猪Myostatin启动子上游调控序列的鉴定
|
摘要
肌肉生长抑制素（Myostatin）基因是生长转化因子β（transforming growth factor-beta，TGF-β）超家族中的一员，是动物肌肉生长发育过程中一个重要的负调控主效基因。Myostatin基因的编码区在不同物种间相对保守，其编码的蛋白前体由三部分组成：N末端信号肽、N端前导肽和C末端成熟肽。但由于其C末端氨基酸序列与TGF-β家族其他成员的同源性较低（最高45%），因而又可归为新的GDF-8（Growth-differentiationfactor8）家族成员之一。
1.猪Myostatin基因启动子上游调控区潜在结合位点的研究
在本研究中，首先，利用PCR的方法扩增得到猪Myostatin基因上游最长为1969bp的启动子片段。将不同长度的启动子片段连接绿色荧光报告基因载体后，转染C2C12成肌细胞和NIH3T3成纤维细胞，结果仅在成肌细胞中出现绿色荧光现象，说明Myostatin基因启动子为组织特异性启动子。其次，对该启动子区域采用逐步删除的方法获得5个新的长度不等的启动子片段，利用荧光素酶报告基因实验检测其在C2C12成肌细胞中的活性。实验结果显示，在Myostatin基因启动子转录起始位点上游1bp至-137bp，-137bp至-466bp内存在有两个转录正调控区域，而在-852bp至-1969bp内存在有一个转录负调控区域。再次，对于转录活性上调效果明显的-137bp至-466bp区域，我们进一步细分后最终确定转录正调控作用的顺式作用元件位点位于-137bp至-218bp区域内。最后，根据已有文献报道及序列特征，设计并合成4条生物素标记的双链DNA探针，通过电泳凝胶迁移实验（Electrophoretic Mobility ShiftAssay，EMSA）验证，-206bp至-189bp区域能够与转录因子蛋白结合，并通过特异位点冷探针竞争实验、-206bp至-189bp区域碱基突变实验、-206bp至-189bp区域特异缺失载体的荧光素酶活性检测实验，最终确定该区域为转录因子蛋白的特异结合位点。
2.转录因子结合蛋白的分析鉴定
首先，根据生物软件预测和文献报道的转录因子结合位点分析，推测该区域为转录因子蛋白MEF2家族成员结合位点。其次，构建真核表达质粒载体pC-MEF2A、pC-MEF2C，以C2C12成肌细胞和诱导的肌管细胞为研究对象，转入含有MEF2结合位点的启动子片段和上述真核表达载体，通过荧光素酶活性检测实验和浓度梯度实验，发现高表达转录因子MEF2C后能够显著增强Myostatin基因启动子活性2~6倍，而高表达另一亚型MEF2A，启动子活性无明显改变，初步证明结合的转录因子蛋白为MEF2C。再次，利用EMSASupershift实验，确定与Myostatin基因启动子上游结合的正调控转录因子蛋白为MEF2C。最后，设计并合成內源MEF2C干扰片段，以C2C12成肌细胞和诱导的肌管细胞为研究对象，分别转入MEF2C真核表达载体及其干扰片段，用实时定量PCR和Western blotting方法检测Myostatin基因转录及蛋白水平的变化，结果发现MEF2C过表达时，Myostatin基因的mRNA转录水平升高了2~4倍，蛋白表达水平也明显升高；当內源MEF2C被干扰沉默后，Myostatin基因的mRNA转录水平和蛋白表达水平明显降低。这些结果显示，MEF2C可以通过激活Myostatin基因，从而在猪肌肉生长发育过程发挥关键性的调节作用。本研究为Myostatin基因的转录调控提供了确切有效的顺式元件作用位点和与之结合的转录因子蛋白，为更加深入的探讨Myostatin的功能和调控网络提供了一种新的研究方向。
Myostatin gene is a member of transforming growth factor β (transforming growthfactor-beta, TGF-β) superfamily, an important negative regulator of the animal muscle growthand development process. Myostatin gene coding region conserved among different species,and its encoded protein precursor consists of three components: N terminal signal peptide,N-terminal propeptide and biologically active carboxyl terminus. Because of its low aminoacid homology of C-terminus to the other TGF-β family members (up to45%), it is alsoclassified as a member of new class of GDF-8(Growth-differentiation factor8) family.
1. The research of porcine Myostatin promoter upstream regulatory region of potentialbinding sites
In this study, first we cloned and amplified up to1969kb upstream of the porcineMyostatin gene promoter region. The different length fragments of promoter were connectedto the report vectors, then transfected into C2C12myoblasts and NIH3T3fibroblasts, whichrevealed that the promoter activity was specific found in myoblasts, indicating that theMyostatin gene promoter is tissue-specific promoter. Then, using a serial deletion strategy, wegot five new length fragments of the promoter, according to the luciferase assay, the resultsshowed that the upstream of the transcription start site there exist two positive transcriptionalregulatory regions among1bp to-137bp,-137bp to-466bp, and exist a negativetranscriptional regulatory region within the-852bp to-1969bp. Then, for obvious effect ofincreased transcriptional activity of-137bp to-466bp, we conducted more report vectors andfinally determined the possible positive regulation region of cis-acting elements located siteswithin the-137bp to-218bp. Finally, according to the existing research papers and sequencecharacteristics, we designed and synthesised four biotin-labeled double-stranded DNA probesto do the Electrophoretic Mobility Shift Assay (EMSA), and verified-206bp to-189bp regioncould be the specific sites of transcription factor protein binding to. Then by using themethods of site-specific cold probe competition,-206bp to-189bp region mutation,-206bpto-189bp region-specific deletion vectors of luciferase assay in the detection experiments,and ultimately we determined the region for the transcription factor protein the specificbinding site was in-206bp to-189bp.
2. Identification of transcription factor-binding proteins
First, according to biological software and reported research papers, we predicted thetranscription factor binding sites, suggesting that trans-acting factor might be the member ofMEF2protein family. Then, Eukaryotic expression vector pC-MEF2A, pC-MEF2C wereconstructed, by luciferase assay and the concentration gradient experiments, overexpressionMEF2C, but not MEF2A increased Myostatin promoter activity with MEF2motifs by two tosix folds, in both myoblasts and myotubes. The initially evidence proved that the MEF2Ctranscription factor protein should be the one combined to the binding sites. Then, by usingEMSA supershift methods, the identification was proved that MEF2C was the specifictranscription factor binding to the upstream regulatory region of Myostatin promoter.Ultimately, designed and synthesised the fragments of endogenous MEF2C interference, wecarried out real-time quantitative PCR reaction and Western blotting to show thatoverexpression of MEF2C, the mRNA levels of Myostatin gene were significantly increasedtwo to four folds and protein expression levels were meanwhile increased; while silence ofendogenous MEF2C, the mRNA levels and protein expression levels of the Myostatin genewere significantly decreased. These results proved that the transcription factor MEF2C couldmodulate and restrain myogenesis by Myostatin activation and Myostatin-dependent genedevelopment processing in porcine. Our research could provide a potential target site and aneffective transcription factor to regulate Myostatin expression and gave a new researchdirection to explore the functional performance of Myostatin.
