多柔比星诱导的骨骼肌功能障碍机制研究进展
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摘要
多柔比星(DOX)作为广谱抗肿瘤药物,临床中用于多种癌症的治疗。然而,DOX在使用时可剂量依赖性诱导骨骼肌功能障碍,致使癌症患者生存质量明显下降。本文通过对DOX毒性作用、DOX诱导骨骼肌功能障碍特点以及DOX诱导骨骼肌功能障碍的相关发生机制进行综述,重点对氧化应激、Ca2+超载、线粒体能量代谢失调、细胞自噬与凋亡、一氧化氮浓度和氨基酸代谢及肌源性调节因子表达等病理机制进行总结,并对未来研究方向予以展望,希望为临床深入研究DOX肌肉毒性作用提供理论依据。
Doxorubicin(DOX) is a widely used clinical anti-tumor drug for cancer. Unfortunately,DOX can also cause skeletal muscle dysfunction in a dose-dependent manner, leading to a significant decline in the quality of life of cancer patients. In this paper, we summarize the toxic effects of DOX, the characteristics of DOX-induced skeletal muscle dysfunction and its related mechanisms. We focus on pathological mechanisms, including oxidative stress, Ca2+overload, mitochondrial energy metabolism disorder, autophagy and apoptosis, nitric oxide concentration and amino acid metabolism and myogenic regulatory factor expression. Research prospects are outlined. It is expected to provide a theoretical basis for the clinical study of DOX toxicity.
Doxorubicin(DOX) is a widely used clinical anti-tumor drug for cancer. Unfortunately,DOX can also cause skeletal muscle dysfunction in a dose-dependent manner, leading to a significant decline in the quality of life of cancer patients. In this paper, we summarize the toxic effects of DOX, the characteristics of DOX-induced skeletal muscle dysfunction and its related mechanisms. We focus on pathological mechanisms, including oxidative stress, Ca2+overload, mitochondrial energy metabolism disorder, autophagy and apoptosis, nitric oxide concentration and amino acid metabolism and myogenic regulatory factor expression. Research prospects are outlined. It is expected to provide a theoretical basis for the clinical study of DOX toxicity.
引文
[1] de Lima Junior EA,Yamashita AS,Pimentel GD,De Sousa LG,Santos RV,Gon?alves CL,et al.Doxorubicin caused severe hyperglycaemia and insulin resistance,mediated by inhibition in AMPK signalling in skeletal muscle[J]. J Cachexia Sarcopenia Muscle,2016,7(5):615-625.
[2] Mazevet M,Moulin M,Llach-Martinez A,Chargari C,Deutsch E,Gomez AM,et al. Complications of chemotherapy,a basic science update[J]. Presse Med,2013,42(9 Pt 2):e352-e361.
[3] Smuder AJ,Kavazis AN,Min K,Powers SK.Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle[J]. J Appl Physiol(1985),2011,110(4):935-942.
[4] Gilliam LA,St Clair DK. Chemotherapy-induced weakness and fatigue in skeletal muscle:the role of oxidative stress[J]. Antioxid Redox Signal,2011,15(9):2543-2563.
[5] Argilés JM,Busquets S,Stemmler B,López-Soriano FJ. Cancer cachexia:understanding the molecular basis[J]. Nat Rev Cancer,2014,14(11):754-762.
[6]Sawyer DB,Peng X,Chen B,Pentassuglia L,Lim CC. Mechanisms of anthracycline cardiac injury:can we identify strategies for cardioprotection?[J]. Prog Cardiovasc Dis,2010,53(2):105-113.
[7] Gorini S,De Angelis A,Berrino L,Malara N,Rosano G,Ferraro E. Chemotherapeutic drugs and mitochondrial dysfunction:focus on doxorubicin,trastuzumab,and sunitinib[J/OL]. Oxid Med Cell Longev,2018,2018:7582730(2018-03-18).https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5878876/
[8] Nissinen TA,Degerman J,R?s?nen M,Poikonen AR,Koskinen S,Mervaala E,et al. Systemic blockade of ACVR2B ligands prevents chemotherapy-induced muscle wasting by restoring muscle protein synthesis without affecting oxidative capacity or atrogenes[J/OL].Sci Rep,2016,6:32695(2016-09-26). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036092/
[9] Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin[J]. Biochem Pharmacol,1999,57(7):727-741.
