
3The molecular mechanism of maternal dietary protein level affecting transcriptional regulation of MSTN gene
From the above, we found that the effects of maternal dietary protein on MSTN expression were distinct at weaning and finishing stages. To investigate the mechanism of maternal programming, we detected the expression of MSTN transcription factors (FOXO1, MyoD, CREB and C/EBPβ) in nuclear lysates of LD muscle by western blot analysis. Significantly lower (p<0.05) C/EBPβ (LAP*) protein content was detected in LD muscle of LP piglets. It suggested that C/EBPP may be involved in transcriptional regulation of MSTN. But it was no difference between the two groups at finishing stage. In order to clarify whether diminished C/EBPβ protein content in nuclear lysates takes part in the transcriptional regulation of MSTN,we performed chromatin immunoprecipitation (ChIP) analysis with anti-C/EBPβ antibody followed by qPCR assay using2pairs of specific primers to amplify MSTN promoter regions containing3putative binding sites for C/EBPP, respectively. The ChIP-qPCR analysis revealed significantly (p<0.05) decreased C/EBPβ binding to all the three binding sites on MSTN promoter in LP piglets at weaning stage. The results indicate that maternal low-protein diet decreases both nuclear content of C/EBPβ protein and C/EBPβ binding to the promoter of MSTN gene, which may be responsible for the down-regulation of MSTN mRNA expression in offspring pigs at weaning. However, the binding of C/EBPβ to putative binding sites2/3at MSTN promoter region was significantly up-regulated (p<0.05) in LP pigs, which was in agreement with the up-regulated MSTN mRNA expression. To determine whether histone modifications, including histone acetylation and methylation, on the promoter of MSTN gene are involved in the transcriptional regulation of MSTN gene, we performed ChIP assay with specific antibodies against4respective histone modification marks, namely acetyl-H3(H3ac), H3K4me3, H3K27me3and H3K9me1.At finishing stage, LP pigs showed increased level of H3ac (p<0.05) and H3K27me3(p<0.01), but decreased H3K9mel (p<0.05) on the promoter of MSTN gene in LD muscle. H3K4me3did not differ between the two groups. None of the histone modification marks showed differences between SP and LP piglets at weaning. Those results imply the involvement of histone modifications in the programming effect of maternal dietary protein on transcriptional regulation of MSTN gene at finishing stage. We also checked the expression of miRNAs predicted to target MSTN. The expression of ssc-miR-136and ssc-miR-500was reduced significantly (p<0.05) in the skeletal muscle of LP pigs at finishing stage, with a trend of decrease for ssc-miR-27a (p=0.057). None was differently expressed between the two groups at weaning stage. These results indicate that maternal dietary protein affects expression of miRNAs predicted to target MSTN at finishing stage. In conclusion, our results indicate that maternal dietary protein affects MSTN expression through distinct transcriptional regulation mechanisms at different stages. The immediate effect at weaning is mediated by C/EBPβ binding without epigenetic modifications, whereas the long-term effect at finishing stage involves both C/EBPβ binding and epigenetic regulations including histone modification and microRNA expression.
1母体日粮蛋白水平对子代血清中胰岛素和氨基酸水平及肌纤维横截面积的影响
本实验选用14头初产的小梅山母猪,体重在36.1±1.8kg范围内,随机分为标准蛋白组和低蛋白组。在妊娠期和哺乳期饲喂等能量但饲料粗蛋白含量不同的饲料。在妊娠和哺乳期间,标准蛋白组分别饲喂粗蛋白含量为12%和14%的日粮,而低蛋白组则分别饲喂粗蛋白含量6%和7%的日粮。在分娩后24小时内,每个处理组每窝调整为7-8只小猪进行实验,在仔猪出生后35天断奶,断奶后,两个处理组的仔猪均给以正常蛋白水平的日粮饲喂,直至8月龄出栏。分别在断奶(35天)和育肥(8月龄)进行样品采集。用BCA法测定断奶仔猪和育肥猪背最长肌的蛋白浓度,用经典HE染色法染色,测定断奶和育肥阶段背最长肌肌纤维横截面积,用放射免疫分析法检测血清中的胰岛素水平,用氨基酸自动分析仪检测血清中的游离氨基酸水平。结果显示：仔猪到35天断奶,低蛋白组的体重、肌肉重及肌肉蛋白含量均显著低于标准蛋白组(P<0.05),低蛋白组断奶阶段背最长肌肌纤维的横截面积显著低于标准蛋白组(P<0.05),低蛋白组断奶阶段血清中胰岛素水平下降,血清中游离氨基酸水平尤其是支链氨基酸水平极显著降低(P<0.01)；而到育肥阶段,无论是体重、肌肉重及肌肉蛋白含量还是血清中胰岛素水平、游离氨基酸水平,两组之间均无明显差异；而与标准蛋白日粮组相比,低蛋白组背最长肌肌纤维的横截面积有上升的趋势(P=0.057),说明母体日粮蛋白水平可能通过影响子代断奶阶段血清中胰岛素及氨基酸的水平来影响背最长肌的蛋白合成。
2母体日粮蛋白水平对子代背最长肌胰岛素和氨基酸-下游信号-通路及MSTN下游信号-通路的影响
通过以上研究发现,母体日粮蛋白水平影响到血清中胰岛素及氨基酸的水平,是否影响其下游信号,从而影响骨骼肌的蛋白合成?是否其它因素也参与影响骨骼肌的蛋白合成?我们运用Western blotting方法检测了胰岛素的下游信号胰岛素受体(Insulin receptor,IR)和Akt的蛋白表达,同时检测了氨基酸下游蛋白质合成关键因子——p70S6K和eIF4E的表达。用Real-time PCR检测了肌肉发育相关基因(MSTN、 MyoD、MEF2和Myogenin)及氨基酸下游相关基因的表达,结果发现,母体日粮蛋白水平并没有影响胰岛素的下游信号,但母体低蛋白日粮显著下调了子代断奶阶段氨基酸下游蛋白合成关键因子p70S6K和eIF4E的磷酸化水平(P<0.05),并显著下调了氨基酸下游信号eIF2a的表达(P<0.05)；同时我们还发现母体低蛋白日粮显著降低了断奶仔猪氨基酸信号下游关键基因ATF4、LAT1和CHOP的表达(P<0.05),然而对肌肉发育相关的基因除MSTN外,并无显著影响。MSTN是氨基酸敏感基因,并且对骨骼肌蛋白质的合成起重要的调节作用。母体低蛋白日粮,显著降低了子代断奶阶段背最长肌MSTN的mRNA水平(P<0.05),但显著上调了育肥阶段MSTN的mRNA水平(P<0.05)。于是,我们检测了MSTN的受体ACVR2B和ALK5的表达,并检测了其下游信号smad2/3、p38-MAPK、ERK和JNK及其磷酸化形式的表达。结果发现,低蛋白组断奶阶段背最长肌ACVR2B的：mRNA水平显著升高(P<0.05),ALK5的nRNA水平有升高的趋势(P=0.073);smad2和p38-MAPK的磷酸化水平显著升高；而育肥猪两组之间没有显著差异,提示母体日粮蛋白水平可能通过氨基酸和MSTN信号通路影响子代断奶阶段骨骼肌蛋白的合成。
3母猪日粮蛋白水-平影响子代背最长肌MSTN转录调节的分子机理
由以上的研究,我们发现母体日粮蛋白水平对MSTN的mRNA水平在断奶和育肥阶段的影响截然相反,为探索母体程序化作用的机制,我们运用Western blotting方法检测背最长肌MSTN转录因子(FOXO1、MyoD、CREB和C/EBPβ在核内的表达。结果显示,到断奶阶段,低蛋白组C/EBPβ (LAP*)在核中的表达显著降低(P<0.05)；提示C/EBPβ可能参与MSTN的转录调控。而到育肥期C/EBPβ的蛋白表达,两组之间均无显著差异。为了探讨C/EBPβ是否参与MSTN的转录调控,采用染色质免疫共沉淀(ChIP)方法检测了C/EBPβ在MSTN启动子区的结合情况。结果发现,断奶阶段,低蛋白组C/EBPβ与MSTN启动子区的3个预测的结合位点的结合情况显著降低(P<0.05),而育肥阶段,低蛋白组C/EBPβ与3个预测的结合位点中的2个的结合情况显著升高(P<0.05)；这与MSTN的mRNA水平变化一致,提示C/EBPβ参与MSTN的转录调控。为探索表遗传是否参与MSTN的转录调控,运用ChIP方法检测了MSTN启动子区的组蛋白修饰情况,结果显示,育肥阶段,低蛋白组组蛋白的乙酰化水平显著升高(P<0.05),组蛋白H3第9位赖氨酸的一甲基化(H3K9me1)水平显著降低(P<0.05),而组蛋白H3第27位赖氨酸的三甲基化(H3K27me3)水平显著升高(P<0.05),而断奶阶段两组之间组蛋白的修饰并无显著差异,提示组蛋白的修饰可能参与了育肥阶段MSTN的转录调控。Real-time PCR险测了以MSTN为靶的miRNA的表达,发现育肥阶段低蛋白组miR-500和miR-136的表达显著降低(P<0.05),miR-27a的表达有下降的趋势(P=0.057),而断奶阶段两组之间miRNA的表达并无显著变化,提示miRNA可能参与了育肥阶段MSTN的转录调控。以上结果提示：妊娠和哺乳期间母体日粮蛋白水平影响MSTN的转录调节,并且这一影响呈阶段特异性。断奶阶段MSTN的转录调节可能由C/EBPβ介导,而育肥阶段MSTN的转录不仅由C/EBPβ调节,而且表遗传因素——组蛋白修饰和miRNA也参与其调节。
Myostatin (MSTN) is a negative regulator of skeletal muscle growth factor. Since MSTN was discovered, the researches about it were focused on the effects of gene knockout or over-expression on muscle and effects on cell proliferation and differentiation in vitro. Recent studies have shown that, MSTN can reduce muscle hypertrophy by inhibition of skeletal muscle protein synthesis, thereby affect muscle growth. However, the signaling pathways of MSTN regulating protein synthesis are not clear. Skeletal muscle is susceptible to nutritional programming, demonstrating high plasticity of muscle fiber phenotype in response to maternal undernutrition or protein restriction during pregnancy and/or lactation. Our previous study found that maternal dietary protein levels can change MyHCIIb gene expression in skeletal muscle of offspring Meishan pigs, and the effects are stage-specific, namely short-term and long-term effects.However, it is not clear whether maternal dietary protein affect protein synthesis and the expression of MSTN in LD muscle, or the effects are stage-specific. Furthermore, the mechanisms underlying such stage-dependent regulation of gene expression in response to maternal nutrition have not been elucidated. Therefore, the present study was aimed to investigate the effects of maternal dietary protein during gestation and lactation on offspring skeletal muscle MSTN activity and transcriptional regulation in Meishan pigs and its mechanism.
1Effects of maternal dietary protein level on the levels of insulin and free amino acid in the plasma and cross-sectional area of muscle fiber of offspring at weaning and finishing stages
Meishan sows were fed traditionally on low-protein diets, whereas the standard commercial diets contain at least2folds higher crude protein. In this study,14primiparous purebred Meishan sows were fed on either low-protein (6%and7%) or standard-protein (12%and14%) diets, during gestation and lactation, respectively. Newborn pigs were counted and individually weighed at parturition. Litter size was adjusted to7to8pigs per litter at24h post farrowing in the same group. Newborn piglets were allowed free access to their mothers and weaned at35days (d) of age. After weaning, piglets were raised following the standard feeding regimen with the starter, grower and finisher diets recommended for the breed. Male pigs were killed at weaning (35days of age) and finishing (8months of age) stages, and the myofiber characteristics were observed.
The longissimus dorsi (LD) was taken for measuring the cross-sectional areas using HE staining, determination muscle protein concentration using bicinchonininc acid (BCA). The levels of insulin and free amino acids in plasma were measured by radioimmunoassay and amino acid auto-analyzer, respectively. The results showed that:Body weight, LD muscle weights and muscle protein concentrations were significantly lower(p<0.05) in LP piglets at weaning stage with decreased cross-sectional area muscle fiber (CSA)(p<0.05). The levels of insulin and free amino acid were decreased significantly in LP piglets at weaning stage (p<0.01).At finishing stage, none of body weight, muscle weight or muscle protein concentration was affected by maternal dietary protein, so did insulin or free amino acid in plasma. However, cross-sectional area of muscle fiber was showed a tendency of increase (p=0.057) in LP pigs. These results suggest that maternal dietary protein level may regulate the growth of skeletal muscle by affecting skeletal muscle protein synthesis in pigs at weaning stage.
2Effects of maternal dietary protein levels on the downstream signal of insulin and amino acid and MSTN downstream signal pathway in LD muscle of offspring at weaning and finishing stages
As mentioned above, maternal dietary protein levels changed the levels of insulin and free amino acids in plasma, and did it affect their downstream signal or not? We investigated insulin receptor (Insulin receptor, IR) and Akt protein expression of insulin downstream signaling and protein aynthesis key factors of amino acid downstream signaling using Western blotting. We detected the expression of genes (MSTN,MyoD, MEF2and Myogenin) related to muscle development and amino acid downstream signal genes using Real-time PCR.We found that maternal dietary protein levels did not affect downstream of insulin signaling, but maternal low dietary protein decreased protein aynthesis key factors p70S6K and eIF4E activity of amino acid downstream signal significantly (p<0.05),and reduced eIF2a expression of amino acid downstream signal in LD muscle of offspring at weaning stage. We also found that the expression of ATF4, LAT1and CHOP of amino acid downstream signal were decreased significantly in LP piglets at weaning stage (p<0.05),but the expression of muscle development related genes were not affected except MSTN.MSTN is susceptive to amino acid, and it played an important role in skeletal muscle protein syntheis. Maternal low dietary protein decreased MSTN mRNA levels significantly in LP piglets at weaning stage, but the MSTN mRNA level was increased in LP pigs significantly at finishing stage (P<0.05). Thus, we examined the expression of MSTN receptor (ACVR2B and ALK5) and the changes of its downstream signal smad2,3, p38-MAPK, ERK, JNK and their phosphorylation forms. The results showed that ACVR2B mRNA levels was significantly increased (p<0.05) and ALK5mRNA levels showed a trend of increase in LP piglets at weaning stage (p=0.073), the phosphorylation levels of smad2and p38-MAPK were significantly increased in LP piglets at weaning stage. Nevertheless, there were no significant differences between the two groups at finishing stages.Our results suggested that maternal dietary protein levels may affect muscle protein synthesis by amino acid and MSTN signaling pathways at weaning stage.
3The molecular mechanism of maternal dietary protein level affecting transcriptional regulation of MSTN gene
From the above, we found that the effects of maternal dietary protein on MSTN expression were distinct at weaning and finishing stages. To investigate the mechanism of maternal programming, we detected the expression of MSTN transcription factors (FOXO1, MyoD, CREB and C/EBPβ) in nuclear lysates of LD muscle by western blot analysis. Significantly lower (p<0.05) C/EBPβ (LAP*) protein content was detected in LD muscle of LP piglets. It suggested that C/EBPP may be involved in transcriptional regulation of MSTN. But it was no difference between the two groups at finishing stage. In order to clarify whether diminished C/EBPβ protein content in nuclear lysates takes part in the transcriptional regulation of MSTN,we performed chromatin immunoprecipitation (ChIP) analysis with anti-C/EBPβ antibody followed by qPCR assay using2pairs of specific primers to amplify MSTN promoter regions containing3putative binding sites for C/EBPP, respectively. The ChIP-qPCR analysis revealed significantly (p<0.05) decreased C/EBPβ binding to all the three binding sites on MSTN promoter in LP piglets at weaning stage. The results indicate that maternal low-protein diet decreases both nuclear content of C/EBPβ protein and C/EBPβ binding to the promoter of MSTN gene, which may be responsible for the down-regulation of MSTN mRNA expression in offspring pigs at weaning. However, the binding of C/EBPβ to putative binding sites2/3at MSTN promoter region was significantly up-regulated (p<0.05) in LP pigs, which was in agreement with the up-regulated MSTN mRNA expression. To determine whether histone modifications, including histone acetylation and methylation, on the promoter of MSTN gene are involved in the transcriptional regulation of MSTN gene, we performed ChIP assay with specific antibodies against4respective histone modification marks, namely acetyl-H3(H3ac), H3K4me3, H3K27me3and H3K9me1.At finishing stage, LP pigs showed increased level of H3ac (p<0.05) and H3K27me3(p<0.01), but decreased H3K9mel (p<0.05) on the promoter of MSTN gene in LD muscle. H3K4me3did not differ between the two groups. None of the histone modification marks showed differences between SP and LP piglets at weaning. Those results imply the involvement of histone modifications in the programming effect of maternal dietary protein on transcriptional regulation of MSTN gene at finishing stage. We also checked the expression of miRNAs predicted to target MSTN. The expression of ssc-miR-136and ssc-miR-500was reduced significantly (p<0.05) in the skeletal muscle of LP pigs at finishing stage, with a trend of decrease for ssc-miR-27a (p=0.057). None was differently expressed between the two groups at weaning stage. These results indicate that maternal dietary protein affects expression of miRNAs predicted to target MSTN at finishing stage. In conclusion, our results indicate that maternal dietary protein affects MSTN expression through distinct transcriptional regulation mechanisms at different stages. The immediate effect at weaning is mediated by C/EBPβ binding without epigenetic modifications, whereas the long-term effect at finishing stage involves both C/EBPβ binding and epigenetic regulations including histone modification and microRNA expression.
引文
[1]Kimball S. R., Farrell P. A., Jefferson L. S. Invited Review: Role of insulin in translational control of protein synthesis in skeletal muscle by amino acids or exercise[J]. JApplPhysiol, 2002,93(3):1168-1180.
[2]Tipton K. D., Wolfe R. R. Exercise, protein metabolism, and muscle growth[J]. IntJSport NutrExercMetab,2001,11(1):109-132.
[3]Tardif N., Salles J., Landrier J. F., et al. Oleate-enriched diet improves insulin sensitivity and restores muscle protein synthesis in old rats[J].2011,6:1-8.
[4]Davis T. A., Nguyen H. V., Suryawan A., et al. Developmental changes in the feeding-induced stimulation of translation initiation in muscle of neonatal pigs[J]. AmJPhysiol EndocrinolMetab, 2000,279(6):E 1226-E1234.