1.猪Myostatin基因启动子上游调控区潜在结合位点的研究
在本研究中，首先，利用PCR的方法扩增得到猪Myostatin基因上游最长为1969bp的启动子片段。将不同长度的启动子片段连接绿色荧光报告基因载体后，转染C2C12成肌细胞和NIH3T3成纤维细胞，结果仅在成肌细胞中出现绿色荧光现象，说明Myostatin基因启动子为组织特异性启动子。其次，对该启动子区域采用逐步删除的方法获得5个新的长度不等的启动子片段，利用荧光素酶报告基因实验检测其在C2C12成肌细胞中的活性。实验结果显示，在Myostatin基因启动子转录起始位点上游1bp至-137bp，-137bp至-466bp内存在有两个转录正调控区域，而在-852bp至-1969bp内存在有一个转录负调控区域。再次，对于转录活性上调效果明显的-137bp至-466bp区域，我们进一步细分后最终确定转录正调控作用的顺式作用元件位点位于-137bp至-218bp区域内。最后，根据已有文献报道及序列特征，设计并合成4条生物素标记的双链DNA探针，通过电泳凝胶迁移实验（Electrophoretic Mobility ShiftAssay，EMSA）验证，-206bp至-189bp区域能够与转录因子蛋白结合，并通过特异位点冷探针竞争实验、-206bp至-189bp区域碱基突变实验、-206bp至-189bp区域特异缺失载体的荧光素酶活性检测实验，最终确定该区域为转录因子蛋白的特异结合位点。
2.转录因子结合蛋白的分析鉴定
首先，根据生物软件预测和文献报道的转录因子结合位点分析，推测该区域为转录因子蛋白MEF2家族成员结合位点。其次，构建真核表达质粒载体pC-MEF2A、pC-MEF2C，以C2C12成肌细胞和诱导的肌管细胞为研究对象，转入含有MEF2结合位点的启动子片段和上述真核表达载体，通过荧光素酶活性检测实验和浓度梯度实验，发现高表达转录因子MEF2C后能够显著增强Myostatin基因启动子活性2~6倍，而高表达另一亚型MEF2A，启动子活性无明显改变，初步证明结合的转录因子蛋白为MEF2C。再次，利用EMSASupershift实验，确定与Myostatin基因启动子上游结合的正调控转录因子蛋白为MEF2C。最后，设计并合成內源MEF2C干扰片段，以C2C12成肌细胞和诱导的肌管细胞为研究对象，分别转入MEF2C真核表达载体及其干扰片段，用实时定量PCR和Western blotting方法检测Myostatin基因转录及蛋白水平的变化，结果发现MEF2C过表达时，Myostatin基因的mRNA转录水平升高了2~4倍，蛋白表达水平也明显升高；当內源MEF2C被干扰沉默后，Myostatin基因的mRNA转录水平和蛋白表达水平明显降低。这些结果显示，MEF2C可以通过激活Myostatin基因，从而在猪肌肉生长发育过程发挥关键性的调节作用。本研究为Myostatin基因的转录调控提供了确切有效的顺式元件作用位点和与之结合的转录因子蛋白，为更加深入的探讨Myostatin的功能和调控网络提供了一种新的研究方向。
Myostatin gene is a member of transforming growth factor β (transforming growthfactor-beta, TGF-β) superfamily, an important negative regulator of the animal muscle growthand development process. Myostatin gene coding region conserved among different species,and its encoded protein precursor consists of three components: N terminal signal peptide,N-terminal propeptide and biologically active carboxyl terminus. Because of its low aminoacid homology of C-terminus to the other TGF-β family members (up to45%), it is alsoclassified as a member of new class of GDF-8(Growth-differentiation factor8) family.
1. The research of porcine Myostatin promoter upstream regulatory region of potentialbinding sites
In this study, first we cloned and amplified up to1969kb upstream of the porcineMyostatin gene promoter region. The different length fragments of promoter were connectedto the report vectors, then transfected into C2C12myoblasts and NIH3T3fibroblasts, whichrevealed that the promoter activity was specific found in myoblasts, indicating that theMyostatin gene promoter is tissue-specific promoter. Then, using a serial deletion strategy, wegot five new length fragments of the promoter, according to the luciferase assay, the resultsshowed that the upstream of the transcription start site there exist two positive transcriptionalregulatory regions among1bp to-137bp,-137bp to-466bp, and exist a negativetranscriptional regulatory region within the-852bp to-1969bp. Then, for obvious effect ofincreased transcriptional activity of-137bp to-466bp, we conducted more report vectors andfinally determined the possible positive regulation region of cis-acting elements located siteswithin the-137bp to-218bp. Finally, according to the existing research papers and sequencecharacteristics, we designed and synthesised four biotin-labeled double-stranded DNA probesto do the Electrophoretic Mobility Shift Assay (EMSA), and verified-206bp to-189bp regioncould be the specific sites of transcription factor protein binding to. Then by using themethods of site-specific cold probe competition,-206bp to-189bp region mutation,-206bpto-189bp region-specific deletion vectors of luciferase assay in the detection experiments,and ultimately we determined the region for the transcription factor protein the specificbinding site was in-206bp to-189bp.
2. Identification of transcription factor-binding proteins
First, according to biological software and reported research papers, we predicted thetranscription factor binding sites, suggesting that trans-acting factor might be the member ofMEF2protein family. Then, Eukaryotic expression vector pC-MEF2A, pC-MEF2C wereconstructed, by luciferase assay and the concentration gradient experiments, overexpressionMEF2C, but not MEF2A increased Myostatin promoter activity with MEF2motifs by two tosix folds, in both myoblasts and myotubes. The initially evidence proved that the MEF2Ctranscription factor protein should be the one combined to the binding sites. Then, by usingEMSA supershift methods, the identification was proved that MEF2C was the specifictranscription factor binding to the upstream regulatory region of Myostatin promoter.Ultimately, designed and synthesised the fragments of endogenous MEF2C interference, wecarried out real-time quantitative PCR reaction and Western blotting to show thatoverexpression of MEF2C, the mRNA levels of Myostatin gene were significantly increasedtwo to four folds and protein expression levels were meanwhile increased; while silence ofendogenous MEF2C, the mRNA levels and protein expression levels of the Myostatin genewere significantly decreased. These results proved that the transcription factor MEF2C couldmodulate and restrain myogenesis by Myostatin activation and Myostatin-dependent genedevelopment processing in porcine. Our research could provide a potential target site and aneffective transcription factor to regulate Myostatin expression and gave a new researchdirection to explore the functional performance of Myostatin.
引文
杜荣(2007)."绵羊Myostatin基因启动子的功能分析."中国科学C辑37(5).
李景芬(2009)."同源重组敲除MSTN基因的猪胎儿成纤维细胞的构建."中国农业科学42(8).
潘求真(2006)."山羊Myostatin基因打靶载体的构建."中国草食动物26(3).
于珊(2008)."肌肉生长抑制因子对肌细胞发育的调控研究."中国实验动物学报16(6).
Allen, D. L. and T. G. Unterman (2007)."Regulation of myostatin expression and myoblast differentiationby FoxO and SMAD transcription factors." Am J Physiol Cell Physiol292(1): C188-199.
Apone, S. and S. D. Hauschka (1995)."Muscle gene E-box control elements. Evidence for quantitativelydifferent transcriptional activities and the binding of distinct regulatory factors." J Biol Chem270(36):21420-21427.
Baker, P. W., K. K. Tanaka, et al.(2005)."Adult myogenesis in Drosophila melanogaster can proceedindependently of myocyte enhancer factor-2." Genetics170(4):1747-1759.
Bish, L. T., K. J. Morine, et al.(2010)."Myostatin is upregulated following stress in an Erk-dependentmanner and negatively regulates cardiomyocyte growth in culture and in a mouse model." PLoS One5(4): e10230.
Bogdanovich, S., E. M. McNally, et al.(2008)."Myostatin blockade improves function but nothistopathology in a murine model of limb-girdle muscular dystrophy2C." Muscle Nerve37(3):308-316.