[10] Shi CH. The mechanism of side effects of doxorubicin and its prevention and treatment research progress[J]. J Clin Med Pract(实用临床医药杂志),2013,17(3):107-110.
[11] Kluza J, Marchetti P, Gallego MA, Lancel S,Fournier C,Loyens A,et al. Mitochondrial proliferation during apoptosis induced by anticancer agents:effects of doxorubicin and mitoxantrone on cancer and cardiac cells[J]. Oncogene,2004,23(42):7018-7030.
[12] Ascens?o A, Lumini-Oliveira J, Machado NG,Ferreira RM,Gon?alves IO,Moreira AC,et al.Acute exercise protects against calcium-induced cardiac mitochondrial permeability transition pore opening in doxorubicin-treated rats[J]. Clin Sci(Lond),2011,120(1):37-49.
[13] Marques-Aleixo I, Santos-Alves E, Bal?a MM,Moreira PI,Oliveira PJ,Magalh?es J,et al. Physical exercise mitigates doxorubicin-induced brain cortex and cerebel um mitochondrial alterations and cel ular quality control signaling[J]. Mitochondrion,2016,26:43-57.
[14] Pugazhendhi A, Edison TNJI, Velmurugan BK,Jacob JA,Karuppusamy I. Toxicity of doxorubicin(Dox)to different experimental organ systems[J].Life Sci,2018,200:26-30.
[15] Hayward R, Hydock D, Gibson N, Greufe S,Bredahl E,Parry T. Tissue retention of doxorubicin and its effects on cardiac,smooth,and skeletal muscle function[J]. J Physiol Biochem,2013,69(2):177-187.
[16] Hydock DS,Lien CY,Jensen BT,Schneider CM,Hayward R. Characterization of the effect of in vivo doxorubicin treatment on skeletal muscle function in the rat[J]. Anticancer Res,2011,31(6):2023-2028.
[17] Westerblad H,Bruton JD,Katz A. Skeletal muscle:energy metabolism,fiber types,fatigue and adaptability[J]. Exp Cell Res,2010,316(18):3093-3099.
[18] Egan B,Zierath JR. Exercise metabolism and the molecular regulation of skeletal muscle adaptation[J]. Cell Metab,2013,17(2):162-184.
[19] Fabris S,MacLean DA. Skeletal muscle an active compartment in the sequestering and metabolism of doxorubicin chemotherapy[J/OL]. PLoS One,2015, 10(9):e0139070(2015-09-24). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581622/
[20] Bredahl EC,Hydock DS. Creatine supplementation and doxorubicin-induced skeletal muscle dysfunction:an ex vivo investigation[J]. Nutr Cancer,2017,69(4):607-615.
[21] Yu AP,Pei XM,Sin TK,Yip SP,Yung BY,Chan LW,et al. Acylated and unacylated ghrelin inhibit doxorubicin-induced apoptosis in skeletal muscle[J]. Acta Physiol(Oxf),2014,211(1):201-213.
[22] Braun TP,Szumowski M,Levasseur PR,Grossberg AJ,Zhu X,Agarwal A,et al. Muscle atrophy in response to cytotoxic chemotherapy is dependent on intact glucocorticoid signaling in skeletal muscle[J/OL]. PLoS One,2014,9(9):e106489(2014-09-25). https://www. ncbi. nlm. nih. gov/pmc/articles/PMC4177815/
[23] QuanJun Y,Gen Jin Y,Li Li W,Yong Long H,Yan H,Jie L, et al. Protective effects of dexrazoxane against doxorubicin-induced cardiotoxicity:a metabolomic study[J/OL]. PLoS One,2017,12(1):e0169567(2017-01-10). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224977/
[24] Xu F,Li X,Liu LF,Pan XH,Zhang L,Zhang SL,et al. Effects of different doses of doxorubicin on cardiac structure and function in mice[J]. Chin J Crtl Endem Dis(中国地方病防治杂志),2017,32(3):328-329.
[25] Gilliam LA,Ferreira LF,Bruton JD,Moylan JS,Westerblad H,St Clair DK,et al. Doxorubicin acts through tumor necrosis factor receptor subtype 1to cause dysfunction of murine skeletal muscle[J].J Appl Physiol(1985),2009,107(6):1935-1942.
[26] Goll DE,Thompson VF,Li H,Wei W,Cong J.The calpain system[J]. Physiol Rev,2003,83(3):731-801.