[5]McPherron A. C., Lawler A. M., Lee S. J. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member[J]. Nature,1997,387(6628):83-90.
[6]Du M., Tong J., Zhao J., et al. Fetal programming of skeletal muscle development in ruminant animals[J]. JAnim Sci,2010,88(13 Suppl):E51-E60.
[7]Toscano A. E., Manhaes-de-Castro R., Canon F. Effect of a low-protein diet during pregnancy on skeletal muscle mechanical properties of offspring rats[J]. Nutrition,2008,24(3):270-278.
[8]Matsakas A., Patel K. Skeletal muscle fibre plasticity in response to selected environmental and physiological stimuli[J]. HistolHistopathol,2009,24(5):611-629.
[9]Wang J., Li X., Yang X., et al. Maternal dietary protein induces opposite myofiber type transition in Meishan pigs at weaning and finishing stages[J]. Meat Sci,2011,89(2):221-227.
[10]Bayol S., Jones D., Goldspink G, et al. The influence of undernutrition during gestation on skeletal muscle cellularity and on the expression of genes that control muscle growth.[J]. BrJNutr,2004,91(3):331-339.
[11]Peiris H. N., Ponnampalam A. P., Osepchook C. C., et al. Placental expression of myostatin and follistatin-like-3 protein in a model of developmental programming[J]. AmJPhysiol EndocrinolMetab,2010,298(4):E854-E861.
[12]Han D. S., Huang H. P., Wang T. G., et al. Transcription activation of myostatin by trichostatin A in differentiated C2C12 myocytes via ASK1-MKK3/4/6-JNK and p38 mitogen-activated protein kinase pathways[J]. JCell Biochem,2010,111(3):564-573.
[13]Hu K. [The meaning of epigenetics][J]. YiChuan,2002,24(6):734-738.
[14]Allen D. L., Loh A. S. Posttranscriptional mechanisms involving microRNA-27a and b contribute to fast-specific and glucocorticoid-mediated myostatin expression in skeletal muscle[J]. AmJPhysiol Cell Physiol,2011,300(1):C124-C137.
[15]Adams G. R. Invited Review:Autocrine/paracrine IGF-Ⅰ and skeletal muscle adaptation[J]. JApplPhysiol,2002,93(3):1159-1167.
[16]Clarke M. S., Feeback D. L. Mechanical load induces sarcoplasmic wounding and FGF release in differentiated human skeletal muscle cultures[J]. FASEB J,1996,10(4):502-509.
[17]Goldspink G. Changes in muscle mass and phenotype and the expression of autocrine and systemic growth factors by muscle in response to stretch and overload[J]. JAnat,1999,194 (Pt 3):323-334.
[18]Adams G. R., Haddad F. The relationships among IGF-1, DNA content, and protein accumulation during skeletal muscle hypertrophy[J]. JApplPhysiol,1996,81(6):2509-2516.
[19]Adams G. R., McCue S. A. Localized infusion of IGF-Ⅰ results in skeletal muscle hypertrophy in rats[J]. J Appl Physiol,1998,84(5):1716-1722.
[20]Rommel C., Bodine S. C., Clarke B. A., et al. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways[J]. NatCell Biol, 2001,3(11):1009-1013.
[21]Escobar J., Frank J. W., Suryawan A., et al. Physiological rise in plasma leucine stimulates muscle protein synthesis in neonatal pigs by enhancing translation initiation factor activation[J]. AmJPhysiol EndocrinolMetab,2005,288(5):E914-E921.
[22]O'Connor P. M., Bush J. A., Suryawan A., et al. Insulin and amino acids independently stimulate skeletal muscle protein synthesis in neonatal pigs[J]. AmJPhysiol EndocrinolMetab, 2003,284(1):E110-E119.
[23]Jefferson L. S., Li J. B., Rannels S. R. Regulation by insulin of amino acid release and protein turnover in the perfused rat hemicorpus[J]. JBiolChem,1977,252(4):1476-1483.
[24]Davis T. A., Fiorotto M. L. Regulation of muscle growth in neonates[J]. CurrOpinClinNutrMetab Care,2009,12(1):78-85.
[25]Zhu M. J., Ford S. P., Means W. J., et al. Maternal nutrient restriction affects properties of skeletal muscle in offspring[J]. JPhysiol,2006,575(Pt 1):241-250.
[26]Inoki K., Zhu T., Guan K. L. TSC2 mediates cellular energy response to control cell growth and survival[J]. Cell,2003,115 (5):577-590.
[27]Wang H., Kubica N., Ellisen L. W., et al. Dexamethasone represses signaling through the mammalian target of rapamycin in muscle cells by enhancing expression of REDD1[J]. JBiolChem,2006,281 (51):39128-39134.
[28]Klionsky D. J., Emr S. D. Autophagy as a regulated pathway of cellular degradation[J]. Science, 2000,290(5497):1717-1721.
[29]Lecker S. H., Solomon V., Mitch W. E., et al. Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states[J]. JNutr,1999,129(1S Suppl):227S-237S.
[30]Nagasawa T., Hirano J., Yoshizawa F., et al. Myofibrillar protein catabolism is rapidly suppressed following protein feeding[J]. BiosciBiotechnolBiochem,1998,62(10):1932-1937.
[31]Nagasawa T., Kido T., Yoshizawa F., et al. Rapid suppression of protein degradation in skeletal muscle after oral feeding of leucine in rats[J]. JNutrBiochem,2002,13(2):121-127.
[32]Lowell B. B., Ruderman N. B., Goodman M. N. Regulation of myofibrillar protein degradation in rat skeletal muscle during brief and prolonged starvation [J]. Metabolism, 1986,35(12):1121-1127.
[33]Lowell B. B., Ruderman N. B., Goodman M. N. Evidence that lysosomes are not involved in the degradation of myofibrillar proteins in rat skeletal muscle[J]. BiochemJ,1986,234(1):237-240.
[34]Schakman O., Gilson H., Thissen J. P. Mechanisms of glucocorticoid-induced myopathy[J]. JEndocrinol,2008,197(1):1-10.
[35]Rock K. L., Gramm C., Rothstein L., et al. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules[J]. Cell, 1994,78(5):761-771.
[36]Kabeya Y., Mizushima N., Ueno T., et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing[J]. EMBO J,2000,19(21):5720-5728.
[37]Mordier S., Deval C., Bechet D., et al. Leucine limitation induces autophagy and activation of lysosome-dependent proteolysis in C2C12 myotubes through a mammalian target of rapamycin-independent signaling pathway[J]. JBiolChem,2000,275(38):29900-29906.
[38]Buse M. G.,Reid S. S. Leucine. A possible regulator of protein turnover in muscle[J]. JClinInvest,1975,56(5):1250-1261.
[39]Fulks R. M.,Li J. B., Goldberg A. L. Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm[J]. JBiolChem,1975,250(1):290-298.
[40]Mortimore G. E.,Wert J. J.,Jr., Miotto G., et al. Leucine-specific binding of photoreactive Leu7-MAP to a high molecular weight protein on the plasma membrane of the isolated rat hepatocyte[J]. BiochemBiophysResCommun,1994,203(1):200-208.
[41]Forsberg H., Ljungdahl P. O. Genetic and biochemical analysis of the yeast plasma membrane Ssylp-Ptr3p-Ssy5p sensor of extracellular amino acids[J]. MolCell Biol,2001,21(3):814-826.
[42]Iraqui I., Vissers S., Bernard F., et al. Amino acid signaling in Saccharomyces cerevisiae:a permease-like sensor of external amino acids and F-Box protein Grrlp are required for transcriptional induction of the AGP1 gene, which encodes a broad-specificity amino acid permease[J]. MolCell Biol,1999,19(2):989-1001.
[43]Blommaart E. F., Luiken J. J., Blommaart P. J., et al. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes[J]. JBiolChem,1995,270(5):2320-2326.
[44]Hara K., Yonezawa K., Weng Q. P., et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism[J]. JBiolChem, 1998,273(23):14484-14494.
[45]Patti M. E., Brambilla E., Luzi L., et al. Bidirectional modulation of insulin action by amino acids[J]. JClinInvest,1998,101(7):1519-1529.
[46]Leverve X. M., Caro L. H., Plomp P. J., et al. Control of proteolysis in perifused rat hepatocytes[J]. FEBS Lett,1987,219(2):455-458.
[47]Berthon P., Duguez S., Favier F. B., et al. Regulation of ubiquitin-proteasome system, caspase enzyme activities, and extracellular proteinases in rat soleus muscle in response to unloading[J]. Pflugers Arch,2007,454(4):625-633.
[48]Lecker S. H., Jagoe R. T., Gilbert A., et al. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression[J]. FASEB J,2004,18(1):39-51.
[49]Sandri M., Sandri C., Gilbert A., et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy[J]. Cell,2004,117(3):399-412.
[50]McFarlane C., Plummer E., Thomas M., et al. Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-kappaB-independent, FoxO1-dependent mechanism[J].JCell Physiol,2006,209(2):501-514.
[51]Amirouche A., Durieux A. C., Banzet S., et al. Down-regulation of Akt/mammalian target of rapamycin signaling pathway in response to myostatin overexpression in skeletal muscle[J]. Endocrinology,2009,150(l):286-294.
[52]Kadowaki M., Kanazawa T. Amino acids as regulators of proteolysis[J].JNutr,2003,133(6 Suppl 1):2052S-2056S.
[53]Jacinto E., Hall M. N. Tor signalling in bugs, brain and brawn[J].NatRevMolCell Biol, 2003,4(2):117-126.
[54]Hornberger T. A., Stuppard R., Conley K. E., et al. Mechanical stimuli regulate rapamycin-sensitive signalling by a phosphoinositide 3-kinase-, protein kinase B- and growth factor-independent mechanism[J]. BiochemJ,2004,380(Pt 3):795-804.
[55]Nader G A., McLoughlin T. J., Esser K. A. mTOR function in skeletal muscle hypertrophy: increased ribosomal RNA via cell cycle regulators[J]. AmJPhysiol Cell Physiol, 2005,289(6):C1457-C1465.
[56]Frost R. A., Lang C. H. Protein kinase B/Akt:a nexus of growth factor and cytokine signaling in determining muscle mass[J]. JApplPhysiol,2007,103(1):378-387.
[57]Dan H. C., Sun M., Yang L., et al. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin[J]. JBiolChem, 2002,277(38):35364-35370.
[58]Gao X., Zhang Y., Arrazola P., et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling[J]. NatCell Biol,2002,4(9):699-704.
[59]Inoki K., Li Y., Zhu T., et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling[J]. NatCell Biol,2002,4(9):648-657.
[60]Potter C. J., Pedraza L. G, Xu T. Akt regulates growth by directly phosphorylating Tsc2[J]. NatCell Biol,2002,4(9):658-665.
[61]Manning B. D., Tee A. R., Logsdon M. N., et al. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway[J]. MolCell,2002,10(1):151-162.
[62]Huang J., Manning B. D. The TSC1-TSC2 complex:a molecular switchboard controlling cell. growth[J]. BiochemJ,2008,412(2):179-190.
[63]Garami A., Zwartkruis F. J., Nobukuni T., et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2[J]. MolCell,2003,11(6):1457-1466.
[64]Inoki K., Li Y.,Xu T., et al. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling[J]. Genes Dev,2003,17(15):1829-1834.
[65]Long X., Ortiz-Vega S., Lin Y., et al. Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency [J]. JBiolChem,2005,280(25):23433-23436.
[66]Smith E. M., Finn S. G., Tee A. R., et al. The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses[J]. JBiolChem,2005,280(19):18717-18727.
[67]Lynch C. J., Fox H. L., Vary T. C., et al. Regulation of amino acid-sensitive TOR signaling by leucine analogues in adipocytes[J]. JCell Biochem,2000,77(2):234-251.
[68]Dreyer H. C., Drummond M. J., Pennings B., et al. Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle[J]. AmJPhysiol EndocrinolMetab,2008,294(2):E392-E400.
[69]Drummond M. J., Dreyer H. C., Pennings B., et al. Skeletal muscle protein anabolic response to resistance exercise and essential amino acids is delayed with aging[J]. JApplPhysiol, 2008,104(5):1452-1461.
[70]Kim D. H., Sarbassov D. D., Ali S. M., et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery[J]. Cell, 2002,110(2):163-175.
[71]Proud C. G Regulation of mammalian translation factors by nutrients[J]. EurJBiochem, 2002,269(22):5338-5349.
[72]Avruch J., Long X., Ortiz-Vega S., et al. Amino acid regulation of TOR complex 1[J]. AmJPhysiol EndocrinolMetab,2009,296(4):E592-E602.
[73]Hornberger T. A., Armstrong D. D., Koh T. J., et al. Intracellular signaling specificity in response to uniaxial vs. multiaxial stretch:implications for mechanotransduction[J]. AmJPhysiol Cell Physiol,2005,288(1):C185-C194.
[74]Hornberger T. A., Chu W. K., Mak Y. W., et al. The role of phospholipase D and phosphatidic acid in the mechanical activation of mTOR signaling in skeletal muscle[J]. ProcNatlAcadSciUSA,2006,103(12):4741-4746.
[75]Fang Y., Vilella-Bach M., Bachmann R., et al. Phosphatidic acid-mediated mitogenic activation of mTOR signaling[J]. Science,2001,294(5548):1942-1945.
[76]Foster D. A. Regulation of mTOR by phosphatidic acid?[J]. Cancer Res,2007,67(1):1-4.
[77]Sun Y Fau-Fang Y, Fang Y Fau-Yoon M. S., Yoon Ms Fau-Zhang C., et al. Phospholipase D1 is an effector of Rheb in the mTOR pathway[J].2008,105(24):8286-8291.
[78]Browne G. J., Proud C. G. Regulation of peptide-chain elongation in mammalian cells[J]. EurJBiochem,2002,269(22):5360-5368.
[79]Dennis P. B., Jaeschke A., Saitoh M., et al. Mammalian TOR:a homeostatic ATP sensor[J]. Science,2001,294(5544):1102-1105.
[80]Kahn B. B., Alquier T., Carling D., et al. AMP-activated protein kinase:ancient energy gauge provides clues to modern understanding of metabolism[J]. Cell Metab,2005,1(1):15-25.
[81]Gwinn D. M., Shackelford D. B., Egan D. F., et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint[J]. MolCell,2008,30(2):214-226.
[82]Bolster D. R., Crozier S. J., Kimball S. R., et al. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling[J].JBiolChem,2002,277(27):23977-23980.
[83]Pruznak A. M., Kazi A. A., Frost R. A., et al. Activation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside prevents leucine-stimulated protein synthesis in rat skeletal muscle[J]. JNutr,2008,138(10):1887-1894.
[84]Reiling J. H., Hafen E. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila[J]. Genes Dev, 2004,18(23):2879-2892.
[85]Corradetti M. N., Inoki K., Guan K. L. The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway [J]. JBiolChem, 2005,280(11):9769-9772.
[86]Brugarolas J., Lei K., Hurley R. L., et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex [J]. Genes Dev, 2004,18(23):2893-2904.
[87]Kimball S. R., Do A. N., Kutzler L., et al. Rapid turnover of the mTOR complex 1 (mTORC1) repressor REDD1 and activation of mTORC1 signaling following inhibition of protein synthesis[J]. JBiolChem,2008,283(6):3465-3475.
[88]Drummond M. J., Fujita S., Abe T., et al. Human muscle gene expression following resistance exercise and blood flow restriction [J]. MedSciSports Exerc,2008,40(4):691-698.
[89]Drummond M. J., Miyazaki M., Dreyer H. C., et al. Expression of growth-related genes in young and older human skeletal muscle following an acute stimulation of protein synthesis [J]. JApplPhysiol,2009,106(4):1403-1411.
[90]Huang Z., Chen X., Chen D. Myostatin:A novel insight into its role in metabolism, signal pathways, and expression regulation[J]. Cell Signal,2011,23(9):1441-1446.
[91]Lipina C., Kendall H., McPherron A. C., et al. Mechanisms involved in the enhancement of mammalian target of rapamycin signalling and hypertrophy in skeletal muscle of myostatin-deficient mice[J]. FEBS Lett,2010,584(11):2403-2408.
[92]Sartori R., Milan G., Patron M., et al. Smad2 and 3 transcription factors control muscle mass in adulthood[J]. AmJPhysiol Cell Physiol,2009,296(6):C1248-C1257.
[93]Gonzalez-Cadavid N. F., Taylor W. E., Yarasheski K., et al. Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting[J]. ProcNatlAcadSciUSA,1998,95(25):14938-14943.
[94]Sonstegard T. S., Rohrer G. A., Smith T. P. Myostatin maps to porcine chromosome 15 by linkage and physical analyses[J]. Anim Genet,1998,29(1):19-22.
[95]Stratil A., Kopecny M. Genomic organization, sequence and polymorphism of the porcine myostatin (GDF8; MSTN) gene[J]. Anim Genet,1999,30(6):468-470.
[96]McPherron A. C., Lee S. J. Double muscling in cattle due to mutations in the myostatin gene[J]. ProcNatlAcadSciUSA,1997,94(23):12457-12461.
[97]Rodino-Klapac L. R., Haidet A. M., Kota J., et al. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease[J]. Muscle Nerve,2009,39(3):283-296.
[98]Wolfman N. M., McPherron A. C., Pappano W. N., et al. Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases[J]. Proc Natl Acad Sci U S A, 2003,100(26):15842-15846.
[99]Rodgers B. D., Garikipati D. K. Clinical, agricultural, and evolutionary biology of myostatin:a comparative review[J]. EndocrRev,2008,29(5):513-534.
[100]Artaza J. N., Reisz-Porszasz S., Dow J. S., et al. Alterations in myostatin expression are associated with changes in cardiac left ventricular mass but not ejection fraction in the mouse[J]. JEndocrinol,2007,194(1):63-76.
[101]Cook S. A., Matsui T., Li L., et al. Transcriptional effects of chronic Akt activation in the heart[J]. JBiolChem,2002,277(25):22528-22533.
[102]McPherron A. C., Lee S. J. Suppression of body fat accumulation in myostatin-deficient mice[J]. JClinInvest,2002,109(5):595-601.
[103]Artaza J. N., Bhasin S., Magee T. R., et al. Myostatin inhibits myogenesis and promotes adipogenesis in C3H 10T(1/2) mesenchymal multipotent cells[J]. Endocrinology, 2005,146(8):3547-3557.