Bradley, L., P. J. Yaworsky, et al.(2008)."Myostatin as a therapeutic target for musculoskeletal disease."Cell Mol Life Sci65(14):2119-2124.
Breitbart, A., M. Auger-Messier, et al.(2011)."Myostatin from the heart: local and systemic actions incardiac failure and muscle wasting." Am J Physiol Heart Circ Physiol300(6): H1973-1982.
Brooks, N. E., K. H. Myburgh, et al.(2011)."Myostatin levels in skeletal muscle of hibernating groundsquirrels." J Exp Biol214(Pt15):2522-2527.
Burks, T. N. and R. D. Cohn (2011)."Role of TGF-beta signaling in inherited and acquired myopathies."Skelet Muscle1(1):19.
Carnac, G., B. Vernus, et al.(2007)."Myostatin in the pathophysiology of skeletal muscle." Curr Genomics8(7):415-422.
Castro-Gago, M., C. Gomez-Lado, et al.(2007)."Muscle myostatin expression in children with musclediseases." J Child Neurol22(1):38-40.
Catala, F., R. Wanner, et al.(1995)."A Skeletal Muscle-Specific Enhancer Regulated by Factors Binding toE and Carg Boxes Is Present in the Promoter of the Mouse Myosin Light-Chain1a Gene." Molecularand Cellular Biology15(8):4585-4596.
Ceccarelli, E., M. J. McGrew, et al.(1999)."An E box comprises a positional sensor for regionaldifferences in skeletal muscle gene expression and methylation." Developmental Biology213(1):217-229.
Chen, Y. H., F. L. Yeh, et al.(2011)."Myocyte enhancer factor-2interacting transcriptional repressor(MITR) is a switch that promotes osteogenesis and inhibits adipogenesis of mesenchymal stem cellsby inactivating peroxisome proliferator-activated receptor gamma-2." J Biol Chem286(12):10671-10680.
Chisada, S., H. Okamoto, et al.(2011)."Myostatin-deficient medaka exhibit a double-muscling phenotypewith hyperplasia and hypertrophy, which occur sequentially during post-hatch development." Dev Biol359(1):82-94.
Cho, H. J., K. E. Baek, et al.(2007)."Snail is required for transforming growth factor-beta-inducedepithelial-mesenchymal transition by activating PI3kinase/Akt signal pathway." Biochem BiophysRes Commun353(2):337-343.
Crisa, A., C. Marchitelli, et al.(2003)."Sequence analysis of myostatin promoter in cattle." CytogenetGenome Res102(1-4):48-52.
Dall'Olio, S., L. Fontanesi, et al.(2010)."Analysis of horse myostatin gene and identification of singlenucleotide polymorphisms in breeds of different morphological types." J Biomed Biotechnol2010.
De Santis, C., B. S. Evans, et al.(2008)."Molecular characterization, tissue expression and sequencevariability of the barramundi (Lates calcarifer) myostatin gene." BMC Genomics9:82.
Deng, B., J. Wen, et al.(2011)."Functional analysis of pig myostatin gene promoter with someadipogenesis-and myogenesis-related factors." Mol Cell Biochem.
Diel, P., D. Baadners, et al.(2008)."C2C12myoblastoma cell differentiation and proliferation is stimulatedby androgens and associated with a modulation of myostatin and Pax7expression." J Mol Endocrinol40(5):231-241.
Dilger, A. C., M. E. Spurlock, et al.(2010)."Myostatin null mice respond differently to dietary-induced andgenetic obesity." Anim Sci J81(5):586-593.
Elkasrawy, M. N. and M. W. Hamrick (2010)."Myostatin (GDF-8) as a key factor linking muscle mass andbone structure." J Musculoskelet Neuronal Interact10(1):56-63.
Elkina, Y., S. von Haehling, et al.(2011)."The role of myostatin in muscle wasting: an overview." JCachexia Sarcopenia Muscle2(3):143-151.
Elliott, B., D. Renshaw, et al.(2012)."The Central Role of Myostatin in Skeletal Muscle and Whole BodyHomeostasis." Acta Physiol (Oxf).
Fakhfakh, R., A. Michaud, et al.(2011)."Blocking the myostatin signal with a dominant negative receptorimproves the success of human myoblast transplantation in dystrophic mice." Mol Ther19(1):204-210.
Feng, H., T. Cheng, et al.(2009)."Myocyte enhancer factor2and microphthalmia-associated transcriptionfactor cooperate with NFATc1to transactivate the V-ATPase d2promoter during RANKL-inducedosteoclastogenesis." J Biol Chem284(21):14667-14676.
Fu, H., Z. Hu, et al.(2009)."TGF-beta promotes invasion and metastasis of gastric cancer cells byincreasing fascin1expression via ERK and JNK signal pathways." Acta Biochim Biophys Sin(Shanghai)41(8):648-656.
Gabriel, J. E., H. J. Alves, et al.(2011)."Abundance of MyoD and myostatin transcripts in chickenembryos submitted to distinct incubation temperatures and timing exposures." Braz J Biol71(2):563-564.
George, I., L. T. Bish, et al.(2010)."Myostatin activation in patients with advanced heart failure and aftermechanical unloading." Eur J Heart Fail12(5):444-453.
Gilson, H., O. Schakman, et al.(2007)."Myostatin gene deletion prevents glucocorticoid-induced muscleatrophy." Endocrinology148(1):452-460.
Gilson, H., O. Schakman, et al.(2009)."Follistatin induces muscle hypertrophy through satellite cellproliferation and inhibition of both myostatin and activin." Am J Physiol Endocrinol Metab297(1):E157-164.
Gonzalez-Cadavid, N. F., W. E. Taylor, et al.(1998)."Organization of the human myostatin gene andexpression in healthy men and HIV-infected men with muscle wasting." Proceedings of the NationalAcademy of Sciences of the United States of America95(25):14938-14943.
Grade, C. V. C., M. S. Salerno, et al.(2009)."An evolutionarily conserved Myostatin proximalpromoter/enhancer confers basal levels of transcription and spatial specificity in vivo." DevelopmentGenes and Evolution219(9-10):497-508.
Han, H. Q. and W. E. Mitch (2011)."Targeting the myostatin signaling pathway to treat muscle wastingdiseases." Curr Opin Support Palliat Care5(4):334-341.
Hayot, M., J. Rodriguez, et al.(2011)."Myostatin up-regulation is associated with the skeletal muscleresponse to hypoxic stimuli." Mol Cell Endocrinol332(1-2):38-47.
He, Y., Y. Wu, et al.(2011)."Molecular analysis of the first intron in the bovine myostatin gene." Mol BiolRep38(7):4643-4649.
Hennebry, A., C. Berry, et al.(2009)."Myostatin regulates fiber-type composition of skeletal muscle byregulating MEF2and MyoD gene expression." Am J Physiol Cell Physiol296(3): C525-534.
Hill, J. J., M. V. Davies, et al.(2002)."The myostatin propeptide and the follistatin-related gene areinhibitory binding proteins of myostatin in normal serum." J Biol Chem277(43):40735-40741.
Hiroki, E., S. Abe, et al.(2011)."A comparative study of myostatin, follistatin and decorin expression inmuscle of different origin." Anat Sci Int86(3):151-159.
Hittel, D. S., M. Axelson, et al.(2010)."Myostatin decreases with aerobic exercise and associates withinsulin resistance." Med Sci Sports Exerc42(11):2023-2029.
Hulmi, J. J., M. Silvennoinen, et al.(2012)."Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPKsignaling in streptozotocin-induced diabetic muscle atrophy." Am J Physiol Endocrinol Metab302(3):E307-315.