[27] Powers SK,Smuder AJ,Criswell DS. Mechanistic links between oxidative stress and disuse muscle atrophy[J]. Antioxid Redox Signal,2011,15(9):2519-2528.
[28] Silva KA,Dong J,Dong Y,Dong Y,Schor N,Tweardy DJ,et al. Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system,leading to preservation of muscle mass in cancer cachexia[J]. J Biol Chem,2015,290(17):11177-11187.
[29] Smuder AJ,Kavazis AN,Hudson MB,Nelson WB,Powers SK. Oxidation enhances myofibril ar protein degradation via calpain and caspase-3[J]. Free Radic Biol Med,2010,49(7):1152-1160.
[30] Fill M,Copello JA. Ryanodine receptor calcium release channels[J]. Physiol Rev,2002,82(4):893-922.
[31] Abramson JJ,Buck E,Salama G,Casida JE,Pessah IN. Mechanism of anthraquinone-induced calcium release from skeletal muscle sarcoplasmic reticulum[J]. J Biol Chem,1988,263(35):18750-18758.
[32] van Norren K, van Helvoort A, Argilés JM,van Tuijl S,Arts K,Gorselink M,et al. Direct effects of doxorubicin on skeletal muscle contribute to fatigue[J]. Br J Cancer,2009,100(2):311-314.
[33] Ertunc M,Sara Y,Onur R. Differential contractile impairment of fast-and slow-twitch skeletal muscles in a rat model of doxorubicin-induced congestive heart failure[J]. Pharmacology,2009,84(4):240-248.
[34] Giliam LAA,Fisher-Welman KH,Lin CT,Maples JM,Cathey BL,Neufer PD. The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle[J]. Free Radic Biol Med,2013,65:988-996.
[35] Min K, Kwon OS, Smuder AJ, Wiggs MP,Sollanek KJ, Christou DD, et al. Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicininduced cardiac and skeletal muscle myopathy[J].J Physiol,2015,593(8):2017-2036.
[36] Rybalka E,Timpani CA,Cheregi BD,Sorensen JC,Nurgali K,Hayes A. Chemotherapeutic agents induce mitochondrial superoxide production and toxicity but do not alter respiration in skeletal muscle in vitro[J]. Mitochondrion,2018,42:33-49.
[37] Smuder AJ,Kavazis AN,Min K,Powers SK. Exercise protects against doxorubicin-induced markers of autophagy signaling in skeletal muscle[J]. J Appl Physiol(1985),2011,111(4):1190-1198.
[38] Campbell TL, Quadrilatero J. Data on skeletal muscle apoptosis,autophagy,and morphology in mice treated with doxorubicin[J]. Data Brief,2016,7:786-793.
[39] Merino H, Singla DK. Secreted frizzled-related protein-2 inhibits doxorubicin-induced apoptosis mediated through the AKT-m TOR pathway in soleus muscle[J/OL]. Oxid Med Cell Longev,2018,2018:6043064(2018-08-01). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093014/
[40] Hirai DM,Copp SW,Ferguson SK,Holdsworth CT,Hageman KS,Poole DC,et al. Neuronal nitric oxide synthase regulation of skeletal muscle functional hyperemia:exercise training and moderate compensated heart failure[J]. Nitric Oxide,2018,74:1-9.
[41]Fabris S,Mac Lean DA. Doxorubicin chemotherapy affects intracellular and interstitial nitric oxide concentrations in skeletal muscle:effect of doxorubicin on intracel ular and interstitial NO in skeletal muscle[J].Cel Biol Toxicol,2016,32(2):121-131.
[42] Gordon BS,Kelleher AR,Kimball SR. Regulation of muscle protein synthesis and the effects of catabolic states[J]. Int J Biochem Cell Biol,2013,45(10):2147-2157.
[43] Fabris S,MacLean DA. Doxorubicin chemotherapy affects the intracel ular and interstitial free amino acid pools in skeletal muscle[J/OL]. PLoS One,2018,13(4):e0195330(2018-04-04). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884546/
[44] Quinn CJ,Hydock DS. Effects of endurance exercise and doxorubicin on skeletal muscle myogenic regulatory factor expression[J]. Muscles Ligaments Tendons J,2018,7(3):418-425.