[104]Geng J., Peng F., Xiong F., et al. Inhibition of myostatin promotes myogenic differentiation of rat bone marrow-derived mesenchymal stromal cells[J].Cytotherapy,2009,11(7):849-863.
[105]Tang Q. Q., Otto T. C., Lane M. D. Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage[J].ProcNatlAcadSciUSA,2004,101(26):9607-9611.
[106]Stolz L. E., Li D., Qadri A., et al. Administration of myostatin does not alter fat mass in adult mice[J]. Diabetes ObesMetab,2008,10(2):135-142.
[107]Kim H. S., Liang L., Dean R. G., et al. Inhibition of preadipocyte differentiation by myostatin treatment in 3T3-L1 cultures[J]. BiochemBiophysResCommun,2001,281(4):902-906.
[108]Guo W., Flanagan J., Jasuja R., et al. The effects of myostatin on adipogenic differentiation of human bone marrow-derived mesenchymal stem cells are mediated through cross-communication between Smad3 and Wnt/beta-catenin signaling pathways[J].JBiolChem, 2008,283(14):9136-9145.
[109]Hirai S., Matsumoto H., Hino N., et al. Myostatin inhibits differentiation of bovine preadipocyte[J]. DomestAnim Endocrinol,2007,32(1):1-14.
[110]Elkasrawy M. N., Hamrick M. W. Myostatin (GDF-8) as a key factor linking muscle mass and bone structure[J]. JMusculoskeletNeuronallnteract,2010,10(1):56-63.
[111]Hamrick M. W., McPherron A. C., Lovejoy C. O. Bone mineral content and density in the humerus of adult myostatin-deficient mice [J]. CalcifTissue Int,2002,71(1):63-68.
[112]Hamrick M. W. Increased bone mineral density in the femora of GDF8 knockout mice[J]. AnatRecA DiscovMolCell EvolBiol,2003,272(1):388-391.
[113]Kellum E., Starr H., Arounleut P., et al. Myostatin (GDF-8) deficiency increases fracture callus size, Sox-5 expression, and callus bone volume[J]. Bone,2009,44(1):17-23.
[114]Cho T. J., Gerstenfeld L. C., Einhorn T. A. Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing[J]. JBone MinerR.es, 2002,17(3):513-520.
[115]Eliasson P., Andersson T., Kulas J., et al. Myostatin in tendon maintenance and repair[J]. Growth Factors,2009,27(4):247-254.
[116]Lee S. J. Regulation of muscle mass by myostatin [J].2001,98(16):9306-9311.
[117]Winters S. J., Moore J. P. Paracrine control of gonadotrophs[J]. SeminReprodMed, 2007,25(5):379-387.
[118]Patel K Fau-Amthor Helge, Amthor H. The function of Myostatin and strategies of Myostatin blockade-new hope for therapies aimed at promoting growth of skeletal muscle[J]. 2005,15(2)117-126.
[119]McCroskery S., Thomas M., Maxwell L., et al. Myostatin negatively regulates satellite cell activation and self-renewal [J]. JCell Biol,2003,162(6):1135-1147.
[120]Huang Z., Chen D., Zhang K., et al. Regulation of myostatin signaling by c-Jun N-terminal kinase in C2C12 cells[J]. Cell Signal,2007,19(11):2286-2295.
[121]Thomas M., Langley B., Berry C., et al. Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation[J]. JBiolChem,2000,275(51):40235-40243.
[122]Yang W., Zhang Y., Li Y., et al. Myostatin induces cyclin D1 degradation to cause cell cycle arrest through a phosphatidylinositol 3-kinase/AKT/GSK-3 beta pathway and is antagonized by insulin-like growth factor 1[J]. JBiolChem,2007,282(6):3799-3808.
[123]Rios R., Carneiro I., Arce V. M., et al. Myostatin is an inhibitor of myogenic differentiation[J]. AmJPhysiol Cell Physiol,2002,282(5):C993-C999.
[124]Joulia D., Bernardi H., Garandel V., et al. Mechanisms involved in the inhibition of myoblast proliferation and differentiation by myostatin[J]. ExpCell Res,2003,286(2):263-275.
[125]Langley B., Thomas M., Bishop A., et al. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression[J]. JBiolChem,2002,277(51):49831-49840.
[126]Yang W., Chen Y., Zhang Y, et al. Extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway is involved in myostatin-regulated differentiation repression[J]. Cancer Res,2006,66(3):1320-1326.
[127]Taylor W. E., Bhasin S., Artaza J., et al. Myostatin inhibits cell proliferation and protein synthesis in C2C12 muscle cells[J]. AmJPhysiol EndocrinolMetab,2001,280(2):E221-E228.
[128]Suryawan A., Frank J. W., Nguyen H. V., et al. Expression of the TGF-beta family of ligands is developmentally regulated in skeletal muscle of neonatal rats[J]. PediatrRes, 2006,59(2):175-179.
[129]Welle S., Bhatt K., Pinkert C. A. Myofibrillar protein synthesis in myostatin-deficient mice[J]. AmJPhysiol EndocrinolMetab,2006,290(3):E409-E415.
[130]Welle S., Burgess K., Mehta S. Stimulation of skeletal muscle myofibrillar protein synthesis, p70 S6 kinase phosphorylation, and ribosomal protein S6 phosphorylation by inhibition of myostatin in mature mice[J]. AmJPhysiol EndocrinolMetab,2009,296(3):E567-E572.
[131]Sarbassov D. D., Ali S. M., Sabatini D. M. Growing roles for the mTOR pathway[J]. CurrOpinCell Biol,2005,17(6):596-603.
[132]Trendelenburg A. U., Meyer A., Rohner D., et al. Myostatin reduces Akt/TORCl/p70S6K signaling, inhibiting myoblast differentiation and myotube size[J]. AmJPhysiol Cell Physiol, 2009,296(6):C1258-C1270.
[133]Sundaresan N. R., Saxena V. K., Singh R., et al. Expression profile of myostatin mRNA during the embryonic organogenesis of domestic chicken (Gallus gallus domesticus)[J]. ResVetSci, 2008,85(1):86-91.
[134]McKoy G., Bicknell K. A., Patel K., et al. Developmental expression of myostatin in cardiomyocytes and its effect on foetal and neonatal rat cardiomyocyte proliferation[J]. CardiovascRes,2007,74(2):304-312.
[135]Morissette M. R., Cook S. A., Foo S., et al. Myostatin regulates cardiomyocyte growth through modulation of Akt signaling[J].CircRes,2006,99(1):15-24.
[136]Shyu K. G., Ko W. H., Yang W. S., et al. Insulin-like growth factor-1 mediates stretch-induced upregulation of myostatin expression in neonatal rat cardiomyocytes[J]. CardiovascRes, 2005,68(3):405-414.
[137]Rodgers B. D., Interlichia J. P., Garikipati D. K., et al. Myostatin represses physiological hypertrophy of the heart and excitation-contraction coupling[J].JPhysiol,2009,587(Pt 20):4873-4886.
[138]Sharma M., Kambadur R., Matthews K. G., et al. Myostatin, a transforming growth factor-beta superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct[J]. JCell Physiol,1999,180(1):1-9.
[139]Mathews Ls Fau-Vale W. W., Vale W. W. Expression cloning of an activin receptor, a predicted transmembrane serine kinase[J].1991,65(6):973-982.
[140]Attisano L., Wrana J. L. Signal transduction by the TGF-beta superfamily[J]. Science, 2002,296(5573):1646-1647.
[141]Mathews L. S., Vale W. W. Expression cloning of an activin receptor, a predicted transmembrane serine kinase[J]. Cell,1991,65(6):973-982.
[142]Harrison C. A., Gray P. C., Vale W. W., et al. Antagonists of activin signaling:mechanisms and potential biological applications[J]. Trends EndocrinolMetab,2005,16(2):73-78.
[143]Feng X. H., Derynck R. Specificity and versatility in tgf-beta signaling through Smads[J]. AnnuRevCell DevBiol,2005,21:659-693.
[144]Chen Yg Fau-Wang Qiang, Wang Q Fau-Lin Shi-Lung, Lin Sl Fau-Chang C. Donald, et al. Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis[J]. 2006,231(5):534-544.
[145]Massague J., Gomis R. R. The logic of TGFbeta signaling[J]. FEBS Lett, 2006,580(12):2811-2820.
[146]Tsuchida K., Nakatani M., Uezumi A., et al. Signal transduction pathway through activin receptors as a therapeutic target of musculoskeletal diseases and cancer[J]. Endocr J, 2008,55(1):11-21.
[147]Tsuchida K., Nakatani M., Hitachi K., et al. Activin signaling as an emerging target for therapeutic interventions [J]. Cell CommunSignal,2009,7(15):1-8.
[148]Lee S. J., McPherron A. C. Regulation of myostatin activity and muscle growth[J]. ProcNatlAcadSciUSA,2001,98(16):9306-9311.
[149]Lee S. J., Reed L. A., Davies M. V, et al. Regulation of muscle growth by multiple ligands signaling through activin type Ⅱ receptors[J]. ProcNatlAcadSciUSA, 2005,102(50):18117-18122.
[150]Heldin Ch Fau-Miyazono K., Miyazono K Fau-ten Dijke P., ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins[J].1997,390(6659):465-471.
[151]Wrana J. L. Crossing Smads[J].2000,2000(23):rel.
[152]Attisano L Fau-Wrana J. L., Wrana J. L. Mads and Smads in TGF beta signalling[J]. 1998,10(2)188-194.
[153]Itoh F Fau-Asao H., Asao H Fau-Sugamura K., Sugamura K Fau-Heldin C. H., et al. Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads[J].2001,20(15)4132-4142.
[154]Rebbapragada A., Benchabane H., Wrana J. L., et al. Myostatin signals through a transforming growth factor beta-like signaling pathway to block adipogenesis[J]. MolCell Biol, 2003,23(20):7230-7242.
[155]Zhu X., Topouzis S., Liang L. F., et al. Myostatin signaling through Smad2, Smad3 and Smad4 is regulated by the inhibitory Smad7 by a negative feedback mechanism[J]. Cytokine, 2004,26(6):262-272.
[156]Xu W., Angelis K., Danielpour D., et al. Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor[J]. ProcNatlAcadSciUSA, 2000,97(11):5924-5929.
[157]Suzuki H., Yagi K., Kondo M., et al. c-Ski inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements[J]. Oncogene, 2004,23(29):5068-5076.
[158]Akiyoshi S., Inoue H., Hanai J., et al. c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads[J].JBiolChem, 1999,274(49):35269-35277.
[159]Kobayashi N., Goto K., Horiguchi K., et al. c-Ski activates MyoD in the nucleus of myoblastic cells through suppression of histone deacetylases[J]. Genes Cells,2007,12(3):375-385.
[160]Philip B., Lu Z., Gao Y. Regulation of GDF-8 signaling by the p38 MAPK[J]. Cell Signal, 2005,17(3):365-375.
[161]Li Z. B., Kollias H. D., Wagner K. R. Myostatin directly regulates skeletal muscle fibrosis[J]. J Biol Chem,2008,283(28):19371-19378.
[162]Kocamis H Fau-Kirkpatrick-Keller D. C., Kirkpatrick-Keller Dc Fau -Richter J., Richter J Fau-Killefer J., et al. The ontogeny of myostatin, follistatin and activin-B mRNA expression during chicken embryonic development[J].1041-1232.
[163]Ji S., Losinski R. L., Cornelius S. G., et al. Myostatin expression in porcine tissues:tissue specificity and developmental and postnatal regulation[J]. AmJPhysiol,1998,275(4 Pt 2):R1265-R1273.
[164]Jeanplong F Fau-Sharma M., Sharma M Fau-Somers W. G, Somers Wg Fau-Bass J. J., et al. Genomic organization and neonatal expression of the bovine myostatin gene[J]. 2001,220(1-2):31-37.
[165]Kubota K Fau-Sato Fuminori, Sato F Fau-Aramaki Shinya, Aramaki S Fau-Soh Tomoki, et al. Ubiquitous expression of myostatin in chicken embryonic tissues:its high expression in testis and ovary[J].2007,148(3):550-555.
[166]Allen D. L., Cleary A. S., Lindsay S. F., et al. Myostatin expression is increased by food deprivation in a muscle-specific manner and contributes to muscle atrophy during prolonged food deprivation in mice[J]. JApplPhysiol,2010,109(3):692-701.
[167]Guernec A., Chevalier B., Duclos M. J. Nutrient supply enhances both IGF-I and MSTN mRNA levels in chicken skeletal muscle[J]. DomestAnim Endocrinol,2004,26(2):143-154.
[168]Rodgers B. D., Weber G M., Kelley K. M., et al. Prolonged fasting and cortisol reduce myostatin mRNA levels in tilapia larvae; short-term fasting elevates [J]. AmJPhysiol RegulIntegrComp Physiol,2003,284(5):R1277-R1286.
[169]Terova G., Bernardini G., Binelli G., et al. cDNA encoding sequences for myostatin and FGF6 in sea bass (Dicentrarchus labrax, L.) and the effect of fasting and refeeding on their abundance levels[J]. DomestAnim Endocrinol,2006,30(4):304-319.
[170]Jeanplong F., Bass J. J., Smith H. K., et al. Prolonged underfeeding of sheep increases myostatin and myogenic regulatory factor Myf-5 in skeletal muscle while IGF-I and myogenin are repressed[J]. JEndocrinol,2003,176(3):425-437.
[171]Larsen A. E., Tunstall R. J., Carey K. A., et al. Actions of short-term fasting on human skeletal muscle myogenic and atrogenic gene expression [J]. AnnNutrMetab,2006,50(5):476-481.
[172]Nakazato K., Hirose T., Song H. Increased myostatin synthesis in rat gastrocnemius muscles under high-protein diet[J]. IntJSport NutrExercMetab,2006,16(2):153-165.
[173]Yang Y. X., Guo J., Jin Z., et al. Lysine restriction and realimentation affected growth, blood profiles and expression of genes related to protein and fat metabolism in weaned pigs[J]. JAnim Physiol Anim Nutr(Berl),2009,93(6):732-743.
[174]Siddiqui S. M., Chang E., Li J., et al. Dietary intervention with vitamin D, calcium, and whey protein reduced fat mass and increased lean mass in rats[J]. NutrRes,2008,28(11):783-790.
[175]Dong F., Hua Y., Zhao P., et al. Chromium supplement inhibits skeletal muscle atrophy in hindlimb-suspended mice[J]. JNutrBiochem,2009,20(12):992-999.
[176]Drummond M. J., Glynn E. L., Fry C. S., et al. Essential amino acids increase microRNA-499,-208b, and-23a and downregulate myostatin and myocyte enhancer factor 2C mRNA expression in human skeletal muscle[J]. JNutr,2009,139(12):2279-2284.
[177]Bonetto A Fau-Penna Fabio, Penna F Fau-Minero Valerio G., Minero Vg Fau-Reffo Patrizia, et al. Glutamine prevents myostatin hyperexpression and protein hypercatabolism induced in C2C12 myotubes by tumor necrosis factor-alpha[J].2011,40(2):585-594.
[178]Louis E., Raue U., Yang Y., et al. Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle[J]. JApplPhysiol, 2007,103(5):1744-1751.
[179]Marimuthu K., Murton A. J., Greenhaff P. L. Mechanisms regulating muscle mass during disuse atrophy and rehabilitation in humans[J]. JApplPhysiol,2011,110(2):555-560.
[180]Costa A., Dalloul H., Hegyesi H., et al. Impact of repeated bouts of eccentric exercise on myogenic gene expression[J]. EurJApplPhysiol,2007,101(4):427-436.
[181]Matsakas A., Friedel A., Hertrampf T., et al. Short-term endurance training results in a muscle-specific decrease of myostatin mRNA content in the rat[J]. Acta Physiol Scand, 2005,183(3):299-307.
[182]Hulmi J. J., Tannerstedt J., Selanne H., et al. Resistance exercise with whey protein ingestion affects mTOR signaling pathway and myostatin in men[J]. JApplPhysiol, 2009,106(5):1720-1729.
[183]Saremi A., Gharakhanloo R., Sharghi S., et al. Effects of oral creatine and resistance training on serum myostatin and GASP-1[J]. MolCell Endocrinol,2010,317(1-2):25-30.
[184]Walker K. S., Kambadur R., Sharma M., et al. Resistance training alters plasma myostatin but not IGF-1 in healthy men[J]. MedSciSports Exerc,2004,36(5):787-793.
[185]Willoughby D. S. Effects of heavy resistance training on myostatin mRNA and protein expression[J]. MedSciSports Exerc,2004,36(4):574-582.
[186]Ryan A. S., Ivey F. M., Prior S., et al. Skeletal muscle hypertrophy and muscle myostatin reduction after resistive training in stroke survivors[J]. Stroke,2011,42(2):416-420.
[187]Kopple J. D., Cohen A. H., Wang H., et al. Effect of exercise on mRNA levels for growth factors in skeletal muscle of hemodialysis patients[J]. JRen Nutr,2006,16(4):312-324.
[188]Troosters T., Probst V. S., Crul T., et al. Resistance training prevents deterioration in quadriceps muscle function during acute exacerbations of chronic obstructive pulmonary disease[J]. AmJRespirCrit Care Med,2010,181(10):1072-1077.
[189]Lenk K., Schur R., Linke A., et al. Impact of exercise training on myostatin expression in the myocardium and skeletal muscle in a chronic heart failure model[J]. EurJHeart Fail, 2009,11(4):342-348.
[190]Peviani S. M., Gomes A. R., Moreira R. F., et al. Short bouts of stretching increase myo-D, myostatin and atrogin-1 in rat soleus muscle[J]. Muscle Nerve,2007,35(3):363-370.
[191]Roth S. M., Martel G. F., Ferrell R. E., et al. Myostatin gene expression is reduced in humans with heavy-resistance strength training:a brief communication[J]. ExpBiolMed(Maywood), 2003,228(6):706-709.
[192]Hittel D. S., Axelson M., Sarna N., et al. Myostatin decreases with aerobic exercise and associates with insulin resistance [J]. MedSciSports Exerc,2010,42(11):2023-2029.
[193]Konopka A. R., Douglass M. D., Kaminsky L. A., et al. Molecular adaptations to aerobic exercise training in skeletal muscle of older women[J]. JGerontolA BiolSciMedSci, 2010,65(11):1201-1207.