Ikushima, H. and K. Miyazono (2012)."TGF-beta signal transduction spreading to a wider field: a broadvariety of mechanisms for context-dependent effects of TGF-beta." Cell Tissue Res347(1):37-49.
Itoh, S. and P. ten Dijke (2007)."Negative regulation of TGF-beta receptor/Smad signal transduction." CurrOpin Cell Biol19(2):176-184.
Jespersen, J. G., A. Nedergaard, et al.(2011)."Myostatin expression during human muscle hypertrophy andsubsequent atrophy: increased myostatin with detraining." Scand J Med Sci Sports21(2):215-223.
Ji, S., R. L. Losinski, et al.(1998)."Myostatin expression in porcine tissues: tissue specificity anddevelopmental and postnatal regulation." Am J Physiol275(4Pt2): R1265-1273.
Jiao, J., T. Yuan, et al.(2011)."Analysis of myostatin and its related factors in various porcine tissues." JAnim Sci89(10):3099-3106.
Joulia-Ekaza, D. and G. Cabello (2007)."The myostatin gene: physiology and pharmacological relevance."Curr Opin Pharmacol7(3):310-315.
Jung, S. Y. and Y. G. Ko (2010)."TRIM72, a novel negative feedback regulator of myogenesis, istranscriptionally activated by the synergism of MyoD (or myogenin) and MEF2." Biochem BiophysRes Commun396(2):238-245.
Kellum, E., H. Starr, et al.(2009)."Myostatin (GDF-8) deficiency increases fracture callus size, Sox-5expression, and callus bone volume." Bone44(1):17-23.
Kemaladewi, D. U., D. J. de Gorter, et al.(2012)."Cell-type specific regulation of myostatin signaling."FASEB J26(4):1462-1472.
Kollias, H. D. and J. C. McDermott (2008)."Transforming growth factor-beta and myostatin signaling inskeletal muscle." J Appl Physiol104(3):579-587.
Kostek, M. A., T. J. Angelopoulos, et al.(2009)."Myostatin and follistatin polymorphisms interact withmuscle phenotypes and ethnicity." Med Sci Sports Exerc41(5):1063-1071.
Langley, B., M. Thomas, et al.(2002)."Myostatin inhibits myoblast differentiation by down-regulatingMyoD expression." J Biol Chem277(51):49831-49840.
LeBrasseur, N. K., T. M. Schelhorn, et al.(2009)."Myostatin inhibition enhances the effects of exercise onperformance and metabolic outcomes in aged mice." J Gerontol A Biol Sci Med Sci64(9):940-948.
Lee, S. J.(2010)."Extracellular Regulation of Myostatin: A Molecular Rheostat for Muscle Mass."Immunol Endocr Metab Agents Med Chem10:183-194.
Lee, S. J. and A. C. McPherron (2001)."Regulation of myostatin activity and muscle growth." Proc NatlAcad Sci U S A98(16):9306-9311.
Lepparanta, O., M. Myllarniemi, et al.(2009)."Reduced phosphorylation of the TGF-Beta signaltransducer Smad2in emphysematous human lung." COPD6(4):234-241.
Li, F., H. Yang, et al.(2011)."Myostatin regulates preadipocyte differentiation and lipid metabolism ofadipocyte via ERK1/2." Cell Biol Int35(11):1141-1146.
Lima, A. R., P. F. Martinez, et al.(2010)."Myostatin and follistatin expression in skeletal muscles of ratswith chronic heart failure." Int J Exp Pathol91(1):54-62.
Lokireddy, S., V. Mouly, et al.(2011)."Myostatin promotes the wasting of human myoblast culturesthrough promoting ubiquitin-proteasome pathway-mediated loss of sarcomeric proteins." Am JPhysiol Cell Physiol301(6): C1316-1324.
Ma, K., C. Mallidis, et al.(2001)."Characterization of5'-regulatory region of human myostatin gene:regulation by dexamethasone in vitro." Am J Physiol Endocrinol Metab281(6): E1128-1136.
Magli, A., C. Angelelli, et al.(2010)."Proline isomerase Pin1represses terminal differentiation andmyocyte enhancer factor2C function in skeletal muscle cells." J Biol Chem285(45):34518-34527.
Manceau, M., J. Gros, et al.(2008)."Myostatin promotes the terminal differentiation of embryonic muscleprogenitors." Genes Dev22(5):668-681.
Matsakas, A., E. Mouisel, et al.(2010)."Myostatin knockout mice increase oxidative muscle phenotype asan adaptive response to exercise." J Muscle Res Cell Motil31(2):111-125.
Matsuzaki, K., C. Kitano, et al.(2009)."Smad2and Smad3phosphorylated at both linker andCOOH-terminal regions transmit malignant TGF-beta signal in later stages of human colorectalcancer." Cancer Res69(13):5321-5330.
McFarlane, C., M. Sharma, et al.(2008)."Myostatin is a procachectic growth factor during postnatalmyogenesis." Curr Opin Clin Nutr Metab Care11(4):422-427.
McPherron, A. C., A. M. Lawler, et al.(1997)."Regulation of skeletal muscle mass in mice by a newTGF-beta superfamily member." Nature387(6628):83-90.
McPherron, A. C. and S. J. Lee (1997)."Double muscling in cattle due to mutations in the myostatin gene."Proceedings of the National Academy of Sciences of the United States of America94(23):12457-12461.
Mehra, A. and J. L. Wrana (2002)."TGF-beta and the Smad signal transduction pathway." Biochem CellBiol80(5):605-622.
Miyake, M., S. Hayashi, et al.(2007)."Myostatin and MyoD family expression in skeletal muscle of IGF-1knockout mice." Cell Biol Int31(10):1274-1279.
Montgomery, E., C. Pennington, et al.(2005)."Muscle-bone interactions in dystrophin-deficient andmyostatin-deficient mice." Anat Rec A Discov Mol Cell Evol Biol286(1):814-822.
Moustakas, A. and C. H. Heldin (2002)."From mono-to oligo-Smads: the heart of the matter in TGF-betasignal transduction." Genes Dev16(15):1867-1871.
Muroya, S., K. Watanabe, et al.(2009)."Muscle type-specific effect of myostatin deficiency on myogenicregulatory factor expression in adult double-muscled Japanese Shorthorn cattle." Anim Sci J80(6):678-685.
Peviani, S. M., A. R. Gomes, et al.(2007)."Short bouts of stretching increase myo-D, myostatin andatrogin-1in rat soleus muscle." Muscle Nerve35(3):363-370.
Potthoff, M. J. and E. N. Olson (2007)."MEF2: a central regulator of diverse developmental programs."Development134(23):4131-4140.
Reisz-Porszasz, S., S. Bhasin, et al.(2003)."Lower skeletal muscle mass in male transgenic mice withmuscle-specific overexpression of myostatin." American Journal of Physiology-Endocrinology andMetabolism285(4): E876-E888.
Rios, R., I. Carneiro, et al.(2002)."Myostatin is an inhibitor of myogenic differentiation." AmericanJournal of Physiology-Cell Physiology282(5): C993-C999.
Russo, T. L., S. M. Peviani, et al.(2010)."Stretching and electrical stimulation reduce the accumulation ofMyoD, myostatin and atrogin-1in denervated rat skeletal muscle." J Muscle Res Cell Motil31(1):45-57.
Ryan, A. S., F. M. Ivey, et al.(2011)."Skeletal muscle hypertrophy and muscle myostatin reduction afterresistive training in stroke survivors." Stroke42(2):416-420.