[45] Capps MJ,Wood N,Busekrus R,Hayward R.Hydock D. Effects of doxorubicin treatment and exercise on skeletal muscle function and myogenic regulatory factors:2704 Board#224 June 2 11[J/OL].Med Sci Sports Exerc,2017,49:773(2017-05).https://www.researchgate.net/publication/318101585_Effects_of_Doxorubicin_Treatment_and_Exercise_on_Skeletal_Muscle_Function_and_Myogenic_Regulatory_Factors_2704_Board_224_June_2_11
[46] Hydock DS,Lien CY,Jensen BT,Schneider CM,Hayward R. Exercise preconditioning provides long-term protection against early chronic doxorubicin cardiotoxicity[J]. Integr Cancer Ther,2011,10(1):47-57.
[47] Martinez PF,Okoshi K,Zornoff LA,Carvalho RF,Oliveira Junior SA,Lima AR,et al. Chronic heart failure-induced skeletal muscle atrophy,necrosis,and changes in myogenic regulatory factors[J].Med Sci Monit,2010,16(12):BR374-BR383.
[48] Hulmi JJ,Nissinen TA,R?s?nen M,Degerman J,Lautaoja JH,Hemanthakumar KA,et al. Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle[J]. J Cachexia Sarcopenia Muscle,2018,9(2):417-432.
[2] Mazevet M,Moulin M,Llach-Martinez A,Chargari C,Deutsch E,Gomez AM,et al. Complications of chemotherapy,a basic science update[J]. Presse Med,2013,42(9 Pt 2):e352-e361.
[3] Smuder AJ,Kavazis AN,Min K,Powers SK.Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle[J]. J Appl Physiol(1985),2011,110(4):935-942.
[4] Gilliam LA,St Clair DK. Chemotherapy-induced weakness and fatigue in skeletal muscle:the role of oxidative stress[J]. Antioxid Redox Signal,2011,15(9):2543-2563.
[5] Argilés JM,Busquets S,Stemmler B,López-Soriano FJ. Cancer cachexia:understanding the molecular basis[J]. Nat Rev Cancer,2014,14(11):754-762.
[6]Sawyer DB,Peng X,Chen B,Pentassuglia L,Lim CC. Mechanisms of anthracycline cardiac injury:can we identify strategies for cardioprotection?[J]. Prog Cardiovasc Dis,2010,53(2):105-113.
[7] Gorini S,De Angelis A,Berrino L,Malara N,Rosano G,Ferraro E. Chemotherapeutic drugs and mitochondrial dysfunction:focus on doxorubicin,trastuzumab,and sunitinib[J/OL]. Oxid Med Cell Longev,2018,2018:7582730(2018-03-18).https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5878876/
[8] Nissinen TA,Degerman J,R?s?nen M,Poikonen AR,Koskinen S,Mervaala E,et al. Systemic blockade of ACVR2B ligands prevents chemotherapy-induced muscle wasting by restoring muscle protein synthesis without affecting oxidative capacity or atrogenes[J/OL].Sci Rep,2016,6:32695(2016-09-26). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036092/
[9] Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin[J]. Biochem Pharmacol,1999,57(7):727-741.
[10] Shi CH. The mechanism of side effects of doxorubicin and its prevention and treatment research progress[J]. J Clin Med Pract(实用临床医药杂志),2013,17(3):107-110.
[11] Kluza J, Marchetti P, Gallego MA, Lancel S,Fournier C,Loyens A,et al. Mitochondrial proliferation during apoptosis induced by anticancer agents:effects of doxorubicin and mitoxantrone on cancer and cardiac cells[J]. Oncogene,2004,23(42):7018-7030.
[12] Ascens?o A, Lumini-Oliveira J, Machado NG,Ferreira RM,Gon?alves IO,Moreira AC,et al.Acute exercise protects against calcium-induced cardiac mitochondrial permeability transition pore opening in doxorubicin-treated rats[J]. Clin Sci(Lond),2011,120(1):37-49.
[13] Marques-Aleixo I, Santos-Alves E, Bal?a MM,Moreira PI,Oliveira PJ,Magalh?es J,et al. Physical exercise mitigates doxorubicin-induced brain cortex and cerebel um mitochondrial alterations and cel ular quality control signaling[J]. Mitochondrion,2016,26:43-57.