[194]Kim J. S., Petrella J. K., Cross J. M., et al. Load-mediated downregulation of myostatin mRNA is not sufficient to promote myofiber hypertrophy in humans:a cluster analysis[J]. JApplPhysiol, 2007,103(5):1488-1495.
[195]Kim J. S., Cross J. M., Bamman M. M. Impact of resistance loading on myostatin expression and cell cycle regulation in young and older men and women[J]. AmJPhysiol EndocrinolMetab, 2005,288(6):E1110-E1119.
[196]Sakuma K., Watanabe K., Hotta N., et al. The adaptive responses in several mediators linked with hypertrophy and atrophy of skeletal muscle after lower limb unloading in humans [J].Acta Physiol (Oxf),2009,197(2):151-159.
[197]Dennis R. A., Przybyla B., Gurley C., et al. Aging alters gene expression of growth and remodeling factors in human skeletal muscle both at rest and in response to acute resistance exercise[J].Physiol Genomics,2008,32(3):393-400.
[198]Jensky N. E., Sims J. K., eli-Conwright C. M., et al. Exercise does not influence myostatin and follistatin messenger RNA expression in young women[J]. JStrengthCondRes, 2010,24(2):522-530.
[199]Heinemeier K. M., Olesen J. L., Schjerling P., et al. Short-term strength training and the expression of myostatin and IGF-I isoforms in rat muscle and tendon:differential effects of specific contraction types[J]. JApplPhysiol,2007,102(2):573-581.
[200]Aversa Z., Bonetto A., Penna F., et al. Changes in Myostatin Signaling in Non-Weight-Losing Cancer Patients[J].2011,4.
[201]Kung T., Szabo T., Springer J., et al. Cachexia in heart disease:highlights from the ESC 2010[J]. 2011,2(1):63-69.
[202]Lima Ar Fau-Martinez Paula Felippe, Martinez Pf Fau-Okoshi Katashi, Okoshi K Fau-Guizoni Daniele Mendes, et al. Myostatin and follistatin expression in skeletal muscles of rats with chronic heart failure[J].2010,91(1):54-62.
[203]Verzola D Fau-Procopio Vanessa, Procopio V Fau-Sofia Antonella, Sofia A Fau-Villaggio Barbara, et al. Apoptosis and myostatin mRNA are upregulated in the skeletal muscle of patients with chronic kidney disease[J].2011,79(7):773-782.
[204]D-C Man W Fau-Natanek S. A., Natanek Sa Fau-Riddoch-Contreras J., Riddoch-Contreras J Fau-Lewis A., et al. Quadriceps myostatin expression in COPD[J].2010,36(3):686-688.
[205]Gilson H., Schakman O., Combaret L., et al. Myostatin gene deletion prevents glucocorticoid-induced muscle atrophy[J]. Endocrinology,2007,148(1):452-460.
[206]Ma K., Mallidis C., Artaza J., et al. Characterization of 5'-regulatory region of human myostatin gene:regulation by dexamethasone in vitro[J]. AmJPhysiol EndocrinolMetab, 2001,281(6):E1128-E1136.
[207]Rigamonti A. E., Locatelli L., Cella S. G, et al. Muscle expressions of MGF, IGF-IEa, and myostatin in intact and hypophysectomized rats:effects of rhGH and testosterone alone or combined[J]. HormMetab Res,2009,41(1):23-29.
[208]Mendler L., Baka Z., Kovacs-Simon A., et al. Androgens negatively regulate myostatin expression in an androgen-dependent skeletal muscle[J]. BiochemBiophysResCommun, 2007,361(1):237-242.
[209]Lakshman K. M., Bhasin S., Corcoran C., et al. Measurement of myostatin concentrations in human serum:Circulating concentrations in young and older men and effects of testosterone administration[J]. MolCell Endocrinol,2009,302(1):26-32.
[210]Sadkowski T., Jank M., Zwierzchowski L., et al. Comparison of skeletal muscle transcriptional profiles in dairy and beef breeds bulls[J]. JApplGenet,2009,50(2):109-123.
[211]Heineke J., uger-Messier M., Xu J., et al. Genetic deletion of myostatin from the heart prevents skeletal muscle atrophy in heart failure[J]. Circulation,2010,121 (3):419-425.
[212]Yamada M., Tatsumi R., Yamanouchi K., et al. High concentrations of HGF inhibit skeletal muscle satellite cell proliferation in vitro by inducing expression of myostatin:a possible mechanism for reestablishing satellite cell quiescence in vivo[J]. AmJPhysiol Cell Physiol, 2010,298(3):C465-C476.
[213]Kurokawa M., Sato F., Aramaki S., et al. Monitor of the myostatin autocrine action during differentiation of embryonic chicken myoblasts into myotubes:effect of IGF-Ⅰ[J]. MolCell Biochem,2009,331(1-2):193-199.
[214]Covi J. A., Bader B. D., Chang E. S., et al. Molt cycle regulation of protein synthesis in skeletal muscle of the blackback land crab, Gecarcinus lateralis, and the differential expression of a myostatin-like factor during atrophy induced by molting or unweighting[J]. JExpBiol, 2010,213(1):172-183.
[215]Wang B. W., Chang H., Kuan P., et al. Angiotensin Ⅱ activates myostatin expression in cultured rat neonatal cardiomyocytes via p38 MAP kinase and myocyte enhance factor 2 pathway[J]. JEndocrinol,2008,197(1):85-93.
[216]Ijiri D., Kanai Y., Hirabayashi M. Possible roles of myostatin and PGC-1 alpha in the increase of skeletal muscle and transformation of fiber type in cold-exposed chicks:expression of myostatin and PGC-lalpha in chicks exposed to cold[J]. DomestAnim Endocrinol,2009,37(1):12-22.
[217]Stinckens A., Luyten T., Bijttebier J., et al. Characterization of the complete porcine MSTN gene and expression levels in pig breeds differing in muscularity[J]. Anim Genet, 2008,39(6):586-596.
[218]Spiller M. P., Kambadur R., Jeanplong F., et al. The myostatin gene is a downstream target gene of basic helix-loop-helix transcription factor MyoD[J]. MolCell Biol,2002,22(20):7066-7082.
[219]Du R., An X. R., Chen Y. F., et al. Some motifs were important for myostatin transcriptional regulation in sheep (Ovis aries)[J]. JBiochemMolBiol,2007,40(4):547-553.
[220]Yu Z., Li Y., Meng Q., et al. Comparative analysis of the pig BAC sequence involved in the regulation of myostatin gene[J]. SciChina CLife Sci,2005,48(2):168-180.
[221]Allen D. L., Unterman T. G. Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors[J]. AmJPhysiol Cell Physiol,2007,292(1):C188-C199.
[222]Allen D. L., Cleary A. S., Hanson A. M., et al. CCAAT/enhancer binding protein-delta expression is increased in fast skeletal muscle by food deprivation and regulates myostatin transcription in vitro[J]. AmJPhysiol RegulIntegrComp Physiol,2010,299(6):R1592-R1601.
[223]Galili N., Davis R. J., Fredericks W. J., et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma[J]. NatGenet,1993,5(3):230-235.
[224]Nagashima T., Shigematsu N., Maruki R., et al. Discovery of novel forkhead box O1 inhibitors for treating type 2 diabetes:improvement of fasting glycemia in diabetic db/db mice[J]. MolPharmacol,2010,78(5):961-970.
[225]McKinnon C. M., Ravier M. A., Rutter G. A. FoxO1 is required for the regulation of preproglucagon gene expression by insulin in pancreatic alphaTC1-9 cells[J]. JBiolChem, 2006,281 (51):39358-39369.
[226]Buteau J., Spatz M. L., Accili D. Transcription factor FoxO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass[J]. Diabetes,2006,55(5):1190-1196.
[227]Nasrin N., Ogg S., Cahill C. M., et al. DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells[J]. ProcNatlAcadSciUSA,2000,97(19):10412-10417.
[228]Cao Y., Kamioka Y., Yokoi N., et al. Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway[J]. JBiolChem, 2006,281 (52):40242-40251.
[229]Li P., Lee H., Guo S., et al. AKT-independent protection of prostate cancer cells from apoptosis mediated through complex formation between the androgen receptor and FKHR[J]. MolCell Biol,2003,23(1):104-118.
[230]Schuur E. R., Loktev A. V., Sharma M., et al. Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family[J]. JBiolChem, 2001,276(36):33554-33560.
[231]Wyzykowski J. C., Winata T. I., Mitin N., et al. Identification of novel MyoD gene targets in proliferating myogenic stem cells[J]. MolCell Biol,2002,22(17):6199-6208.
[232]Sabourin L. A., Girgis-Gabardo A., Seale P., et al. Reduced differentiation potential of primary MyoD-/-myogenic cells derived from adult skeletal muscle[J]. JCell Biol, 1999,144(4):631-643.
[233]Halevy O., Novitch B. G., Spicer D. B., et al. Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD[J]. Science,1995,267(5200):1018-1021.
[234]Ramji D. P., Foka P. CCAAT/enhancer-binding proteins:structure, function and regulation[J]. BiochemJ,2002,365(Pt 3):561-575.
[235]Jain R., Police S., Phelps K., et al. Tumour necrosis factor-alpha regulates expression of the CCAAT-enhancer-binding proteins (C/EBPs) alpha and beta and determines the occupation of the C/EBP site in the promoter of the insulin-responsive glucose-transporter gene in 3T3-L1 adipocytes[J]. BiochemJ,1999,338 (Pt 3):737-743.
[236]Paquin A., Barnabe-Heider F., Kageyama R., et al. CCAAT/enhancer-binding protein phosphorylation biases cortical precursors to generate neurons rather than astrocytes in vivo[J]. JNeurosci,2005,25(46):10747-10758.
[237]Tang Q. Q., Gronborg M., Huang H., et al. Sequential phosphorylation of CCAAT enhancer-binding protein beta by MAPK and glycogen synthase kinase 3beta is required for adipogenesis[J]. ProcNatlAcadSciUSA,2005,102(28):9766-9771.
[238]Croniger C. M., Millward C., Yang J., et al. Mice with a deletion in the gene for CCAAT/enhancer-binding protein beta have an attenuated response to cAMP and impaired carbohydrate metabolism[J]. JBiolChem,2001,276(1):629-638.
[239]Wang L., Shao J., Muhlenkamp P., et al. Increased insulin receptor substrate-1 and enhanced skeletal muscle insulin sensitivity in mice lacking CCAAT/enhancer-binding protein beta[J]. JBiolChem,2000,275(19):14173-14181.
[240]Chen C., Dudenhausen E., Chen H., et al. Amino-acid limitation induces transcription from the human C/EBPbeta gene via an enhancer activity located downstream of the protein coding sequence[J]. BiochemJ,2005,391(Pt 3):649-658.
[241]Siu F., Chen C., Zhong C., et al. CCAAT/enhancer-binding protein-beta is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene[J]. JBiolChem,2001,276(51):48100-48107.
[242]Du K., Ding J. Insulin regulates TRB3 and other stress-responsive gene expression through induction of C/EBPbeta[J]. MolEndocrinol,2009,23(4):475-485.
[243]Zheng S., Rollet M., Pan Y. X. Maternal protein restriction during pregnancy induces CCAAT/enhancer-binding protein (C/EBPbeta) expression through the regulation of histone modification at its promoter region in female offspring rat skeletal muscle[J]. Epigenetics, 2011,6(2).
[244]Beato M., Herrlich P., Schutz G. Steroid hormone receptors:many actors in search of a plot[J]. Cell,1995,83(6):851-857.
[245]Giguere V., Hollenberg S. M., Rosenfeld M. G., et al. Functional domains of the human glucocorticoid receptor[J]. Cell,1986,46(5):645-652.
[246]Rupprecht R., Arriza J. L., Spengler D., et al. Transactivation and synergistic properties of the mineralocorticoid receptor:relationship to the glucocorticoid receptor [J]. MolEndocrinol, 1993,7(4):597-603.
[247]Bamberger Cm Fau-Schulte H. M., Schulte Hm Fau-Chrousos G. P., Chrousos G. P. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids[J].1996,17(3):245-261.
[248]Dumont A., Hehner S. P., Schmitz M. L., et al. Cross-talk between steroids and NF-kappa B: what language?[J]. Trends BiochemSci,1998,23(7):233-235.
[249]Refojo D., Liberman A. C., Holsboer F., et al. Transcription factor-mediated molecular mechanisms involved in the functional cross-talk between cytokines and glucocorticoids[J]. ImmunolCell Biol,2001,79(4):385-394.
[250]De Kloet Er Fau-Vreugdenhil E., Vreugdenhil E Fau-Oitzl M. S., Oitzl Ms Fau-Joels M., et al. Brain corticosteroid receptor balance in health and disease[J].1998,19(3):269-301.
[251]Waetzig V Fau-Herdegen Thomas, Herdegen T. Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage[J].2005,26(9):455-461.
[252]Ip Yt Fau-Davis R. J., Davis R. J. Signal transduction by the c-Jun N-terminal kinase (JNK)-from inflammation to development[J].1998,10(2):205-219.
[253]Kim D. S., Kim J. H., Lee G H., et al. p38 Mitogen-activated protein kinase is involved in endoplasmic reticulum stress-induced cell death and autophagy in human gingival fibroblasts[J]. BiolPharmBull,2010,33(4):545-549.
[254]Van Speybroeck L. From epigenesis to epigenetics:the case of C. H. Waddington[J].2002,981:61-81.
[255]Vertino P. M., Yen R. W., Gao J., et al. De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase[J]. Mol Cell Biol, 1996,16(8):4555-4565.
[256]Bird A. The essentials of DNA methylation[J]. Cell,1992,70(1):5-8.
[257]Robertson K. D. DNA methylation and human disease[J]. Nat Rev Genet,2005,6(8):597-610.
[258]Reed M. C., Nijhout H. F., Neuhouser M. L., et al. A mathematical model gives insights into nutritional and genetic aspects of folate-mediated one-carbon metabolism[J]. JNutr, 2006,136(10):2653-2661.
[259]Steegers-Theunissen R. P., Obermann-Borst S. A., Kremer D., et al. Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child[J]. PLoSOne,2009,4(11):e7845.
[260]Pogribny I. P., Karpf A. R., James S. R., et al. Epigenetic alterations in the brains of Fisher 344 rats induced by long-term administration of folate/methyl-deficient diet[J]. Brain Res, 2008,1237:25-34.
[261]Mathers J. C., Strathdee G, Relton C. L. Induction of epigenetic alterations by dietary and other environmental factors[J]. AdvGenet,2010,71:3-39.
[262]Eilertsen K. J., Power R. A., Harkins L. L., et al. Targeting cellular memory to reprogram the epigenome, restore potential, and improve somatic cell nuclear transfer[J]. Anim ReprodSci, 2007,98(1-2):129-146.
[263]Gibney E. R., Nolan C. M. Epigenetics and gene expression[J]. Heredity,2010,105(1):4-13.
[264]Kouzarides T. Chromatin modifications and their function[J]. Cell,2007,128(4):693-705.
[265]He Y. Control of the transition to flowering by chromatin modifications [J]. MolPlant, 2009,2(4):554-564.
[266]Barski A., Cuddapah S., Cui K., et al. High-resolution profiling of histone methylations in the human genome[J]. Cell,2007,129(4):823-837.
[267]Huang Y., Greene E., Murray Stewart T., et al. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes[J]. ProcNatlAcadSciUSA,2007,104(19):8023-8028.
[268]Kalushkova A., Fryknas M., Lemaire M., et al. Polycomb target genes are silenced in multiple myeloma[J]. PLoSOne,2010,5(7):e11483.
[269]Vakoc C. R., Mandat S. A., Olenchock B. A., et al. Histone H3 lysine 9 methylation and HP1 gamma are associated with transcription elongation through mammalian chromatin[J]. MolCell,2005,19(3):381-391.
[270]Oliver S. S., Denu J. M. Dynamic interplay between histone H3 modifications and protein interpreters:emerging evidence for a "histone language" [J]. Chembiochem, 2011,12(2):299-307.
[271]Bartel D. P. MicroRNAs:genomics, biogenesis, mechanism, and function[J]. Cell, 2004,116(2):281-297.
[272]Hamilton A. J., Baulcombe D. C. A species of small antisense RNA in posttranscriptional gene silencing in plants[J]. Science,1999,286(5441):950-952.
[273]Reinhart B. J., Slack F. J., Basson M., et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans[J]. Nature,2000,403(6772):901-906.
[274]Lewis B. P., Shih I. H., Jones-Rhoades M. W., et al. Prediction of mammalian microRNA targets[J]. Cell,2003,115(7):787-798.
[275]van Rooij E., Liu N., Olson E. N. MicroRNAs flex their muscles[J]. Trends Genet, 2008,24(4):159-166.
[276]van Rooij E., Quiat D., Johnson B. A., et al. A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance[J]. DevCell,2009,17(5):662-673.
[277]Small E. M., O'Rourke J. R., Moresi V., et al. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486[J]. ProcNatlAcadSciUSA,2010,107(9):4218-4223.
[278]McCarthy J. J., Esser K. A., Andrade F. H. MicroRNA-206 is overexpressed in the diaphragm but not the hindlimb muscle of mdx mouse[J]. AmJPhysiol Cell Physiol, 2007,293(1):C451-C457.
[279]Callis T. E., Deng Z., Chen J. F., et al. Muscling through the microRNA world[J]. ExpBiolMed(Maywood),2008,233(2):131-138.
[280]Liu N., Williams A. H., Kim Y., et al. An intragenic MEF2-dependent enhancer directs muscle-specific expression of microRNAs 1 and 133[J]. ProcNatlAcadSciUSA, 2007,104(52):20844-20849.
[281]Rao P. K., Kumar R. M., Farkhondeh M., et al. Myogenic factors that regulate expression of muscle-specific microRNAs[J]. ProcNatlAcadSciUSA,2006,103(23):8721-8726.
[282]Chen J. F., Mandel E. M., Thomson J. M., et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation[J].NatGenet,2006,38(2):228-233.
[283]Kim H. K., Lee Y. S., Sivaprasad U., et al. Muscle-specific microRNA miR-206 promotes muscle differentiation[J]. JCell Biol,2006,174(5):677-687.
[284]McCarthy J. J., Esser K. A., Peterson C. A., et al. Evidence of MyomiR network regulation of beta-myosin heavy chain gene expression during skeletal muscle atrophy[J]. Physiol Genomics, 2009,39(3):219-226.