Saika, S.(2004)."TGF-beta signal transduction in corneal wound healing as a therapeutic target." Cornea23(8Suppl): S25-30.
Sandri, M., C. Sandri, et al.(2004)."Foxo transcription factors induce the atrophy-related ubiquitin ligaseatrogin-1and cause skeletal muscle atrophy." Cell117(3):399-412.
Schnaper, H. W., S. Jandeska, et al.(2009)."TGF-beta signal transduction in chronic kidney disease." FrontBiosci14:2448-2465.
Schuelke, M., K. R. Wagner, et al.(2004)."Myostatin mutation associated with gross muscle hypertrophyin a child." N Engl J Med350(26):2682-2688.
Sekiyama, Y., H. Suzuki, et al.(2012)."Functional gene expression analysis of tissue-specific isoforms ofmef2c." Cell Mol Neurobiol32(1):129-139.
She, H. and Z. Mao (2011)."Regulation of myocyte enhancer factor-2transcription factors byneurotoxins." Neurotoxicology32(5):563-566.
Sofronescu, A. G., Y. Jin, et al.(2008)."A myocyte enhancer factor2(MEF2) site located in ahypersensitive region of the FGF16gene locus is required for preferential promoter activity inneonatal cardiac myocytes." DNA Cell Biol27(4):173-182.
Song, W., Y. Zhang, et al.(2012)."Up-regulation of TGF-beta via the activation of extracellularsignal-regulated kinase1and2induced by prorenin in human renal mesangial cells." Mol Med Report5(1):223-227.
Spiller, M. P., R. Kambadur, et al.(2002)."The myostatin gene is a downstream target gene of basichelix-loop-helix transcription factor MyoD." Mol Cell Biol22(20):7066-7082.
Spiller, M. P., R. Kambadur, et al.(2002)."The myostatin gene is a downstream target gene of basichelix-loop-helix transcription factor MyoD." Molecular and Cellular Biology22(20):7066-7082.
Sriram, S., S. Subramanian, et al.(2011)."Modulation of reactive oxygen species in skeletal muscle bymyostatin is mediated through NF-kappaB." Aging Cell10(6):931-948.
Sumioka, T., K. Ikeda, et al.(2008)."Inhibitory effect of blocking TGF-beta/Smad signal on injury-inducedfibrosis of corneal endothelium." Mol Vis14:2272-2281.
Sunada, Y.(2011)."[Myostatin blockade therapy for muscular atrophy]." Brain Nerve63(11):1271-1277.
Sundaresan, N. R., V. K. Saxena, et al.(2008)."Expression profile of myostatin mRNA during theembryonic organogenesis of domestic chicken (Gallus gallus domesticus)." Res Vet Sci85(1):86-91.
Susarla, B. T., E. D. Laing, et al.(2011)."Smad proteins differentially regulate transforming growthfactor-beta-mediated induction of chondroitin sulfate proteoglycans." J Neurochem119(4):868-878.
Tanaka, K. K., A. L. Bryantsev, et al.(2008)."Myocyte enhancer factor2and chorion factor2collaboratein activation of the myogenic program in Drosophila." Mol Cell Biol28(5):1616-1629.
Tee, J. M., C. van Rooijen, et al.(2009)."Regulation of slow and fast muscle myofibrillogenesis byWnt/beta-catenin and myostatin signaling." PLoS One4(6): e5880.
Thatcher, J. D.(2010)."The TGF-beta signal transduction pathway." Sci Signal3(119): tr4.
Tiwari, R., W. Bargmann, et al.(2011)."Activation of the TGF-beta/Smad signaling pathway in oncogenictransformation by v-Rel." Virology413(1):60-71.
Tobin, J. F. and A. J. Celeste (2005)."Myostatin, a negative regulator of muscle mass: implications formuscle degenerative diseases." Curr Opin Pharmacol5(3):328-332.
Trendelenburg, A. U., A. Meyer, et al.(2009)."Myostatin reduces Akt/TORC1/p70S6K signaling,inhibiting myoblast differentiation and myotube size." Am J Physiol Cell Physiol296(6): C1258-1270.
Tsuchida, K.(2006)."The role of myostatin and bone morphogenetic proteins in muscular disorders."Expert Opin Biol Ther6(2):147-154.
van Rooij, E., J. Fielitz, et al.(2010)."Myocyte enhancer factor2and class II histone deacetylases controla gender-specific pathway of cardioprotection mediated by the estrogen receptor." Circ Res106(1):155-165.
Vilar, J. M., R. Jansen, et al.(2006)."Signal processing in the TGF-beta superfamily ligand-receptornetwork." PLoS Comput Biol2(1): e3.
Wang, B. W., H. Chang, et al.(2008)."Angiotensin II activates myostatin expression in cultured ratneonatal cardiomyocytes via p38MAP kinase and myocyte enhance factor2pathway." J Endocrinol197(1):85-93.
Welle, S. L.(2009)."Myostatin and muscle fiber size. Focus on "Smad2and3transcription factors controlmuscle mass in adulthood" and "Myostatin reduces Akt/TORC1/p70S6K signaling, inhibitingmyoblast differentiation and myotube size"." Am J Physiol Cell Physiol296(6): C1245-1247.
Wicik, Z., T. Sadkowski, et al.(2011)."The transcriptomic signature of myostatin inhibitory influence onthe differentiation of mouse C2C12myoblasts." Pol J Vet Sci14(4):643-652.
Wojcik, S., A. Nogalska, et al.(2007)."Myostatin precursor protein is increased and associates withamyloid-beta precursor protein in inclusion-body myositis culture model." Neuropathol ApplNeurobiol33(2):238-242.
Wolfman, N. M., A. C. McPherron, et al.(2003)."Activation of latent myostatin by the BMP-1/tolloidfamily of metalloproteinases." Proc Natl Acad Sci U S A100(26):15842-15846.
Wurm, S. and C. Wechselberger (2006)."Prion protein modifies TGF-beta induced signal transduction."Biochem Biophys Res Commun349(2):525-532.
Youn, H. D., C. M. Grozinger, et al.(2000)."Calcium regulates transcriptional repression of myocyteenhancer factor2by histone deacetylase4." J Biol Chem275(29):22563-22567.
Zhang, C., C. McFarlane, et al.(2011)."Myostatin-deficient mice exhibit reduced insulin resistancethrough activating the AMP-activated protein kinase signalling pathway." Diabetologia54(6):1491-1501.
Zhang, L., X. Yang, et al.(2007)."Myostatin gene targeting in cultured China Han ovine myoblast cells."Animal1(10):1401-1408.
Zheng, Y. L., H. M. Ma, et al.(2011)."Site-directed mutagenesis of the myostatin gene in ovine fetalmyoblast cells in vitro." Res Vet Sci.
Zunwen, L., Z. Shizhen, et al.(2011)."Effect of tetrandrine on the TGF-beta-induced smad signaltransduction pathway in human hypertrophic scar fibroblasts in vitro." Burns.
李景芬(2009)."同源重组敲除MSTN基因的猪胎儿成纤维细胞的构建."中国农业科学42(8).
潘求真(2006)."山羊Myostatin基因打靶载体的构建."中国草食动物26(3).
于珊(2008)."肌肉生长抑制因子对肌细胞发育的调控研究."中国实验动物学报16(6).
Allen, D. L. and T. G. Unterman (2007)."Regulation of myostatin expression and myoblast differentiationby FoxO and SMAD transcription factors." Am J Physiol Cell Physiol292(1): C188-199.
Apone, S. and S. D. Hauschka (1995)."Muscle gene E-box control elements. Evidence for quantitativelydifferent transcriptional activities and the binding of distinct regulatory factors." J Biol Chem270(36):21420-21427.