[14] Pugazhendhi A, Edison TNJI, Velmurugan BK,Jacob JA,Karuppusamy I. Toxicity of doxorubicin(Dox)to different experimental organ systems[J].Life Sci,2018,200:26-30.
[15] Hayward R, Hydock D, Gibson N, Greufe S,Bredahl E,Parry T. Tissue retention of doxorubicin and its effects on cardiac,smooth,and skeletal muscle function[J]. J Physiol Biochem,2013,69(2):177-187.
[16] Hydock DS,Lien CY,Jensen BT,Schneider CM,Hayward R. Characterization of the effect of in vivo doxorubicin treatment on skeletal muscle function in the rat[J]. Anticancer Res,2011,31(6):2023-2028.
[17] Westerblad H,Bruton JD,Katz A. Skeletal muscle:energy metabolism,fiber types,fatigue and adaptability[J]. Exp Cell Res,2010,316(18):3093-3099.
[18] Egan B,Zierath JR. Exercise metabolism and the molecular regulation of skeletal muscle adaptation[J]. Cell Metab,2013,17(2):162-184.
[19] Fabris S,MacLean DA. Skeletal muscle an active compartment in the sequestering and metabolism of doxorubicin chemotherapy[J/OL]. PLoS One,2015, 10(9):e0139070(2015-09-24). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581622/
[20] Bredahl EC,Hydock DS. Creatine supplementation and doxorubicin-induced skeletal muscle dysfunction:an ex vivo investigation[J]. Nutr Cancer,2017,69(4):607-615.
[21] Yu AP,Pei XM,Sin TK,Yip SP,Yung BY,Chan LW,et al. Acylated and unacylated ghrelin inhibit doxorubicin-induced apoptosis in skeletal muscle[J]. Acta Physiol(Oxf),2014,211(1):201-213.
[22] Braun TP,Szumowski M,Levasseur PR,Grossberg AJ,Zhu X,Agarwal A,et al. Muscle atrophy in response to cytotoxic chemotherapy is dependent on intact glucocorticoid signaling in skeletal muscle[J/OL]. PLoS One,2014,9(9):e106489(2014-09-25). https://www. ncbi. nlm. nih. gov/pmc/articles/PMC4177815/
[23] QuanJun Y,Gen Jin Y,Li Li W,Yong Long H,Yan H,Jie L, et al. Protective effects of dexrazoxane against doxorubicin-induced cardiotoxicity:a metabolomic study[J/OL]. PLoS One,2017,12(1):e0169567(2017-01-10). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224977/
[24] Xu F,Li X,Liu LF,Pan XH,Zhang L,Zhang SL,et al. Effects of different doses of doxorubicin on cardiac structure and function in mice[J]. Chin J Crtl Endem Dis(中国地方病防治杂志),2017,32(3):328-329.
[25] Gilliam LA,Ferreira LF,Bruton JD,Moylan JS,Westerblad H,St Clair DK,et al. Doxorubicin acts through tumor necrosis factor receptor subtype 1to cause dysfunction of murine skeletal muscle[J].J Appl Physiol(1985),2009,107(6):1935-1942.
[26] Goll DE,Thompson VF,Li H,Wei W,Cong J.The calpain system[J]. Physiol Rev,2003,83(3):731-801.
[27] Powers SK,Smuder AJ,Criswell DS. Mechanistic links between oxidative stress and disuse muscle atrophy[J]. Antioxid Redox Signal,2011,15(9):2519-2528.
[28] Silva KA,Dong J,Dong Y,Dong Y,Schor N,Tweardy DJ,et al. Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system,leading to preservation of muscle mass in cancer cachexia[J]. J Biol Chem,2015,290(17):11177-11187.
[29] Smuder AJ,Kavazis AN,Hudson MB,Nelson WB,Powers SK. Oxidation enhances myofibril ar protein degradation via calpain and caspase-3[J]. Free Radic Biol Med,2010,49(7):1152-1160.
[30] Fill M,Copello JA. Ryanodine receptor calcium release channels[J]. Physiol Rev,2002,82(4):893-922.
[31] Abramson JJ,Buck E,Salama G,Casida JE,Pessah IN. Mechanism of anthraquinone-induced calcium release from skeletal muscle sarcoplasmic reticulum[J]. J Biol Chem,1988,263(35):18750-18758.
[32] van Norren K, van Helvoort A, Argilés JM,van Tuijl S,Arts K,Gorselink M,et al. Direct effects of doxorubicin on skeletal muscle contribute to fatigue[J]. Br J Cancer,2009,100(2):311-314.