[285]Safdar A., Abadi A., Akhtar M., et al. miRNA in the regulation of skeletal muscle adaptation to acute endurance exercise in C57B1/6J male mice[J]. PLoSOne,2009,4(5):e5610.
[286]Aoi W., Naito Y., Mizushima K., et al. The microRNA miR-696 regulates PGC-1{alpha} in mouse skeletal muscle in response to physical activity[J]. AmJPhysiol EndocrinolMetab, 2010,298(4):E799-E806.
[287]Drummond M. J., McCarthy J. J., Fry C. S., et al. Aging differentially affects human skeletal muscle microRNA expression at rest and after an anabolic stimulus of resistance exercise and essential amino acids[J]. AmJPhysiol EndocrinolMetab,2008,295(6):E1333-E1340.
[288]Clop A., Marcq F., Takeda H., et al. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep[J]. NatGenet,2006,38(7):813-818.
[289]Gaedicke S., Zhang X., Schmelzer C., et al. Vitamin E dependent microRNA regulation in rat liver[J]. FEBS Lett,2008,582(23-24):3542-3546.
[290]Tryndyak V. P., Ross S. A., Beland F. A., et al. Down-regulation of the microRNAs miR-34a, miR-127, and miR-200b in rat liver during hepatocarcinogenesis induced by a methyl-deficient diet[J]. MolCarcinog,2009,48(6):479-487.
[291]Marsit C. J., Eddy K., Kelsey K. T. MicroRNA responses to cellular stress[J]. Cancer Res, 2006,66(22):10843-10848.
[292]Wang B., Majumder S., Nuovo G., et al. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice[J]. Hepatology,2009,50(4):1152-1161.
[293]Takanabe R., Ono K., Abe Y., et al. Up-regulated expression of microRNA-143 in association with obesity in adipose tissue of mice fed high-fat diet[J]. BiochemBiophysResCommun, 2008,376(4):728-732.
[294]Zhang J., Zhang F., Didelot X., et al. Maternal high fat diet during pregnancy and lactation alters hepatic expression of insulin like growth factor-2 and key microRNAs in the adult offspring[J]. BMCGenomics,2009,10(478.
[295]Wang L. L., Zhang Z., Li Q., et al. Ethanol exposure induces differential microRNA and target gene expression and teratogenic effects which can be suppressed by folic acid supplementation[J]. HumReprod,2009,24(3):562-579.
[296]Tang Y., Banan A., Forsyth C. B., et al. Effect of alcohol on miR-212 expression in intestinal epithelial cells and its potential role in alcoholic liver disease[J]. Alcohol ClinExpRes, 2008,32(2):355-364.
[297]Goyal R., Goyal D., Leitzke A., et al. Brain renin-angiotensin system:fetal epigenetic programming by maternal protein restriction during pregnancy [J]. ReprodSci, 2010,17(3):227-238.
[298]Plasma free amino acid levels reflect excess or deficiency of dietary amino acids[J]. NutrRev, 1966,24(6):170-174.
[299]Essen-Gustavsson B., Connysson M., Jansson A. Effects of crude protein intake from forage-only diets on muscle amino acids and glycogen levels in horses in training[J]. Equine VetJ,2010,42 Suppl 38:341-346.
[300]Silver M., Fowden A. L., Taylor P. M., et al. Blood amino acids in the pregnant mare and fetus: the effects of maternal fasting and intrafetal insulin[J]. ExpPhysiol,1994,79(3):423-433.
[301]Knoll-Kohler E., Handke A., Wojnorowicz F. Effect of ovarian sex hormones on the pool of free amino acids in maternal tissues of pregnant rats fed a protein-free diet[J]. JReprodFertil, 1976,46(1):137-142.
[302]Hsu Jm Fau-Anthony W. L., Anthony W1 Fau-Rider A. A., Rider A. A. Free amino acids in plasma and tissue of rats born to underfed dams[J].1975,148(4):1087-1089.
[303]Kwon H Fau-Ford Stephen P., Ford Sp Fau-Bazer Fuller W., Bazer Fw Fau-Spencer Thomas E., et al. Maternal nutrient restriction reduces concentrations of amino acids and polyamines in ovine maternal and fetal plasma and fetal fluids[J].2004,71(3):901-908.
[304]Wykes L. J., Fiorotto M., Burrin D. G, et al. Chronic low protein intake reduces tissue protein synthesis in a pig model of protein malnutrition[J]. JNutr,1996,126(5):1481-1488.
[305]Jansson N., Pettersson J., Haafiz A., et al. Down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet[J]. JPhysiol,2006,576(Pt 3):935-946.
[306]Chen C. Y., Crott J., Liu Z., et al. Fructose and saturated fats predispose hyperinsulinemia in lean male rat offspring[J]. Eur J Nutr,2010,49(6):337-343.
[307]Anthony J. C., Yoshizawa F., Anthony T. G., et al. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway[J].JNutr, 2000,130(10):2413-2419.
[308]Anthony J. C., Anthony T. G., Kimball S. R., et al. Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation[J]. JNutr,2000,130(2):139-145.
[309]Timmerman Kl Fau-Lee Jessica L., Lee Jl Fan-Dreyer Hans C., Dreyer He Fau-Dhanani Shaheen, et al. Insulin stimulates human skeletal muscle protein synthesis via an indirect mechanism involving endothelial-dependent vasodilation and mammalian target of rapamycin complex 1 signaling[J].2010,95(8):3848-3857.
[310]Miyazaki M Fau-Esser Karyn A., Esser K. A. Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals[J].2009,106(4):1367-1373.
[311]Murgas Torrazza R Fau-Suryawan Agus, Suryawan A Fau-Gazzaneo Maria C., Gazzaneo Mc Fau-Orellana Renan A., et al. Leucine supplementation of a low-protein meal increases skeletal muscle and visceral tissue protein synthesis in neonatal pigs by stimulating mTOR-dependent translation initiation[J].2010,140(12):2145-2152.
[312]Sikalidis Ak Fau-Stipanuk Martha H., Stipanuk M. H. Growing rats respond to a sulfur amino acid-deficient diet by phosphorylation of the alpha subunit of eukaryotic initiation factor 2 heterotrimeric complex and induction of adaptive components of the integrated stress response[J].2010,140(6):1080-1085.
[313]Drummond M. J., Bell J. A., Fujita S., et al. Amino acids are necessary for the insulin-induced activation of mTOR/S6K1 signaling and protein synthesis in healthy and insulin resistant human skeletal muscle[J]. ClinNutr,2008,27(3):447-456.
[314]Suryawan A., O'Connor P. M., Kimball S. R., et al. Amino acids do not alter the insulin-induced activation of the insulin signaling pathway in neonatal pigs[J].JNutr,2004,134(1):24-30.
[315]Wang X., Beugnet A., Murakami M., et al. Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins[J].MolCell Biol,2005,25(7):2558-2572.
[316]Fujita S., Dreyer H. C., Drummond M. J., et al. Essential amino acid and carbohydrate ingestion before resistance exercise does not enhance postexercise muscle protein synthesis[J]. JApplPhysiol,2009,106(5):1730-1739.
[317]Yang Yx Fau-Guo J., Guo J Fau-Jin Z., Jin Z Fau-Yoon S. Y., et al. Lysine restriction and realimentation affected growth, blood profiles and expression of genes related to protein and fat metabolism in weaned pigs[J].2009,93(6):732-743.
[318]Siddiqui Sm Fau-Chang Eugene, Chang E Fau-Li Jia, Li J Fau-Burlage Catherine, et al. Dietary intervention with vitamin D, calcium, and whey protein reduced fat mass and increased lean mass in rats[J].2008,28(11):783-790.
[319]Carlson C. J., Booth F. W., Gordon S. E. Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloading[J]. AmJPhysiol,1999,277(2 Pt 2):R601-R606.
[320]Girgenrath S Fau-Song Kening, Song K Fau-Whittemore Lisa-Anne, Whittemore L. A. Loss of myostatin expression alters fiber-type distribution and expression of myosin heavy chain isoforms in slow-and fast-type skeletal muscle[J].2005,31(1):34-40.
[321]Elashry Mi Fau-Otto Anthony, Otto A Fau-Matsakas Antonios, Matsakas A Fau-El-Morsy Salah E., et al. Morphology and myofiber composition of skeletal musculature of the forelimb in young and aged wild type and myostatin null mice[J].2009,12(4):269-281.
[322]Winter S., Fischle W. Epigenetic markers and their cross-talk[J]. Essays Biochem, 2010,48(1):45-61.
[323]Campion J., Milagro F. I., Martinez J. A. Individuality and epigenetics in obesity[J]. ObesRev, 2009,10(4):383-392.
[324]Eriksson J. G. Early programming of later health and disease:factors acting during prenatal life might have lifelong consequences[J]. Diabetes,2010,59(10):2349-2350.
[325]Plagemann A., Harder T., Brunn M., et al. Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding:an epigenetic model of obesity and the metabolic syndrome[J]. JPhysiol,2009,587(Pt 20):4963-4976.
[2]Tipton K. D., Wolfe R. R. Exercise, protein metabolism, and muscle growth[J]. IntJSport NutrExercMetab,2001,11(1):109-132.
[3]Tardif N., Salles J., Landrier J. F., et al. Oleate-enriched diet improves insulin sensitivity and restores muscle protein synthesis in old rats[J].2011,6:1-8.
[4]Davis T. A., Nguyen H. V., Suryawan A., et al. Developmental changes in the feeding-induced stimulation of translation initiation in muscle of neonatal pigs[J]. AmJPhysiol EndocrinolMetab, 2000,279(6):E 1226-E1234.
[5]McPherron A. C., Lawler A. M., Lee S. J. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member[J]. Nature,1997,387(6628):83-90.
[6]Du M., Tong J., Zhao J., et al. Fetal programming of skeletal muscle development in ruminant animals[J]. JAnim Sci,2010,88(13 Suppl):E51-E60.
[7]Toscano A. E., Manhaes-de-Castro R., Canon F. Effect of a low-protein diet during pregnancy on skeletal muscle mechanical properties of offspring rats[J]. Nutrition,2008,24(3):270-278.
[8]Matsakas A., Patel K. Skeletal muscle fibre plasticity in response to selected environmental and physiological stimuli[J]. HistolHistopathol,2009,24(5):611-629.
[9]Wang J., Li X., Yang X., et al. Maternal dietary protein induces opposite myofiber type transition in Meishan pigs at weaning and finishing stages[J]. Meat Sci,2011,89(2):221-227.
[10]Bayol S., Jones D., Goldspink G, et al. The influence of undernutrition during gestation on skeletal muscle cellularity and on the expression of genes that control muscle growth.[J]. BrJNutr,2004,91(3):331-339.
[11]Peiris H. N., Ponnampalam A. P., Osepchook C. C., et al. Placental expression of myostatin and follistatin-like-3 protein in a model of developmental programming[J]. AmJPhysiol EndocrinolMetab,2010,298(4):E854-E861.
[12]Han D. S., Huang H. P., Wang T. G., et al. Transcription activation of myostatin by trichostatin A in differentiated C2C12 myocytes via ASK1-MKK3/4/6-JNK and p38 mitogen-activated protein kinase pathways[J]. JCell Biochem,2010,111(3):564-573.
[13]Hu K. [The meaning of epigenetics][J]. YiChuan,2002,24(6):734-738.
[14]Allen D. L., Loh A. S. Posttranscriptional mechanisms involving microRNA-27a and b contribute to fast-specific and glucocorticoid-mediated myostatin expression in skeletal muscle[J]. AmJPhysiol Cell Physiol,2011,300(1):C124-C137.
[15]Adams G. R. Invited Review:Autocrine/paracrine IGF-Ⅰ and skeletal muscle adaptation[J]. JApplPhysiol,2002,93(3):1159-1167.
[16]Clarke M. S., Feeback D. L. Mechanical load induces sarcoplasmic wounding and FGF release in differentiated human skeletal muscle cultures[J]. FASEB J,1996,10(4):502-509.
[17]Goldspink G. Changes in muscle mass and phenotype and the expression of autocrine and systemic growth factors by muscle in response to stretch and overload[J]. JAnat,1999,194 (Pt 3):323-334.
[18]Adams G. R., Haddad F. The relationships among IGF-1, DNA content, and protein accumulation during skeletal muscle hypertrophy[J]. JApplPhysiol,1996,81(6):2509-2516.
[19]Adams G. R., McCue S. A. Localized infusion of IGF-Ⅰ results in skeletal muscle hypertrophy in rats[J]. J Appl Physiol,1998,84(5):1716-1722.
[20]Rommel C., Bodine S. C., Clarke B. A., et al. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways[J]. NatCell Biol, 2001,3(11):1009-1013.
[21]Escobar J., Frank J. W., Suryawan A., et al. Physiological rise in plasma leucine stimulates muscle protein synthesis in neonatal pigs by enhancing translation initiation factor activation[J]. AmJPhysiol EndocrinolMetab,2005,288(5):E914-E921.
[22]O'Connor P. M., Bush J. A., Suryawan A., et al. Insulin and amino acids independently stimulate skeletal muscle protein synthesis in neonatal pigs[J]. AmJPhysiol EndocrinolMetab, 2003,284(1):E110-E119.
[23]Jefferson L. S., Li J. B., Rannels S. R. Regulation by insulin of amino acid release and protein turnover in the perfused rat hemicorpus[J]. JBiolChem,1977,252(4):1476-1483.
[24]Davis T. A., Fiorotto M. L. Regulation of muscle growth in neonates[J]. CurrOpinClinNutrMetab Care,2009,12(1):78-85.
[25]Zhu M. J., Ford S. P., Means W. J., et al. Maternal nutrient restriction affects properties of skeletal muscle in offspring[J]. JPhysiol,2006,575(Pt 1):241-250.
[26]Inoki K., Zhu T., Guan K. L. TSC2 mediates cellular energy response to control cell growth and survival[J]. Cell,2003,115 (5):577-590.
[27]Wang H., Kubica N., Ellisen L. W., et al. Dexamethasone represses signaling through the mammalian target of rapamycin in muscle cells by enhancing expression of REDD1[J]. JBiolChem,2006,281 (51):39128-39134.
[28]Klionsky D. J., Emr S. D. Autophagy as a regulated pathway of cellular degradation[J]. Science, 2000,290(5497):1717-1721.
[29]Lecker S. H., Solomon V., Mitch W. E., et al. Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states[J]. JNutr,1999,129(1S Suppl):227S-237S.
[30]Nagasawa T., Hirano J., Yoshizawa F., et al. Myofibrillar protein catabolism is rapidly suppressed following protein feeding[J]. BiosciBiotechnolBiochem,1998,62(10):1932-1937.
[31]Nagasawa T., Kido T., Yoshizawa F., et al. Rapid suppression of protein degradation in skeletal muscle after oral feeding of leucine in rats[J]. JNutrBiochem,2002,13(2):121-127.
[32]Lowell B. B., Ruderman N. B., Goodman M. N. Regulation of myofibrillar protein degradation in rat skeletal muscle during brief and prolonged starvation [J]. Metabolism, 1986,35(12):1121-1127.
[33]Lowell B. B., Ruderman N. B., Goodman M. N. Evidence that lysosomes are not involved in the degradation of myofibrillar proteins in rat skeletal muscle[J]. BiochemJ,1986,234(1):237-240.
[34]Schakman O., Gilson H., Thissen J. P. Mechanisms of glucocorticoid-induced myopathy[J]. JEndocrinol,2008,197(1):1-10.
[35]Rock K. L., Gramm C., Rothstein L., et al. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules[J]. Cell, 1994,78(5):761-771.
[36]Kabeya Y., Mizushima N., Ueno T., et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing[J]. EMBO J,2000,19(21):5720-5728.
[37]Mordier S., Deval C., Bechet D., et al. Leucine limitation induces autophagy and activation of lysosome-dependent proteolysis in C2C12 myotubes through a mammalian target of rapamycin-independent signaling pathway[J]. JBiolChem,2000,275(38):29900-29906.
[38]Buse M. G.,Reid S. S. Leucine. A possible regulator of protein turnover in muscle[J]. JClinInvest,1975,56(5):1250-1261.
[39]Fulks R. M.,Li J. B., Goldberg A. L. Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm[J]. JBiolChem,1975,250(1):290-298.
[40]Mortimore G. E.,Wert J. J.,Jr., Miotto G., et al. Leucine-specific binding of photoreactive Leu7-MAP to a high molecular weight protein on the plasma membrane of the isolated rat hepatocyte[J]. BiochemBiophysResCommun,1994,203(1):200-208.
[41]Forsberg H., Ljungdahl P. O. Genetic and biochemical analysis of the yeast plasma membrane Ssylp-Ptr3p-Ssy5p sensor of extracellular amino acids[J]. MolCell Biol,2001,21(3):814-826.
[42]Iraqui I., Vissers S., Bernard F., et al. Amino acid signaling in Saccharomyces cerevisiae:a permease-like sensor of external amino acids and F-Box protein Grrlp are required for transcriptional induction of the AGP1 gene, which encodes a broad-specificity amino acid permease[J]. MolCell Biol,1999,19(2):989-1001.
[43]Blommaart E. F., Luiken J. J., Blommaart P. J., et al. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes[J]. JBiolChem,1995,270(5):2320-2326.
[44]Hara K., Yonezawa K., Weng Q. P., et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism[J]. JBiolChem, 1998,273(23):14484-14494.
[45]Patti M. E., Brambilla E., Luzi L., et al. Bidirectional modulation of insulin action by amino acids[J]. JClinInvest,1998,101(7):1519-1529.
[46]Leverve X. M., Caro L. H., Plomp P. J., et al. Control of proteolysis in perifused rat hepatocytes[J]. FEBS Lett,1987,219(2):455-458.
[47]Berthon P., Duguez S., Favier F. B., et al. Regulation of ubiquitin-proteasome system, caspase enzyme activities, and extracellular proteinases in rat soleus muscle in response to unloading[J]. Pflugers Arch,2007,454(4):625-633.
[48]Lecker S. H., Jagoe R. T., Gilbert A., et al. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression[J]. FASEB J,2004,18(1):39-51.
[49]Sandri M., Sandri C., Gilbert A., et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy[J]. Cell,2004,117(3):399-412.
[50]McFarlane C., Plummer E., Thomas M., et al. Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-kappaB-independent, FoxO1-dependent mechanism[J].JCell Physiol,2006,209(2):501-514.