Baker, P. W., K. K. Tanaka, et al.(2005)."Adult myogenesis in Drosophila melanogaster can proceedindependently of myocyte enhancer factor-2." Genetics170(4):1747-1759.
Bish, L. T., K. J. Morine, et al.(2010)."Myostatin is upregulated following stress in an Erk-dependentmanner and negatively regulates cardiomyocyte growth in culture and in a mouse model." PLoS One5(4): e10230.
Bogdanovich, S., E. M. McNally, et al.(2008)."Myostatin blockade improves function but nothistopathology in a murine model of limb-girdle muscular dystrophy2C." Muscle Nerve37(3):308-316.
Bradley, L., P. J. Yaworsky, et al.(2008)."Myostatin as a therapeutic target for musculoskeletal disease."Cell Mol Life Sci65(14):2119-2124.
Breitbart, A., M. Auger-Messier, et al.(2011)."Myostatin from the heart: local and systemic actions incardiac failure and muscle wasting." Am J Physiol Heart Circ Physiol300(6): H1973-1982.
Brooks, N. E., K. H. Myburgh, et al.(2011)."Myostatin levels in skeletal muscle of hibernating groundsquirrels." J Exp Biol214(Pt15):2522-2527.
Burks, T. N. and R. D. Cohn (2011)."Role of TGF-beta signaling in inherited and acquired myopathies."Skelet Muscle1(1):19.
Carnac, G., B. Vernus, et al.(2007)."Myostatin in the pathophysiology of skeletal muscle." Curr Genomics8(7):415-422.
Castro-Gago, M., C. Gomez-Lado, et al.(2007)."Muscle myostatin expression in children with musclediseases." J Child Neurol22(1):38-40.
Catala, F., R. Wanner, et al.(1995)."A Skeletal Muscle-Specific Enhancer Regulated by Factors Binding toE and Carg Boxes Is Present in the Promoter of the Mouse Myosin Light-Chain1a Gene." Molecularand Cellular Biology15(8):4585-4596.
Ceccarelli, E., M. J. McGrew, et al.(1999)."An E box comprises a positional sensor for regionaldifferences in skeletal muscle gene expression and methylation." Developmental Biology213(1):217-229.
Chen, Y. H., F. L. Yeh, et al.(2011)."Myocyte enhancer factor-2interacting transcriptional repressor(MITR) is a switch that promotes osteogenesis and inhibits adipogenesis of mesenchymal stem cellsby inactivating peroxisome proliferator-activated receptor gamma-2." J Biol Chem286(12):10671-10680.
Chisada, S., H. Okamoto, et al.(2011)."Myostatin-deficient medaka exhibit a double-muscling phenotypewith hyperplasia and hypertrophy, which occur sequentially during post-hatch development." Dev Biol359(1):82-94.
Cho, H. J., K. E. Baek, et al.(2007)."Snail is required for transforming growth factor-beta-inducedepithelial-mesenchymal transition by activating PI3kinase/Akt signal pathway." Biochem BiophysRes Commun353(2):337-343.
Crisa, A., C. Marchitelli, et al.(2003)."Sequence analysis of myostatin promoter in cattle." CytogenetGenome Res102(1-4):48-52.
Dall'Olio, S., L. Fontanesi, et al.(2010)."Analysis of horse myostatin gene and identification of singlenucleotide polymorphisms in breeds of different morphological types." J Biomed Biotechnol2010.
De Santis, C., B. S. Evans, et al.(2008)."Molecular characterization, tissue expression and sequencevariability of the barramundi (Lates calcarifer) myostatin gene." BMC Genomics9:82.
Deng, B., J. Wen, et al.(2011)."Functional analysis of pig myostatin gene promoter with someadipogenesis-and myogenesis-related factors." Mol Cell Biochem.
Diel, P., D. Baadners, et al.(2008)."C2C12myoblastoma cell differentiation and proliferation is stimulatedby androgens and associated with a modulation of myostatin and Pax7expression." J Mol Endocrinol40(5):231-241.
Dilger, A. C., M. E. Spurlock, et al.(2010)."Myostatin null mice respond differently to dietary-induced andgenetic obesity." Anim Sci J81(5):586-593.
Elkasrawy, M. N. and M. W. Hamrick (2010)."Myostatin (GDF-8) as a key factor linking muscle mass andbone structure." J Musculoskelet Neuronal Interact10(1):56-63.
Elkina, Y., S. von Haehling, et al.(2011)."The role of myostatin in muscle wasting: an overview." JCachexia Sarcopenia Muscle2(3):143-151.
Elliott, B., D. Renshaw, et al.(2012)."The Central Role of Myostatin in Skeletal Muscle and Whole BodyHomeostasis." Acta Physiol (Oxf).
Fakhfakh, R., A. Michaud, et al.(2011)."Blocking the myostatin signal with a dominant negative receptorimproves the success of human myoblast transplantation in dystrophic mice." Mol Ther19(1):204-210.
Feng, H., T. Cheng, et al.(2009)."Myocyte enhancer factor2and microphthalmia-associated transcriptionfactor cooperate with NFATc1to transactivate the V-ATPase d2promoter during RANKL-inducedosteoclastogenesis." J Biol Chem284(21):14667-14676.
Fu, H., Z. Hu, et al.(2009)."TGF-beta promotes invasion and metastasis of gastric cancer cells byincreasing fascin1expression via ERK and JNK signal pathways." Acta Biochim Biophys Sin(Shanghai)41(8):648-656.
Gabriel, J. E., H. J. Alves, et al.(2011)."Abundance of MyoD and myostatin transcripts in chickenembryos submitted to distinct incubation temperatures and timing exposures." Braz J Biol71(2):563-564.
George, I., L. T. Bish, et al.(2010)."Myostatin activation in patients with advanced heart failure and aftermechanical unloading." Eur J Heart Fail12(5):444-453.
Gilson, H., O. Schakman, et al.(2007)."Myostatin gene deletion prevents glucocorticoid-induced muscleatrophy." Endocrinology148(1):452-460.
Gilson, H., O. Schakman, et al.(2009)."Follistatin induces muscle hypertrophy through satellite cellproliferation and inhibition of both myostatin and activin." Am J Physiol Endocrinol Metab297(1):E157-164.
Gonzalez-Cadavid, N. F., W. E. Taylor, et al.(1998)."Organization of the human myostatin gene andexpression in healthy men and HIV-infected men with muscle wasting." Proceedings of the NationalAcademy of Sciences of the United States of America95(25):14938-14943.
Grade, C. V. C., M. S. Salerno, et al.(2009)."An evolutionarily conserved Myostatin proximalpromoter/enhancer confers basal levels of transcription and spatial specificity in vivo." DevelopmentGenes and Evolution219(9-10):497-508.
Han, H. Q. and W. E. Mitch (2011)."Targeting the myostatin signaling pathway to treat muscle wastingdiseases." Curr Opin Support Palliat Care5(4):334-341.
Hayot, M., J. Rodriguez, et al.(2011)."Myostatin up-regulation is associated with the skeletal muscleresponse to hypoxic stimuli." Mol Cell Endocrinol332(1-2):38-47.
He, Y., Y. Wu, et al.(2011)."Molecular analysis of the first intron in the bovine myostatin gene." Mol BiolRep38(7):4643-4649.
Hennebry, A., C. Berry, et al.(2009)."Myostatin regulates fiber-type composition of skeletal muscle byregulating MEF2and MyoD gene expression." Am J Physiol Cell Physiol296(3): C525-534.