[33] Ertunc M,Sara Y,Onur R. Differential contractile impairment of fast-and slow-twitch skeletal muscles in a rat model of doxorubicin-induced congestive heart failure[J]. Pharmacology,2009,84(4):240-248.
[34] Giliam LAA,Fisher-Welman KH,Lin CT,Maples JM,Cathey BL,Neufer PD. The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle[J]. Free Radic Biol Med,2013,65:988-996.
[35] Min K, Kwon OS, Smuder AJ, Wiggs MP,Sollanek KJ, Christou DD, et al. Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicininduced cardiac and skeletal muscle myopathy[J].J Physiol,2015,593(8):2017-2036.
[36] Rybalka E,Timpani CA,Cheregi BD,Sorensen JC,Nurgali K,Hayes A. Chemotherapeutic agents induce mitochondrial superoxide production and toxicity but do not alter respiration in skeletal muscle in vitro[J]. Mitochondrion,2018,42:33-49.
[37] Smuder AJ,Kavazis AN,Min K,Powers SK. Exercise protects against doxorubicin-induced markers of autophagy signaling in skeletal muscle[J]. J Appl Physiol(1985),2011,111(4):1190-1198.
[38] Campbell TL, Quadrilatero J. Data on skeletal muscle apoptosis,autophagy,and morphology in mice treated with doxorubicin[J]. Data Brief,2016,7:786-793.
[39] Merino H, Singla DK. Secreted frizzled-related protein-2 inhibits doxorubicin-induced apoptosis mediated through the AKT-m TOR pathway in soleus muscle[J/OL]. Oxid Med Cell Longev,2018,2018:6043064(2018-08-01). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093014/
[40] Hirai DM,Copp SW,Ferguson SK,Holdsworth CT,Hageman KS,Poole DC,et al. Neuronal nitric oxide synthase regulation of skeletal muscle functional hyperemia:exercise training and moderate compensated heart failure[J]. Nitric Oxide,2018,74:1-9.
[41]Fabris S,Mac Lean DA. Doxorubicin chemotherapy affects intracellular and interstitial nitric oxide concentrations in skeletal muscle:effect of doxorubicin on intracel ular and interstitial NO in skeletal muscle[J].Cel Biol Toxicol,2016,32(2):121-131.
[42] Gordon BS,Kelleher AR,Kimball SR. Regulation of muscle protein synthesis and the effects of catabolic states[J]. Int J Biochem Cell Biol,2013,45(10):2147-2157.
[43] Fabris S,MacLean DA. Doxorubicin chemotherapy affects the intracel ular and interstitial free amino acid pools in skeletal muscle[J/OL]. PLoS One,2018,13(4):e0195330(2018-04-04). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884546/
[44] Quinn CJ,Hydock DS. Effects of endurance exercise and doxorubicin on skeletal muscle myogenic regulatory factor expression[J]. Muscles Ligaments Tendons J,2018,7(3):418-425.
[45] Capps MJ,Wood N,Busekrus R,Hayward R.Hydock D. Effects of doxorubicin treatment and exercise on skeletal muscle function and myogenic regulatory factors:2704 Board#224 June 2 11[J/OL].Med Sci Sports Exerc,2017,49:773(2017-05).https://www.researchgate.net/publication/318101585_Effects_of_Doxorubicin_Treatment_and_Exercise_on_Skeletal_Muscle_Function_and_Myogenic_Regulatory_Factors_2704_Board_224_June_2_11
[46] Hydock DS,Lien CY,Jensen BT,Schneider CM,Hayward R. Exercise preconditioning provides long-term protection against early chronic doxorubicin cardiotoxicity[J]. Integr Cancer Ther,2011,10(1):47-57.
[47] Martinez PF,Okoshi K,Zornoff LA,Carvalho RF,Oliveira Junior SA,Lima AR,et al. Chronic heart failure-induced skeletal muscle atrophy,necrosis,and changes in myogenic regulatory factors[J].Med Sci Monit,2010,16(12):BR374-BR383.
[48] Hulmi JJ,Nissinen TA,R?s?nen M,Degerman J,Lautaoja JH,Hemanthakumar KA,et al. Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle[J]. J Cachexia Sarcopenia Muscle,2018,9(2):417-432.