[51]Amirouche A., Durieux A. C., Banzet S., et al. Down-regulation of Akt/mammalian target of rapamycin signaling pathway in response to myostatin overexpression in skeletal muscle[J]. Endocrinology,2009,150(l):286-294.
[52]Kadowaki M., Kanazawa T. Amino acids as regulators of proteolysis[J].JNutr,2003,133(6 Suppl 1):2052S-2056S.
[53]Jacinto E., Hall M. N. Tor signalling in bugs, brain and brawn[J].NatRevMolCell Biol, 2003,4(2):117-126.
[54]Hornberger T. A., Stuppard R., Conley K. E., et al. Mechanical stimuli regulate rapamycin-sensitive signalling by a phosphoinositide 3-kinase-, protein kinase B- and growth factor-independent mechanism[J]. BiochemJ,2004,380(Pt 3):795-804.
[55]Nader G A., McLoughlin T. J., Esser K. A. mTOR function in skeletal muscle hypertrophy: increased ribosomal RNA via cell cycle regulators[J]. AmJPhysiol Cell Physiol, 2005,289(6):C1457-C1465.
[56]Frost R. A., Lang C. H. Protein kinase B/Akt:a nexus of growth factor and cytokine signaling in determining muscle mass[J]. JApplPhysiol,2007,103(1):378-387.
[57]Dan H. C., Sun M., Yang L., et al. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin[J]. JBiolChem, 2002,277(38):35364-35370.
[58]Gao X., Zhang Y., Arrazola P., et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling[J]. NatCell Biol,2002,4(9):699-704.
[59]Inoki K., Li Y., Zhu T., et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling[J]. NatCell Biol,2002,4(9):648-657.
[60]Potter C. J., Pedraza L. G, Xu T. Akt regulates growth by directly phosphorylating Tsc2[J]. NatCell Biol,2002,4(9):658-665.
[61]Manning B. D., Tee A. R., Logsdon M. N., et al. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway[J]. MolCell,2002,10(1):151-162.
[62]Huang J., Manning B. D. The TSC1-TSC2 complex:a molecular switchboard controlling cell. growth[J]. BiochemJ,2008,412(2):179-190.
[63]Garami A., Zwartkruis F. J., Nobukuni T., et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2[J]. MolCell,2003,11(6):1457-1466.
[64]Inoki K., Li Y.,Xu T., et al. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling[J]. Genes Dev,2003,17(15):1829-1834.
[65]Long X., Ortiz-Vega S., Lin Y., et al. Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency [J]. JBiolChem,2005,280(25):23433-23436.
[66]Smith E. M., Finn S. G., Tee A. R., et al. The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses[J]. JBiolChem,2005,280(19):18717-18727.
[67]Lynch C. J., Fox H. L., Vary T. C., et al. Regulation of amino acid-sensitive TOR signaling by leucine analogues in adipocytes[J]. JCell Biochem,2000,77(2):234-251.
[68]Dreyer H. C., Drummond M. J., Pennings B., et al. Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle[J]. AmJPhysiol EndocrinolMetab,2008,294(2):E392-E400.
[69]Drummond M. J., Dreyer H. C., Pennings B., et al. Skeletal muscle protein anabolic response to resistance exercise and essential amino acids is delayed with aging[J]. JApplPhysiol, 2008,104(5):1452-1461.
[70]Kim D. H., Sarbassov D. D., Ali S. M., et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery[J]. Cell, 2002,110(2):163-175.
[71]Proud C. G Regulation of mammalian translation factors by nutrients[J]. EurJBiochem, 2002,269(22):5338-5349.
[72]Avruch J., Long X., Ortiz-Vega S., et al. Amino acid regulation of TOR complex 1[J]. AmJPhysiol EndocrinolMetab,2009,296(4):E592-E602.
[73]Hornberger T. A., Armstrong D. D., Koh T. J., et al. Intracellular signaling specificity in response to uniaxial vs. multiaxial stretch:implications for mechanotransduction[J]. AmJPhysiol Cell Physiol,2005,288(1):C185-C194.
[74]Hornberger T. A., Chu W. K., Mak Y. W., et al. The role of phospholipase D and phosphatidic acid in the mechanical activation of mTOR signaling in skeletal muscle[J]. ProcNatlAcadSciUSA,2006,103(12):4741-4746.
[75]Fang Y., Vilella-Bach M., Bachmann R., et al. Phosphatidic acid-mediated mitogenic activation of mTOR signaling[J]. Science,2001,294(5548):1942-1945.
[76]Foster D. A. Regulation of mTOR by phosphatidic acid?[J]. Cancer Res,2007,67(1):1-4.
[77]Sun Y Fau-Fang Y, Fang Y Fau-Yoon M. S., Yoon Ms Fau-Zhang C., et al. Phospholipase D1 is an effector of Rheb in the mTOR pathway[J].2008,105(24):8286-8291.
[78]Browne G. J., Proud C. G. Regulation of peptide-chain elongation in mammalian cells[J]. EurJBiochem,2002,269(22):5360-5368.
[79]Dennis P. B., Jaeschke A., Saitoh M., et al. Mammalian TOR:a homeostatic ATP sensor[J]. Science,2001,294(5544):1102-1105.
[80]Kahn B. B., Alquier T., Carling D., et al. AMP-activated protein kinase:ancient energy gauge provides clues to modern understanding of metabolism[J]. Cell Metab,2005,1(1):15-25.
[81]Gwinn D. M., Shackelford D. B., Egan D. F., et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint[J]. MolCell,2008,30(2):214-226.
[82]Bolster D. R., Crozier S. J., Kimball S. R., et al. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling[J].JBiolChem,2002,277(27):23977-23980.
[83]Pruznak A. M., Kazi A. A., Frost R. A., et al. Activation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside prevents leucine-stimulated protein synthesis in rat skeletal muscle[J]. JNutr,2008,138(10):1887-1894.
[84]Reiling J. H., Hafen E. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila[J]. Genes Dev, 2004,18(23):2879-2892.
[85]Corradetti M. N., Inoki K., Guan K. L. The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway [J]. JBiolChem, 2005,280(11):9769-9772.
[86]Brugarolas J., Lei K., Hurley R. L., et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex [J]. Genes Dev, 2004,18(23):2893-2904.
[87]Kimball S. R., Do A. N., Kutzler L., et al. Rapid turnover of the mTOR complex 1 (mTORC1) repressor REDD1 and activation of mTORC1 signaling following inhibition of protein synthesis[J]. JBiolChem,2008,283(6):3465-3475.
[88]Drummond M. J., Fujita S., Abe T., et al. Human muscle gene expression following resistance exercise and blood flow restriction [J]. MedSciSports Exerc,2008,40(4):691-698.
[89]Drummond M. J., Miyazaki M., Dreyer H. C., et al. Expression of growth-related genes in young and older human skeletal muscle following an acute stimulation of protein synthesis [J]. JApplPhysiol,2009,106(4):1403-1411.
[90]Huang Z., Chen X., Chen D. Myostatin:A novel insight into its role in metabolism, signal pathways, and expression regulation[J]. Cell Signal,2011,23(9):1441-1446.
[91]Lipina C., Kendall H., McPherron A. C., et al. Mechanisms involved in the enhancement of mammalian target of rapamycin signalling and hypertrophy in skeletal muscle of myostatin-deficient mice[J]. FEBS Lett,2010,584(11):2403-2408.
[92]Sartori R., Milan G., Patron M., et al. Smad2 and 3 transcription factors control muscle mass in adulthood[J]. AmJPhysiol Cell Physiol,2009,296(6):C1248-C1257.
[93]Gonzalez-Cadavid N. F., Taylor W. E., Yarasheski K., et al. Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting[J]. ProcNatlAcadSciUSA,1998,95(25):14938-14943.
[94]Sonstegard T. S., Rohrer G. A., Smith T. P. Myostatin maps to porcine chromosome 15 by linkage and physical analyses[J]. Anim Genet,1998,29(1):19-22.
[95]Stratil A., Kopecny M. Genomic organization, sequence and polymorphism of the porcine myostatin (GDF8; MSTN) gene[J]. Anim Genet,1999,30(6):468-470.
[96]McPherron A. C., Lee S. J. Double muscling in cattle due to mutations in the myostatin gene[J]. ProcNatlAcadSciUSA,1997,94(23):12457-12461.
[97]Rodino-Klapac L. R., Haidet A. M., Kota J., et al. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease[J]. Muscle Nerve,2009,39(3):283-296.
[98]Wolfman N. M., McPherron A. C., Pappano W. N., et al. Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases[J]. Proc Natl Acad Sci U S A, 2003,100(26):15842-15846.
[99]Rodgers B. D., Garikipati D. K. Clinical, agricultural, and evolutionary biology of myostatin:a comparative review[J]. EndocrRev,2008,29(5):513-534.
[100]Artaza J. N., Reisz-Porszasz S., Dow J. S., et al. Alterations in myostatin expression are associated with changes in cardiac left ventricular mass but not ejection fraction in the mouse[J]. JEndocrinol,2007,194(1):63-76.
[101]Cook S. A., Matsui T., Li L., et al. Transcriptional effects of chronic Akt activation in the heart[J]. JBiolChem,2002,277(25):22528-22533.
[102]McPherron A. C., Lee S. J. Suppression of body fat accumulation in myostatin-deficient mice[J]. JClinInvest,2002,109(5):595-601.
[103]Artaza J. N., Bhasin S., Magee T. R., et al. Myostatin inhibits myogenesis and promotes adipogenesis in C3H 10T(1/2) mesenchymal multipotent cells[J]. Endocrinology, 2005,146(8):3547-3557.
[104]Geng J., Peng F., Xiong F., et al. Inhibition of myostatin promotes myogenic differentiation of rat bone marrow-derived mesenchymal stromal cells[J].Cytotherapy,2009,11(7):849-863.
[105]Tang Q. Q., Otto T. C., Lane M. D. Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage[J].ProcNatlAcadSciUSA,2004,101(26):9607-9611.
[106]Stolz L. E., Li D., Qadri A., et al. Administration of myostatin does not alter fat mass in adult mice[J]. Diabetes ObesMetab,2008,10(2):135-142.
[107]Kim H. S., Liang L., Dean R. G., et al. Inhibition of preadipocyte differentiation by myostatin treatment in 3T3-L1 cultures[J]. BiochemBiophysResCommun,2001,281(4):902-906.
[108]Guo W., Flanagan J., Jasuja R., et al. The effects of myostatin on adipogenic differentiation of human bone marrow-derived mesenchymal stem cells are mediated through cross-communication between Smad3 and Wnt/beta-catenin signaling pathways[J].JBiolChem, 2008,283(14):9136-9145.
[109]Hirai S., Matsumoto H., Hino N., et al. Myostatin inhibits differentiation of bovine preadipocyte[J]. DomestAnim Endocrinol,2007,32(1):1-14.
[110]Elkasrawy M. N., Hamrick M. W. Myostatin (GDF-8) as a key factor linking muscle mass and bone structure[J]. JMusculoskeletNeuronallnteract,2010,10(1):56-63.
[111]Hamrick M. W., McPherron A. C., Lovejoy C. O. Bone mineral content and density in the humerus of adult myostatin-deficient mice [J]. CalcifTissue Int,2002,71(1):63-68.
[112]Hamrick M. W. Increased bone mineral density in the femora of GDF8 knockout mice[J]. AnatRecA DiscovMolCell EvolBiol,2003,272(1):388-391.
[113]Kellum E., Starr H., Arounleut P., et al. Myostatin (GDF-8) deficiency increases fracture callus size, Sox-5 expression, and callus bone volume[J]. Bone,2009,44(1):17-23.
[114]Cho T. J., Gerstenfeld L. C., Einhorn T. A. Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing[J]. JBone MinerR.es, 2002,17(3):513-520.
[115]Eliasson P., Andersson T., Kulas J., et al. Myostatin in tendon maintenance and repair[J]. Growth Factors,2009,27(4):247-254.
[116]Lee S. J. Regulation of muscle mass by myostatin [J].2001,98(16):9306-9311.
[117]Winters S. J., Moore J. P. Paracrine control of gonadotrophs[J]. SeminReprodMed, 2007,25(5):379-387.
[118]Patel K Fau-Amthor Helge, Amthor H. The function of Myostatin and strategies of Myostatin blockade-new hope for therapies aimed at promoting growth of skeletal muscle[J]. 2005,15(2)117-126.
[119]McCroskery S., Thomas M., Maxwell L., et al. Myostatin negatively regulates satellite cell activation and self-renewal [J]. JCell Biol,2003,162(6):1135-1147.
[120]Huang Z., Chen D., Zhang K., et al. Regulation of myostatin signaling by c-Jun N-terminal kinase in C2C12 cells[J]. Cell Signal,2007,19(11):2286-2295.
[121]Thomas M., Langley B., Berry C., et al. Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation[J]. JBiolChem,2000,275(51):40235-40243.
[122]Yang W., Zhang Y., Li Y., et al. Myostatin induces cyclin D1 degradation to cause cell cycle arrest through a phosphatidylinositol 3-kinase/AKT/GSK-3 beta pathway and is antagonized by insulin-like growth factor 1[J]. JBiolChem,2007,282(6):3799-3808.
[123]Rios R., Carneiro I., Arce V. M., et al. Myostatin is an inhibitor of myogenic differentiation[J]. AmJPhysiol Cell Physiol,2002,282(5):C993-C999.
[124]Joulia D., Bernardi H., Garandel V., et al. Mechanisms involved in the inhibition of myoblast proliferation and differentiation by myostatin[J]. ExpCell Res,2003,286(2):263-275.
[125]Langley B., Thomas M., Bishop A., et al. Myostatin inhibits myoblast differentiation by down-regulating MyoD expression[J]. JBiolChem,2002,277(51):49831-49840.
[126]Yang W., Chen Y., Zhang Y, et al. Extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway is involved in myostatin-regulated differentiation repression[J]. Cancer Res,2006,66(3):1320-1326.
[127]Taylor W. E., Bhasin S., Artaza J., et al. Myostatin inhibits cell proliferation and protein synthesis in C2C12 muscle cells[J]. AmJPhysiol EndocrinolMetab,2001,280(2):E221-E228.
[128]Suryawan A., Frank J. W., Nguyen H. V., et al. Expression of the TGF-beta family of ligands is developmentally regulated in skeletal muscle of neonatal rats[J]. PediatrRes, 2006,59(2):175-179.
[129]Welle S., Bhatt K., Pinkert C. A. Myofibrillar protein synthesis in myostatin-deficient mice[J]. AmJPhysiol EndocrinolMetab,2006,290(3):E409-E415.
[130]Welle S., Burgess K., Mehta S. Stimulation of skeletal muscle myofibrillar protein synthesis, p70 S6 kinase phosphorylation, and ribosomal protein S6 phosphorylation by inhibition of myostatin in mature mice[J]. AmJPhysiol EndocrinolMetab,2009,296(3):E567-E572.
[131]Sarbassov D. D., Ali S. M., Sabatini D. M. Growing roles for the mTOR pathway[J]. CurrOpinCell Biol,2005,17(6):596-603.
[132]Trendelenburg A. U., Meyer A., Rohner D., et al. Myostatin reduces Akt/TORCl/p70S6K signaling, inhibiting myoblast differentiation and myotube size[J]. AmJPhysiol Cell Physiol, 2009,296(6):C1258-C1270.
[133]Sundaresan N. R., Saxena V. K., Singh R., et al. Expression profile of myostatin mRNA during the embryonic organogenesis of domestic chicken (Gallus gallus domesticus)[J]. ResVetSci, 2008,85(1):86-91.
[134]McKoy G., Bicknell K. A., Patel K., et al. Developmental expression of myostatin in cardiomyocytes and its effect on foetal and neonatal rat cardiomyocyte proliferation[J]. CardiovascRes,2007,74(2):304-312.
[135]Morissette M. R., Cook S. A., Foo S., et al. Myostatin regulates cardiomyocyte growth through modulation of Akt signaling[J].CircRes,2006,99(1):15-24.
[136]Shyu K. G., Ko W. H., Yang W. S., et al. Insulin-like growth factor-1 mediates stretch-induced upregulation of myostatin expression in neonatal rat cardiomyocytes[J]. CardiovascRes, 2005,68(3):405-414.
[137]Rodgers B. D., Interlichia J. P., Garikipati D. K., et al. Myostatin represses physiological hypertrophy of the heart and excitation-contraction coupling[J].JPhysiol,2009,587(Pt 20):4873-4886.
[138]Sharma M., Kambadur R., Matthews K. G., et al. Myostatin, a transforming growth factor-beta superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct[J]. JCell Physiol,1999,180(1):1-9.
[139]Mathews Ls Fau-Vale W. W., Vale W. W. Expression cloning of an activin receptor, a predicted transmembrane serine kinase[J].1991,65(6):973-982.
[140]Attisano L., Wrana J. L. Signal transduction by the TGF-beta superfamily[J]. Science, 2002,296(5573):1646-1647.
[141]Mathews L. S., Vale W. W. Expression cloning of an activin receptor, a predicted transmembrane serine kinase[J]. Cell,1991,65(6):973-982.
[142]Harrison C. A., Gray P. C., Vale W. W., et al. Antagonists of activin signaling:mechanisms and potential biological applications[J]. Trends EndocrinolMetab,2005,16(2):73-78.
[143]Feng X. H., Derynck R. Specificity and versatility in tgf-beta signaling through Smads[J]. AnnuRevCell DevBiol,2005,21:659-693.
[144]Chen Yg Fau-Wang Qiang, Wang Q Fau-Lin Shi-Lung, Lin Sl Fau-Chang C. Donald, et al. Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis[J]. 2006,231(5):534-544.
[145]Massague J., Gomis R. R. The logic of TGFbeta signaling[J]. FEBS Lett, 2006,580(12):2811-2820.
[146]Tsuchida K., Nakatani M., Uezumi A., et al. Signal transduction pathway through activin receptors as a therapeutic target of musculoskeletal diseases and cancer[J]. Endocr J, 2008,55(1):11-21.
[147]Tsuchida K., Nakatani M., Hitachi K., et al. Activin signaling as an emerging target for therapeutic interventions [J]. Cell CommunSignal,2009,7(15):1-8.
[148]Lee S. J., McPherron A. C. Regulation of myostatin activity and muscle growth[J]. ProcNatlAcadSciUSA,2001,98(16):9306-9311.