Hill, J. J., M. V. Davies, et al.(2002)."The myostatin propeptide and the follistatin-related gene areinhibitory binding proteins of myostatin in normal serum." J Biol Chem277(43):40735-40741.
Hiroki, E., S. Abe, et al.(2011)."A comparative study of myostatin, follistatin and decorin expression inmuscle of different origin." Anat Sci Int86(3):151-159.
Hittel, D. S., M. Axelson, et al.(2010)."Myostatin decreases with aerobic exercise and associates withinsulin resistance." Med Sci Sports Exerc42(11):2023-2029.
Hulmi, J. J., M. Silvennoinen, et al.(2012)."Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPKsignaling in streptozotocin-induced diabetic muscle atrophy." Am J Physiol Endocrinol Metab302(3):E307-315.
Ikushima, H. and K. Miyazono (2012)."TGF-beta signal transduction spreading to a wider field: a broadvariety of mechanisms for context-dependent effects of TGF-beta." Cell Tissue Res347(1):37-49.
Itoh, S. and P. ten Dijke (2007)."Negative regulation of TGF-beta receptor/Smad signal transduction." CurrOpin Cell Biol19(2):176-184.
Jespersen, J. G., A. Nedergaard, et al.(2011)."Myostatin expression during human muscle hypertrophy andsubsequent atrophy: increased myostatin with detraining." Scand J Med Sci Sports21(2):215-223.
Ji, S., R. L. Losinski, et al.(1998)."Myostatin expression in porcine tissues: tissue specificity anddevelopmental and postnatal regulation." Am J Physiol275(4Pt2): R1265-1273.
Jiao, J., T. Yuan, et al.(2011)."Analysis of myostatin and its related factors in various porcine tissues." JAnim Sci89(10):3099-3106.
Joulia-Ekaza, D. and G. Cabello (2007)."The myostatin gene: physiology and pharmacological relevance."Curr Opin Pharmacol7(3):310-315.
Jung, S. Y. and Y. G. Ko (2010)."TRIM72, a novel negative feedback regulator of myogenesis, istranscriptionally activated by the synergism of MyoD (or myogenin) and MEF2." Biochem BiophysRes Commun396(2):238-245.
Kellum, E., H. Starr, et al.(2009)."Myostatin (GDF-8) deficiency increases fracture callus size, Sox-5expression, and callus bone volume." Bone44(1):17-23.
Kemaladewi, D. U., D. J. de Gorter, et al.(2012)."Cell-type specific regulation of myostatin signaling."FASEB J26(4):1462-1472.
Kollias, H. D. and J. C. McDermott (2008)."Transforming growth factor-beta and myostatin signaling inskeletal muscle." J Appl Physiol104(3):579-587.
Kostek, M. A., T. J. Angelopoulos, et al.(2009)."Myostatin and follistatin polymorphisms interact withmuscle phenotypes and ethnicity." Med Sci Sports Exerc41(5):1063-1071.
Langley, B., M. Thomas, et al.(2002)."Myostatin inhibits myoblast differentiation by down-regulatingMyoD expression." J Biol Chem277(51):49831-49840.
LeBrasseur, N. K., T. M. Schelhorn, et al.(2009)."Myostatin inhibition enhances the effects of exercise onperformance and metabolic outcomes in aged mice." J Gerontol A Biol Sci Med Sci64(9):940-948.
Lee, S. J.(2010)."Extracellular Regulation of Myostatin: A Molecular Rheostat for Muscle Mass."Immunol Endocr Metab Agents Med Chem10:183-194.
Lee, S. J. and A. C. McPherron (2001)."Regulation of myostatin activity and muscle growth." Proc NatlAcad Sci U S A98(16):9306-9311.
Lepparanta, O., M. Myllarniemi, et al.(2009)."Reduced phosphorylation of the TGF-Beta signaltransducer Smad2in emphysematous human lung." COPD6(4):234-241.
Li, F., H. Yang, et al.(2011)."Myostatin regulates preadipocyte differentiation and lipid metabolism ofadipocyte via ERK1/2." Cell Biol Int35(11):1141-1146.
Lima, A. R., P. F. Martinez, et al.(2010)."Myostatin and follistatin expression in skeletal muscles of ratswith chronic heart failure." Int J Exp Pathol91(1):54-62.
Lokireddy, S., V. Mouly, et al.(2011)."Myostatin promotes the wasting of human myoblast culturesthrough promoting ubiquitin-proteasome pathway-mediated loss of sarcomeric proteins." Am JPhysiol Cell Physiol301(6): C1316-1324.
Ma, K., C. Mallidis, et al.(2001)."Characterization of5'-regulatory region of human myostatin gene:regulation by dexamethasone in vitro." Am J Physiol Endocrinol Metab281(6): E1128-1136.
Magli, A., C. Angelelli, et al.(2010)."Proline isomerase Pin1represses terminal differentiation andmyocyte enhancer factor2C function in skeletal muscle cells." J Biol Chem285(45):34518-34527.
Manceau, M., J. Gros, et al.(2008)."Myostatin promotes the terminal differentiation of embryonic muscleprogenitors." Genes Dev22(5):668-681.
Matsakas, A., E. Mouisel, et al.(2010)."Myostatin knockout mice increase oxidative muscle phenotype asan adaptive response to exercise." J Muscle Res Cell Motil31(2):111-125.
Matsuzaki, K., C. Kitano, et al.(2009)."Smad2and Smad3phosphorylated at both linker andCOOH-terminal regions transmit malignant TGF-beta signal in later stages of human colorectalcancer." Cancer Res69(13):5321-5330.
McFarlane, C., M. Sharma, et al.(2008)."Myostatin is a procachectic growth factor during postnatalmyogenesis." Curr Opin Clin Nutr Metab Care11(4):422-427.
McPherron, A. C., A. M. Lawler, et al.(1997)."Regulation of skeletal muscle mass in mice by a newTGF-beta superfamily member." Nature387(6628):83-90.
McPherron, A. C. and S. J. Lee (1997)."Double muscling in cattle due to mutations in the myostatin gene."Proceedings of the National Academy of Sciences of the United States of America94(23):12457-12461.
Mehra, A. and J. L. Wrana (2002)."TGF-beta and the Smad signal transduction pathway." Biochem CellBiol80(5):605-622.
Miyake, M., S. Hayashi, et al.(2007)."Myostatin and MyoD family expression in skeletal muscle of IGF-1knockout mice." Cell Biol Int31(10):1274-1279.
Montgomery, E., C. Pennington, et al.(2005)."Muscle-bone interactions in dystrophin-deficient andmyostatin-deficient mice." Anat Rec A Discov Mol Cell Evol Biol286(1):814-822.
Moustakas, A. and C. H. Heldin (2002)."From mono-to oligo-Smads: the heart of the matter in TGF-betasignal transduction." Genes Dev16(15):1867-1871.
Muroya, S., K. Watanabe, et al.(2009)."Muscle type-specific effect of myostatin deficiency on myogenicregulatory factor expression in adult double-muscled Japanese Shorthorn cattle." Anim Sci J80(6):678-685.
Peviani, S. M., A. R. Gomes, et al.(2007)."Short bouts of stretching increase myo-D, myostatin andatrogin-1in rat soleus muscle." Muscle Nerve35(3):363-370.
Potthoff, M. J. and E. N. Olson (2007)."MEF2: a central regulator of diverse developmental programs."Development134(23):4131-4140.
Reisz-Porszasz, S., S. Bhasin, et al.(2003)."Lower skeletal muscle mass in male transgenic mice withmuscle-specific overexpression of myostatin." American Journal of Physiology-Endocrinology andMetabolism285(4): E876-E888.