[149]Lee S. J., Reed L. A., Davies M. V, et al. Regulation of muscle growth by multiple ligands signaling through activin type Ⅱ receptors[J]. ProcNatlAcadSciUSA, 2005,102(50):18117-18122.
[150]Heldin Ch Fau-Miyazono K., Miyazono K Fau-ten Dijke P., ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins[J].1997,390(6659):465-471.
[151]Wrana J. L. Crossing Smads[J].2000,2000(23):rel.
[152]Attisano L Fau-Wrana J. L., Wrana J. L. Mads and Smads in TGF beta signalling[J]. 1998,10(2)188-194.
[153]Itoh F Fau-Asao H., Asao H Fau-Sugamura K., Sugamura K Fau-Heldin C. H., et al. Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads[J].2001,20(15)4132-4142.
[154]Rebbapragada A., Benchabane H., Wrana J. L., et al. Myostatin signals through a transforming growth factor beta-like signaling pathway to block adipogenesis[J]. MolCell Biol, 2003,23(20):7230-7242.
[155]Zhu X., Topouzis S., Liang L. F., et al. Myostatin signaling through Smad2, Smad3 and Smad4 is regulated by the inhibitory Smad7 by a negative feedback mechanism[J]. Cytokine, 2004,26(6):262-272.
[156]Xu W., Angelis K., Danielpour D., et al. Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor[J]. ProcNatlAcadSciUSA, 2000,97(11):5924-5929.
[157]Suzuki H., Yagi K., Kondo M., et al. c-Ski inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements[J]. Oncogene, 2004,23(29):5068-5076.
[158]Akiyoshi S., Inoue H., Hanai J., et al. c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads[J].JBiolChem, 1999,274(49):35269-35277.
[159]Kobayashi N., Goto K., Horiguchi K., et al. c-Ski activates MyoD in the nucleus of myoblastic cells through suppression of histone deacetylases[J]. Genes Cells,2007,12(3):375-385.
[160]Philip B., Lu Z., Gao Y. Regulation of GDF-8 signaling by the p38 MAPK[J]. Cell Signal, 2005,17(3):365-375.
[161]Li Z. B., Kollias H. D., Wagner K. R. Myostatin directly regulates skeletal muscle fibrosis[J]. J Biol Chem,2008,283(28):19371-19378.
[162]Kocamis H Fau-Kirkpatrick-Keller D. C., Kirkpatrick-Keller Dc Fau -Richter J., Richter J Fau-Killefer J., et al. The ontogeny of myostatin, follistatin and activin-B mRNA expression during chicken embryonic development[J].1041-1232.
[163]Ji S., Losinski R. L., Cornelius S. G., et al. Myostatin expression in porcine tissues:tissue specificity and developmental and postnatal regulation[J]. AmJPhysiol,1998,275(4 Pt 2):R1265-R1273.
[164]Jeanplong F Fau-Sharma M., Sharma M Fau-Somers W. G, Somers Wg Fau-Bass J. J., et al. Genomic organization and neonatal expression of the bovine myostatin gene[J]. 2001,220(1-2):31-37.
[165]Kubota K Fau-Sato Fuminori, Sato F Fau-Aramaki Shinya, Aramaki S Fau-Soh Tomoki, et al. Ubiquitous expression of myostatin in chicken embryonic tissues:its high expression in testis and ovary[J].2007,148(3):550-555.
[166]Allen D. L., Cleary A. S., Lindsay S. F., et al. Myostatin expression is increased by food deprivation in a muscle-specific manner and contributes to muscle atrophy during prolonged food deprivation in mice[J]. JApplPhysiol,2010,109(3):692-701.
[167]Guernec A., Chevalier B., Duclos M. J. Nutrient supply enhances both IGF-I and MSTN mRNA levels in chicken skeletal muscle[J]. DomestAnim Endocrinol,2004,26(2):143-154.
[168]Rodgers B. D., Weber G M., Kelley K. M., et al. Prolonged fasting and cortisol reduce myostatin mRNA levels in tilapia larvae; short-term fasting elevates [J]. AmJPhysiol RegulIntegrComp Physiol,2003,284(5):R1277-R1286.
[169]Terova G., Bernardini G., Binelli G., et al. cDNA encoding sequences for myostatin and FGF6 in sea bass (Dicentrarchus labrax, L.) and the effect of fasting and refeeding on their abundance levels[J]. DomestAnim Endocrinol,2006,30(4):304-319.
[170]Jeanplong F., Bass J. J., Smith H. K., et al. Prolonged underfeeding of sheep increases myostatin and myogenic regulatory factor Myf-5 in skeletal muscle while IGF-I and myogenin are repressed[J]. JEndocrinol,2003,176(3):425-437.
[171]Larsen A. E., Tunstall R. J., Carey K. A., et al. Actions of short-term fasting on human skeletal muscle myogenic and atrogenic gene expression [J]. AnnNutrMetab,2006,50(5):476-481.
[172]Nakazato K., Hirose T., Song H. Increased myostatin synthesis in rat gastrocnemius muscles under high-protein diet[J]. IntJSport NutrExercMetab,2006,16(2):153-165.
[173]Yang Y. X., Guo J., Jin Z., et al. Lysine restriction and realimentation affected growth, blood profiles and expression of genes related to protein and fat metabolism in weaned pigs[J]. JAnim Physiol Anim Nutr(Berl),2009,93(6):732-743.
[174]Siddiqui S. M., Chang E., Li J., et al. Dietary intervention with vitamin D, calcium, and whey protein reduced fat mass and increased lean mass in rats[J]. NutrRes,2008,28(11):783-790.
[175]Dong F., Hua Y., Zhao P., et al. Chromium supplement inhibits skeletal muscle atrophy in hindlimb-suspended mice[J]. JNutrBiochem,2009,20(12):992-999.
[176]Drummond M. J., Glynn E. L., Fry C. S., et al. Essential amino acids increase microRNA-499,-208b, and-23a and downregulate myostatin and myocyte enhancer factor 2C mRNA expression in human skeletal muscle[J]. JNutr,2009,139(12):2279-2284.
[177]Bonetto A Fau-Penna Fabio, Penna F Fau-Minero Valerio G., Minero Vg Fau-Reffo Patrizia, et al. Glutamine prevents myostatin hyperexpression and protein hypercatabolism induced in C2C12 myotubes by tumor necrosis factor-alpha[J].2011,40(2):585-594.
[178]Louis E., Raue U., Yang Y., et al. Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle[J]. JApplPhysiol, 2007,103(5):1744-1751.
[179]Marimuthu K., Murton A. J., Greenhaff P. L. Mechanisms regulating muscle mass during disuse atrophy and rehabilitation in humans[J]. JApplPhysiol,2011,110(2):555-560.
[180]Costa A., Dalloul H., Hegyesi H., et al. Impact of repeated bouts of eccentric exercise on myogenic gene expression[J]. EurJApplPhysiol,2007,101(4):427-436.
[181]Matsakas A., Friedel A., Hertrampf T., et al. Short-term endurance training results in a muscle-specific decrease of myostatin mRNA content in the rat[J]. Acta Physiol Scand, 2005,183(3):299-307.
[182]Hulmi J. J., Tannerstedt J., Selanne H., et al. Resistance exercise with whey protein ingestion affects mTOR signaling pathway and myostatin in men[J]. JApplPhysiol, 2009,106(5):1720-1729.
[183]Saremi A., Gharakhanloo R., Sharghi S., et al. Effects of oral creatine and resistance training on serum myostatin and GASP-1[J]. MolCell Endocrinol,2010,317(1-2):25-30.
[184]Walker K. S., Kambadur R., Sharma M., et al. Resistance training alters plasma myostatin but not IGF-1 in healthy men[J]. MedSciSports Exerc,2004,36(5):787-793.
[185]Willoughby D. S. Effects of heavy resistance training on myostatin mRNA and protein expression[J]. MedSciSports Exerc,2004,36(4):574-582.
[186]Ryan A. S., Ivey F. M., Prior S., et al. Skeletal muscle hypertrophy and muscle myostatin reduction after resistive training in stroke survivors[J]. Stroke,2011,42(2):416-420.
[187]Kopple J. D., Cohen A. H., Wang H., et al. Effect of exercise on mRNA levels for growth factors in skeletal muscle of hemodialysis patients[J]. JRen Nutr,2006,16(4):312-324.
[188]Troosters T., Probst V. S., Crul T., et al. Resistance training prevents deterioration in quadriceps muscle function during acute exacerbations of chronic obstructive pulmonary disease[J]. AmJRespirCrit Care Med,2010,181(10):1072-1077.
[189]Lenk K., Schur R., Linke A., et al. Impact of exercise training on myostatin expression in the myocardium and skeletal muscle in a chronic heart failure model[J]. EurJHeart Fail, 2009,11(4):342-348.
[190]Peviani S. M., Gomes A. R., Moreira R. F., et al. Short bouts of stretching increase myo-D, myostatin and atrogin-1 in rat soleus muscle[J]. Muscle Nerve,2007,35(3):363-370.
[191]Roth S. M., Martel G. F., Ferrell R. E., et al. Myostatin gene expression is reduced in humans with heavy-resistance strength training:a brief communication[J]. ExpBiolMed(Maywood), 2003,228(6):706-709.
[192]Hittel D. S., Axelson M., Sarna N., et al. Myostatin decreases with aerobic exercise and associates with insulin resistance [J]. MedSciSports Exerc,2010,42(11):2023-2029.
[193]Konopka A. R., Douglass M. D., Kaminsky L. A., et al. Molecular adaptations to aerobic exercise training in skeletal muscle of older women[J]. JGerontolA BiolSciMedSci, 2010,65(11):1201-1207.
[194]Kim J. S., Petrella J. K., Cross J. M., et al. Load-mediated downregulation of myostatin mRNA is not sufficient to promote myofiber hypertrophy in humans:a cluster analysis[J]. JApplPhysiol, 2007,103(5):1488-1495.
[195]Kim J. S., Cross J. M., Bamman M. M. Impact of resistance loading on myostatin expression and cell cycle regulation in young and older men and women[J]. AmJPhysiol EndocrinolMetab, 2005,288(6):E1110-E1119.
[196]Sakuma K., Watanabe K., Hotta N., et al. The adaptive responses in several mediators linked with hypertrophy and atrophy of skeletal muscle after lower limb unloading in humans [J].Acta Physiol (Oxf),2009,197(2):151-159.
[197]Dennis R. A., Przybyla B., Gurley C., et al. Aging alters gene expression of growth and remodeling factors in human skeletal muscle both at rest and in response to acute resistance exercise[J].Physiol Genomics,2008,32(3):393-400.
[198]Jensky N. E., Sims J. K., eli-Conwright C. M., et al. Exercise does not influence myostatin and follistatin messenger RNA expression in young women[J]. JStrengthCondRes, 2010,24(2):522-530.
[199]Heinemeier K. M., Olesen J. L., Schjerling P., et al. Short-term strength training and the expression of myostatin and IGF-I isoforms in rat muscle and tendon:differential effects of specific contraction types[J]. JApplPhysiol,2007,102(2):573-581.
[200]Aversa Z., Bonetto A., Penna F., et al. Changes in Myostatin Signaling in Non-Weight-Losing Cancer Patients[J].2011,4.
[201]Kung T., Szabo T., Springer J., et al. Cachexia in heart disease:highlights from the ESC 2010[J]. 2011,2(1):63-69.
[202]Lima Ar Fau-Martinez Paula Felippe, Martinez Pf Fau-Okoshi Katashi, Okoshi K Fau-Guizoni Daniele Mendes, et al. Myostatin and follistatin expression in skeletal muscles of rats with chronic heart failure[J].2010,91(1):54-62.
[203]Verzola D Fau-Procopio Vanessa, Procopio V Fau-Sofia Antonella, Sofia A Fau-Villaggio Barbara, et al. Apoptosis and myostatin mRNA are upregulated in the skeletal muscle of patients with chronic kidney disease[J].2011,79(7):773-782.
[204]D-C Man W Fau-Natanek S. A., Natanek Sa Fau-Riddoch-Contreras J., Riddoch-Contreras J Fau-Lewis A., et al. Quadriceps myostatin expression in COPD[J].2010,36(3):686-688.
[205]Gilson H., Schakman O., Combaret L., et al. Myostatin gene deletion prevents glucocorticoid-induced muscle atrophy[J]. Endocrinology,2007,148(1):452-460.
[206]Ma K., Mallidis C., Artaza J., et al. Characterization of 5'-regulatory region of human myostatin gene:regulation by dexamethasone in vitro[J]. AmJPhysiol EndocrinolMetab, 2001,281(6):E1128-E1136.
[207]Rigamonti A. E., Locatelli L., Cella S. G, et al. Muscle expressions of MGF, IGF-IEa, and myostatin in intact and hypophysectomized rats:effects of rhGH and testosterone alone or combined[J]. HormMetab Res,2009,41(1):23-29.
[208]Mendler L., Baka Z., Kovacs-Simon A., et al. Androgens negatively regulate myostatin expression in an androgen-dependent skeletal muscle[J]. BiochemBiophysResCommun, 2007,361(1):237-242.
[209]Lakshman K. M., Bhasin S., Corcoran C., et al. Measurement of myostatin concentrations in human serum:Circulating concentrations in young and older men and effects of testosterone administration[J]. MolCell Endocrinol,2009,302(1):26-32.
[210]Sadkowski T., Jank M., Zwierzchowski L., et al. Comparison of skeletal muscle transcriptional profiles in dairy and beef breeds bulls[J]. JApplGenet,2009,50(2):109-123.
[211]Heineke J., uger-Messier M., Xu J., et al. Genetic deletion of myostatin from the heart prevents skeletal muscle atrophy in heart failure[J]. Circulation,2010,121 (3):419-425.
[212]Yamada M., Tatsumi R., Yamanouchi K., et al. High concentrations of HGF inhibit skeletal muscle satellite cell proliferation in vitro by inducing expression of myostatin:a possible mechanism for reestablishing satellite cell quiescence in vivo[J]. AmJPhysiol Cell Physiol, 2010,298(3):C465-C476.
[213]Kurokawa M., Sato F., Aramaki S., et al. Monitor of the myostatin autocrine action during differentiation of embryonic chicken myoblasts into myotubes:effect of IGF-Ⅰ[J]. MolCell Biochem,2009,331(1-2):193-199.
[214]Covi J. A., Bader B. D., Chang E. S., et al. Molt cycle regulation of protein synthesis in skeletal muscle of the blackback land crab, Gecarcinus lateralis, and the differential expression of a myostatin-like factor during atrophy induced by molting or unweighting[J]. JExpBiol, 2010,213(1):172-183.
[215]Wang B. W., Chang H., Kuan P., et al. Angiotensin Ⅱ activates myostatin expression in cultured rat neonatal cardiomyocytes via p38 MAP kinase and myocyte enhance factor 2 pathway[J]. JEndocrinol,2008,197(1):85-93.
[216]Ijiri D., Kanai Y., Hirabayashi M. Possible roles of myostatin and PGC-1 alpha in the increase of skeletal muscle and transformation of fiber type in cold-exposed chicks:expression of myostatin and PGC-lalpha in chicks exposed to cold[J]. DomestAnim Endocrinol,2009,37(1):12-22.
[217]Stinckens A., Luyten T., Bijttebier J., et al. Characterization of the complete porcine MSTN gene and expression levels in pig breeds differing in muscularity[J]. Anim Genet, 2008,39(6):586-596.
[218]Spiller M. P., Kambadur R., Jeanplong F., et al. The myostatin gene is a downstream target gene of basic helix-loop-helix transcription factor MyoD[J]. MolCell Biol,2002,22(20):7066-7082.
[219]Du R., An X. R., Chen Y. F., et al. Some motifs were important for myostatin transcriptional regulation in sheep (Ovis aries)[J]. JBiochemMolBiol,2007,40(4):547-553.
[220]Yu Z., Li Y., Meng Q., et al. Comparative analysis of the pig BAC sequence involved in the regulation of myostatin gene[J]. SciChina CLife Sci,2005,48(2):168-180.
[221]Allen D. L., Unterman T. G. Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors[J]. AmJPhysiol Cell Physiol,2007,292(1):C188-C199.
[222]Allen D. L., Cleary A. S., Hanson A. M., et al. CCAAT/enhancer binding protein-delta expression is increased in fast skeletal muscle by food deprivation and regulates myostatin transcription in vitro[J]. AmJPhysiol RegulIntegrComp Physiol,2010,299(6):R1592-R1601.
[223]Galili N., Davis R. J., Fredericks W. J., et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma[J]. NatGenet,1993,5(3):230-235.
[224]Nagashima T., Shigematsu N., Maruki R., et al. Discovery of novel forkhead box O1 inhibitors for treating type 2 diabetes:improvement of fasting glycemia in diabetic db/db mice[J]. MolPharmacol,2010,78(5):961-970.
[225]McKinnon C. M., Ravier M. A., Rutter G. A. FoxO1 is required for the regulation of preproglucagon gene expression by insulin in pancreatic alphaTC1-9 cells[J]. JBiolChem, 2006,281 (51):39358-39369.
[226]Buteau J., Spatz M. L., Accili D. Transcription factor FoxO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass[J]. Diabetes,2006,55(5):1190-1196.
[227]Nasrin N., Ogg S., Cahill C. M., et al. DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells[J]. ProcNatlAcadSciUSA,2000,97(19):10412-10417.
[228]Cao Y., Kamioka Y., Yokoi N., et al. Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway[J]. JBiolChem, 2006,281 (52):40242-40251.
[229]Li P., Lee H., Guo S., et al. AKT-independent protection of prostate cancer cells from apoptosis mediated through complex formation between the androgen receptor and FKHR[J]. MolCell Biol,2003,23(1):104-118.
[230]Schuur E. R., Loktev A. V., Sharma M., et al. Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family[J]. JBiolChem, 2001,276(36):33554-33560.
[231]Wyzykowski J. C., Winata T. I., Mitin N., et al. Identification of novel MyoD gene targets in proliferating myogenic stem cells[J]. MolCell Biol,2002,22(17):6199-6208.
[232]Sabourin L. A., Girgis-Gabardo A., Seale P., et al. Reduced differentiation potential of primary MyoD-/-myogenic cells derived from adult skeletal muscle[J]. JCell Biol, 1999,144(4):631-643.
[233]Halevy O., Novitch B. G., Spicer D. B., et al. Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD[J]. Science,1995,267(5200):1018-1021.
[234]Ramji D. P., Foka P. CCAAT/enhancer-binding proteins:structure, function and regulation[J]. BiochemJ,2002,365(Pt 3):561-575.
[235]Jain R., Police S., Phelps K., et al. Tumour necrosis factor-alpha regulates expression of the CCAAT-enhancer-binding proteins (C/EBPs) alpha and beta and determines the occupation of the C/EBP site in the promoter of the insulin-responsive glucose-transporter gene in 3T3-L1 adipocytes[J]. BiochemJ,1999,338 (Pt 3):737-743.
[236]Paquin A., Barnabe-Heider F., Kageyama R., et al. CCAAT/enhancer-binding protein phosphorylation biases cortical precursors to generate neurons rather than astrocytes in vivo[J]. JNeurosci,2005,25(46):10747-10758.
[237]Tang Q. Q., Gronborg M., Huang H., et al. Sequential phosphorylation of CCAAT enhancer-binding protein beta by MAPK and glycogen synthase kinase 3beta is required for adipogenesis[J]. ProcNatlAcadSciUSA,2005,102(28):9766-9771.
[238]Croniger C. M., Millward C., Yang J., et al. Mice with a deletion in the gene for CCAAT/enhancer-binding protein beta have an attenuated response to cAMP and impaired carbohydrate metabolism[J]. JBiolChem,2001,276(1):629-638.
[239]Wang L., Shao J., Muhlenkamp P., et al. Increased insulin receptor substrate-1 and enhanced skeletal muscle insulin sensitivity in mice lacking CCAAT/enhancer-binding protein beta[J]. JBiolChem,2000,275(19):14173-14181.
[240]Chen C., Dudenhausen E., Chen H., et al. Amino-acid limitation induces transcription from the human C/EBPbeta gene via an enhancer activity located downstream of the protein coding sequence[J]. BiochemJ,2005,391(Pt 3):649-658.
[241]Siu F., Chen C., Zhong C., et al. CCAAT/enhancer-binding protein-beta is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene[J]. JBiolChem,2001,276(51):48100-48107.
[242]Du K., Ding J. Insulin regulates TRB3 and other stress-responsive gene expression through induction of C/EBPbeta[J]. MolEndocrinol,2009,23(4):475-485.
[243]Zheng S., Rollet M., Pan Y. X. Maternal protein restriction during pregnancy induces CCAAT/enhancer-binding protein (C/EBPbeta) expression through the regulation of histone modification at its promoter region in female offspring rat skeletal muscle[J]. Epigenetics, 2011,6(2).
[244]Beato M., Herrlich P., Schutz G. Steroid hormone receptors:many actors in search of a plot[J]. Cell,1995,83(6):851-857.
[245]Giguere V., Hollenberg S. M., Rosenfeld M. G., et al. Functional domains of the human glucocorticoid receptor[J]. Cell,1986,46(5):645-652.
[246]Rupprecht R., Arriza J. L., Spengler D., et al. Transactivation and synergistic properties of the mineralocorticoid receptor:relationship to the glucocorticoid receptor [J]. MolEndocrinol, 1993,7(4):597-603.
[247]Bamberger Cm Fau-Schulte H. M., Schulte Hm Fau-Chrousos G. P., Chrousos G. P. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids[J].1996,17(3):245-261.
[248]Dumont A., Hehner S. P., Schmitz M. L., et al. Cross-talk between steroids and NF-kappa B: what language?[J]. Trends BiochemSci,1998,23(7):233-235.
[249]Refojo D., Liberman A. C., Holsboer F., et al. Transcription factor-mediated molecular mechanisms involved in the functional cross-talk between cytokines and glucocorticoids[J]. ImmunolCell Biol,2001,79(4):385-394.
[250]De Kloet Er Fau-Vreugdenhil E., Vreugdenhil E Fau-Oitzl M. S., Oitzl Ms Fau-Joels M., et al. Brain corticosteroid receptor balance in health and disease[J].1998,19(3):269-301.
[251]Waetzig V Fau-Herdegen Thomas, Herdegen T. Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage[J].2005,26(9):455-461.
[252]Ip Yt Fau-Davis R. J., Davis R. J. Signal transduction by the c-Jun N-terminal kinase (JNK)-from inflammation to development[J].1998,10(2):205-219.
[253]Kim D. S., Kim J. H., Lee G H., et al. p38 Mitogen-activated protein kinase is involved in endoplasmic reticulum stress-induced cell death and autophagy in human gingival fibroblasts[J]. BiolPharmBull,2010,33(4):545-549.
[254]Van Speybroeck L. From epigenesis to epigenetics:the case of C. H. Waddington[J].2002,981:61-81.
[255]Vertino P. M., Yen R. W., Gao J., et al. De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase[J]. Mol Cell Biol, 1996,16(8):4555-4565.
[256]Bird A. The essentials of DNA methylation[J]. Cell,1992,70(1):5-8.
[257]Robertson K. D. DNA methylation and human disease[J]. Nat Rev Genet,2005,6(8):597-610.
[258]Reed M. C., Nijhout H. F., Neuhouser M. L., et al. A mathematical model gives insights into nutritional and genetic aspects of folate-mediated one-carbon metabolism[J]. JNutr, 2006,136(10):2653-2661.
[259]Steegers-Theunissen R. P., Obermann-Borst S. A., Kremer D., et al. Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child[J]. PLoSOne,2009,4(11):e7845.
[260]Pogribny I. P., Karpf A. R., James S. R., et al. Epigenetic alterations in the brains of Fisher 344 rats induced by long-term administration of folate/methyl-deficient diet[J]. Brain Res, 2008,1237:25-34.
[261]Mathers J. C., Strathdee G, Relton C. L. Induction of epigenetic alterations by dietary and other environmental factors[J]. AdvGenet,2010,71:3-39.
[262]Eilertsen K. J., Power R. A., Harkins L. L., et al. Targeting cellular memory to reprogram the epigenome, restore potential, and improve somatic cell nuclear transfer[J]. Anim ReprodSci, 2007,98(1-2):129-146.
[263]Gibney E. R., Nolan C. M. Epigenetics and gene expression[J]. Heredity,2010,105(1):4-13.
[264]Kouzarides T. Chromatin modifications and their function[J]. Cell,2007,128(4):693-705.
[265]He Y. Control of the transition to flowering by chromatin modifications [J]. MolPlant, 2009,2(4):554-564.
[266]Barski A., Cuddapah S., Cui K., et al. High-resolution profiling of histone methylations in the human genome[J]. Cell,2007,129(4):823-837.
[267]Huang Y., Greene E., Murray Stewart T., et al. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes[J]. ProcNatlAcadSciUSA,2007,104(19):8023-8028.
[268]Kalushkova A., Fryknas M., Lemaire M., et al. Polycomb target genes are silenced in multiple myeloma[J]. PLoSOne,2010,5(7):e11483.
[269]Vakoc C. R., Mandat S. A., Olenchock B. A., et al. Histone H3 lysine 9 methylation and HP1 gamma are associated with transcription elongation through mammalian chromatin[J]. MolCell,2005,19(3):381-391.
[270]Oliver S. S., Denu J. M. Dynamic interplay between histone H3 modifications and protein interpreters:emerging evidence for a "histone language" [J]. Chembiochem, 2011,12(2):299-307.
[271]Bartel D. P. MicroRNAs:genomics, biogenesis, mechanism, and function[J]. Cell, 2004,116(2):281-297.
[272]Hamilton A. J., Baulcombe D. C. A species of small antisense RNA in posttranscriptional gene silencing in plants[J]. Science,1999,286(5441):950-952.
[273]Reinhart B. J., Slack F. J., Basson M., et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans[J]. Nature,2000,403(6772):901-906.
[274]Lewis B. P., Shih I. H., Jones-Rhoades M. W., et al. Prediction of mammalian microRNA targets[J]. Cell,2003,115(7):787-798.
[275]van Rooij E., Liu N., Olson E. N. MicroRNAs flex their muscles[J]. Trends Genet, 2008,24(4):159-166.
[276]van Rooij E., Quiat D., Johnson B. A., et al. A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance[J]. DevCell,2009,17(5):662-673.
[277]Small E. M., O'Rourke J. R., Moresi V., et al. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486[J]. ProcNatlAcadSciUSA,2010,107(9):4218-4223.
[278]McCarthy J. J., Esser K. A., Andrade F. H. MicroRNA-206 is overexpressed in the diaphragm but not the hindlimb muscle of mdx mouse[J]. AmJPhysiol Cell Physiol, 2007,293(1):C451-C457.
[279]Callis T. E., Deng Z., Chen J. F., et al. Muscling through the microRNA world[J]. ExpBiolMed(Maywood),2008,233(2):131-138.
[280]Liu N., Williams A. H., Kim Y., et al. An intragenic MEF2-dependent enhancer directs muscle-specific expression of microRNAs 1 and 133[J]. ProcNatlAcadSciUSA, 2007,104(52):20844-20849.
[281]Rao P. K., Kumar R. M., Farkhondeh M., et al. Myogenic factors that regulate expression of muscle-specific microRNAs[J]. ProcNatlAcadSciUSA,2006,103(23):8721-8726.
[282]Chen J. F., Mandel E. M., Thomson J. M., et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation[J].NatGenet,2006,38(2):228-233.
[283]Kim H. K., Lee Y. S., Sivaprasad U., et al. Muscle-specific microRNA miR-206 promotes muscle differentiation[J]. JCell Biol,2006,174(5):677-687.
[284]McCarthy J. J., Esser K. A., Peterson C. A., et al. Evidence of MyomiR network regulation of beta-myosin heavy chain gene expression during skeletal muscle atrophy[J]. Physiol Genomics, 2009,39(3):219-226.
[285]Safdar A., Abadi A., Akhtar M., et al. miRNA in the regulation of skeletal muscle adaptation to acute endurance exercise in C57B1/6J male mice[J]. PLoSOne,2009,4(5):e5610.
[286]Aoi W., Naito Y., Mizushima K., et al. The microRNA miR-696 regulates PGC-1{alpha} in mouse skeletal muscle in response to physical activity[J]. AmJPhysiol EndocrinolMetab, 2010,298(4):E799-E806.
[287]Drummond M. J., McCarthy J. J., Fry C. S., et al. Aging differentially affects human skeletal muscle microRNA expression at rest and after an anabolic stimulus of resistance exercise and essential amino acids[J]. AmJPhysiol EndocrinolMetab,2008,295(6):E1333-E1340.
[288]Clop A., Marcq F., Takeda H., et al. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep[J]. NatGenet,2006,38(7):813-818.
[289]Gaedicke S., Zhang X., Schmelzer C., et al. Vitamin E dependent microRNA regulation in rat liver[J]. FEBS Lett,2008,582(23-24):3542-3546.
[290]Tryndyak V. P., Ross S. A., Beland F. A., et al. Down-regulation of the microRNAs miR-34a, miR-127, and miR-200b in rat liver during hepatocarcinogenesis induced by a methyl-deficient diet[J]. MolCarcinog,2009,48(6):479-487.
[291]Marsit C. J., Eddy K., Kelsey K. T. MicroRNA responses to cellular stress[J]. Cancer Res, 2006,66(22):10843-10848.
[292]Wang B., Majumder S., Nuovo G., et al. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice[J]. Hepatology,2009,50(4):1152-1161.
[293]Takanabe R., Ono K., Abe Y., et al. Up-regulated expression of microRNA-143 in association with obesity in adipose tissue of mice fed high-fat diet[J]. BiochemBiophysResCommun, 2008,376(4):728-732.
[294]Zhang J., Zhang F., Didelot X., et al. Maternal high fat diet during pregnancy and lactation alters hepatic expression of insulin like growth factor-2 and key microRNAs in the adult offspring[J]. BMCGenomics,2009,10(478.
[295]Wang L. L., Zhang Z., Li Q., et al. Ethanol exposure induces differential microRNA and target gene expression and teratogenic effects which can be suppressed by folic acid supplementation[J]. HumReprod,2009,24(3):562-579.
[296]Tang Y., Banan A., Forsyth C. B., et al. Effect of alcohol on miR-212 expression in intestinal epithelial cells and its potential role in alcoholic liver disease[J]. Alcohol ClinExpRes, 2008,32(2):355-364.
[297]Goyal R., Goyal D., Leitzke A., et al. Brain renin-angiotensin system:fetal epigenetic programming by maternal protein restriction during pregnancy [J]. ReprodSci, 2010,17(3):227-238.
[298]Plasma free amino acid levels reflect excess or deficiency of dietary amino acids[J]. NutrRev, 1966,24(6):170-174.
[299]Essen-Gustavsson B., Connysson M., Jansson A. Effects of crude protein intake from forage-only diets on muscle amino acids and glycogen levels in horses in training[J]. Equine VetJ,2010,42 Suppl 38:341-346.
[300]Silver M., Fowden A. L., Taylor P. M., et al. Blood amino acids in the pregnant mare and fetus: the effects of maternal fasting and intrafetal insulin[J]. ExpPhysiol,1994,79(3):423-433.
[301]Knoll-Kohler E., Handke A., Wojnorowicz F. Effect of ovarian sex hormones on the pool of free amino acids in maternal tissues of pregnant rats fed a protein-free diet[J]. JReprodFertil, 1976,46(1):137-142.
[302]Hsu Jm Fau-Anthony W. L., Anthony W1 Fau-Rider A. A., Rider A. A. Free amino acids in plasma and tissue of rats born to underfed dams[J].1975,148(4):1087-1089.
[303]Kwon H Fau-Ford Stephen P., Ford Sp Fau-Bazer Fuller W., Bazer Fw Fau-Spencer Thomas E., et al. Maternal nutrient restriction reduces concentrations of amino acids and polyamines in ovine maternal and fetal plasma and fetal fluids[J].2004,71(3):901-908.
[304]Wykes L. J., Fiorotto M., Burrin D. G, et al. Chronic low protein intake reduces tissue protein synthesis in a pig model of protein malnutrition[J]. JNutr,1996,126(5):1481-1488.
[305]Jansson N., Pettersson J., Haafiz A., et al. Down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet[J]. JPhysiol,2006,576(Pt 3):935-946.
[306]Chen C. Y., Crott J., Liu Z., et al. Fructose and saturated fats predispose hyperinsulinemia in lean male rat offspring[J]. Eur J Nutr,2010,49(6):337-343.
[307]Anthony J. C., Yoshizawa F., Anthony T. G., et al. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway[J].JNutr, 2000,130(10):2413-2419.
[308]Anthony J. C., Anthony T. G., Kimball S. R., et al. Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation[J]. JNutr,2000,130(2):139-145.
[309]Timmerman Kl Fau-Lee Jessica L., Lee Jl Fan-Dreyer Hans C., Dreyer He Fau-Dhanani Shaheen, et al. Insulin stimulates human skeletal muscle protein synthesis via an indirect mechanism involving endothelial-dependent vasodilation and mammalian target of rapamycin complex 1 signaling[J].2010,95(8):3848-3857.
[310]Miyazaki M Fau-Esser Karyn A., Esser K. A. Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals[J].2009,106(4):1367-1373.
[311]Murgas Torrazza R Fau-Suryawan Agus, Suryawan A Fau-Gazzaneo Maria C., Gazzaneo Mc Fau-Orellana Renan A., et al. Leucine supplementation of a low-protein meal increases skeletal muscle and visceral tissue protein synthesis in neonatal pigs by stimulating mTOR-dependent translation initiation[J].2010,140(12):2145-2152.
[312]Sikalidis Ak Fau-Stipanuk Martha H., Stipanuk M. H. Growing rats respond to a sulfur amino acid-deficient diet by phosphorylation of the alpha subunit of eukaryotic initiation factor 2 heterotrimeric complex and induction of adaptive components of the integrated stress response[J].2010,140(6):1080-1085.
[313]Drummond M. J., Bell J. A., Fujita S., et al. Amino acids are necessary for the insulin-induced activation of mTOR/S6K1 signaling and protein synthesis in healthy and insulin resistant human skeletal muscle[J]. ClinNutr,2008,27(3):447-456.
[314]Suryawan A., O'Connor P. M., Kimball S. R., et al. Amino acids do not alter the insulin-induced activation of the insulin signaling pathway in neonatal pigs[J].JNutr,2004,134(1):24-30.
[315]Wang X., Beugnet A., Murakami M., et al. Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins[J].MolCell Biol,2005,25(7):2558-2572.
[316]Fujita S., Dreyer H. C., Drummond M. J., et al. Essential amino acid and carbohydrate ingestion before resistance exercise does not enhance postexercise muscle protein synthesis[J]. JApplPhysiol,2009,106(5):1730-1739.
[317]Yang Yx Fau-Guo J., Guo J Fau-Jin Z., Jin Z Fau-Yoon S. Y., et al. Lysine restriction and realimentation affected growth, blood profiles and expression of genes related to protein and fat metabolism in weaned pigs[J].2009,93(6):732-743.
[318]Siddiqui Sm Fau-Chang Eugene, Chang E Fau-Li Jia, Li J Fau-Burlage Catherine, et al. Dietary intervention with vitamin D, calcium, and whey protein reduced fat mass and increased lean mass in rats[J].2008,28(11):783-790.
[319]Carlson C. J., Booth F. W., Gordon S. E. Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloading[J]. AmJPhysiol,1999,277(2 Pt 2):R601-R606.
[320]Girgenrath S Fau-Song Kening, Song K Fau-Whittemore Lisa-Anne, Whittemore L. A. Loss of myostatin expression alters fiber-type distribution and expression of myosin heavy chain isoforms in slow-and fast-type skeletal muscle[J].2005,31(1):34-40.
[321]Elashry Mi Fau-Otto Anthony, Otto A Fau-Matsakas Antonios, Matsakas A Fau-El-Morsy Salah E., et al. Morphology and myofiber composition of skeletal musculature of the forelimb in young and aged wild type and myostatin null mice[J].2009,12(4):269-281.
[322]Winter S., Fischle W. Epigenetic markers and their cross-talk[J]. Essays Biochem, 2010,48(1):45-61.
[323]Campion J., Milagro F. I., Martinez J. A. Individuality and epigenetics in obesity[J]. ObesRev, 2009,10(4):383-392.
[324]Eriksson J. G. Early programming of later health and disease:factors acting during prenatal life might have lifelong consequences[J]. Diabetes,2010,59(10):2349-2350.
[325]Plagemann A., Harder T., Brunn M., et al. Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding:an epigenetic model of obesity and the metabolic syndrome[J]. JPhysiol,2009,587(Pt 20):4963-4976.