Rios, R., I. Carneiro, et al.(2002)."Myostatin is an inhibitor of myogenic differentiation." AmericanJournal of Physiology-Cell Physiology282(5): C993-C999.
Russo, T. L., S. M. Peviani, et al.(2010)."Stretching and electrical stimulation reduce the accumulation ofMyoD, myostatin and atrogin-1in denervated rat skeletal muscle." J Muscle Res Cell Motil31(1):45-57.
Ryan, A. S., F. M. Ivey, et al.(2011)."Skeletal muscle hypertrophy and muscle myostatin reduction afterresistive training in stroke survivors." Stroke42(2):416-420.
Saika, S.(2004)."TGF-beta signal transduction in corneal wound healing as a therapeutic target." Cornea23(8Suppl): S25-30.
Sandri, M., C. Sandri, et al.(2004)."Foxo transcription factors induce the atrophy-related ubiquitin ligaseatrogin-1and cause skeletal muscle atrophy." Cell117(3):399-412.
Schnaper, H. W., S. Jandeska, et al.(2009)."TGF-beta signal transduction in chronic kidney disease." FrontBiosci14:2448-2465.
Schuelke, M., K. R. Wagner, et al.(2004)."Myostatin mutation associated with gross muscle hypertrophyin a child." N Engl J Med350(26):2682-2688.
Sekiyama, Y., H. Suzuki, et al.(2012)."Functional gene expression analysis of tissue-specific isoforms ofmef2c." Cell Mol Neurobiol32(1):129-139.
She, H. and Z. Mao (2011)."Regulation of myocyte enhancer factor-2transcription factors byneurotoxins." Neurotoxicology32(5):563-566.
Sofronescu, A. G., Y. Jin, et al.(2008)."A myocyte enhancer factor2(MEF2) site located in ahypersensitive region of the FGF16gene locus is required for preferential promoter activity inneonatal cardiac myocytes." DNA Cell Biol27(4):173-182.
Song, W., Y. Zhang, et al.(2012)."Up-regulation of TGF-beta via the activation of extracellularsignal-regulated kinase1and2induced by prorenin in human renal mesangial cells." Mol Med Report5(1):223-227.
Spiller, M. P., R. Kambadur, et al.(2002)."The myostatin gene is a downstream target gene of basichelix-loop-helix transcription factor MyoD." Mol Cell Biol22(20):7066-7082.
Spiller, M. P., R. Kambadur, et al.(2002)."The myostatin gene is a downstream target gene of basichelix-loop-helix transcription factor MyoD." Molecular and Cellular Biology22(20):7066-7082.
Sriram, S., S. Subramanian, et al.(2011)."Modulation of reactive oxygen species in skeletal muscle bymyostatin is mediated through NF-kappaB." Aging Cell10(6):931-948.
Sumioka, T., K. Ikeda, et al.(2008)."Inhibitory effect of blocking TGF-beta/Smad signal on injury-inducedfibrosis of corneal endothelium." Mol Vis14:2272-2281.
Sunada, Y.(2011)."[Myostatin blockade therapy for muscular atrophy]." Brain Nerve63(11):1271-1277.
Sundaresan, N. R., V. K. Saxena, et al.(2008)."Expression profile of myostatin mRNA during theembryonic organogenesis of domestic chicken (Gallus gallus domesticus)." Res Vet Sci85(1):86-91.
Susarla, B. T., E. D. Laing, et al.(2011)."Smad proteins differentially regulate transforming growthfactor-beta-mediated induction of chondroitin sulfate proteoglycans." J Neurochem119(4):868-878.
Tanaka, K. K., A. L. Bryantsev, et al.(2008)."Myocyte enhancer factor2and chorion factor2collaboratein activation of the myogenic program in Drosophila." Mol Cell Biol28(5):1616-1629.
Tee, J. M., C. van Rooijen, et al.(2009)."Regulation of slow and fast muscle myofibrillogenesis byWnt/beta-catenin and myostatin signaling." PLoS One4(6): e5880.
Thatcher, J. D.(2010)."The TGF-beta signal transduction pathway." Sci Signal3(119): tr4.
Tiwari, R., W. Bargmann, et al.(2011)."Activation of the TGF-beta/Smad signaling pathway in oncogenictransformation by v-Rel." Virology413(1):60-71.
Tobin, J. F. and A. J. Celeste (2005)."Myostatin, a negative regulator of muscle mass: implications formuscle degenerative diseases." Curr Opin Pharmacol5(3):328-332.
Trendelenburg, A. U., A. Meyer, et al.(2009)."Myostatin reduces Akt/TORC1/p70S6K signaling,inhibiting myoblast differentiation and myotube size." Am J Physiol Cell Physiol296(6): C1258-1270.
Tsuchida, K.(2006)."The role of myostatin and bone morphogenetic proteins in muscular disorders."Expert Opin Biol Ther6(2):147-154.
van Rooij, E., J. Fielitz, et al.(2010)."Myocyte enhancer factor2and class II histone deacetylases controla gender-specific pathway of cardioprotection mediated by the estrogen receptor." Circ Res106(1):155-165.
Vilar, J. M., R. Jansen, et al.(2006)."Signal processing in the TGF-beta superfamily ligand-receptornetwork." PLoS Comput Biol2(1): e3.
Wang, B. W., H. Chang, et al.(2008)."Angiotensin II activates myostatin expression in cultured ratneonatal cardiomyocytes via p38MAP kinase and myocyte enhance factor2pathway." J Endocrinol197(1):85-93.
Welle, S. L.(2009)."Myostatin and muscle fiber size. Focus on "Smad2and3transcription factors controlmuscle mass in adulthood" and "Myostatin reduces Akt/TORC1/p70S6K signaling, inhibitingmyoblast differentiation and myotube size"." Am J Physiol Cell Physiol296(6): C1245-1247.
Wicik, Z., T. Sadkowski, et al.(2011)."The transcriptomic signature of myostatin inhibitory influence onthe differentiation of mouse C2C12myoblasts." Pol J Vet Sci14(4):643-652.
Wojcik, S., A. Nogalska, et al.(2007)."Myostatin precursor protein is increased and associates withamyloid-beta precursor protein in inclusion-body myositis culture model." Neuropathol ApplNeurobiol33(2):238-242.
Wolfman, N. M., A. C. McPherron, et al.(2003)."Activation of latent myostatin by the BMP-1/tolloidfamily of metalloproteinases." Proc Natl Acad Sci U S A100(26):15842-15846.
Wurm, S. and C. Wechselberger (2006)."Prion protein modifies TGF-beta induced signal transduction."Biochem Biophys Res Commun349(2):525-532.
Youn, H. D., C. M. Grozinger, et al.(2000)."Calcium regulates transcriptional repression of myocyteenhancer factor2by histone deacetylase4." J Biol Chem275(29):22563-22567.
Zhang, C., C. McFarlane, et al.(2011)."Myostatin-deficient mice exhibit reduced insulin resistancethrough activating the AMP-activated protein kinase signalling pathway." Diabetologia54(6):1491-1501.
Zhang, L., X. Yang, et al.(2007)."Myostatin gene targeting in cultured China Han ovine myoblast cells."Animal1(10):1401-1408.
Zheng, Y. L., H. M. Ma, et al.(2011)."Site-directed mutagenesis of the myostatin gene in ovine fetalmyoblast cells in vitro." Res Vet Sci.
Zunwen, L., Z. Shizhen, et al.(2011)."Effect of tetrandrine on the TGF-beta-induced smad signaltransduction pathway in human hypertrophic scar fibroblasts in vitro." Burns.