**Author details**

Linlin Chen, Hong Zhang, Mengyi Chi, Quanjun Yang\* and Cheng Guo\* Department of Pharmacy, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China

\*Address all correspondence to: myotime@sjt.edu.cn and guopharm@126.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**93**

*Drugs for the Treatment of Muscle Atrophy DOI: http://dx.doi.org/10.5772/intechopen.93503*

[1] Jackman RW, Kandarian SC. The molecular basis of skeletal muscle atrophy. American Journal of Physiology. Cell Physiology. 2004;**287**:C834-C843. DOI: 10.1152/ mice. The Journal of Cell Biology. 2010;**188**:833-849. DOI: 10.1083/

[9] Frost RA, Lang CH. Protein kinase B/Akt: A nexus of growth factor and cytokine signaling in determining muscle mass. Journal of Applied Physiology (Bethesda, MD: 1985). 2007;**103**:378-387. DOI: 10.1152/ japplphysiol.00089.2007

[10] Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M. Mechanisms regulating skeletal muscle growth and atrophy. The FEBS Journal. 2013;**280**:4294-4314. DOI: 10.1111/

[11] Bhasin S, Woodhouse L, Storer TW. Proof of the effect of testosterone on skeletal muscle. The Journal of Endocrinology. 2001;**170**:27-38. DOI:

[12] Ferrando AA, Sheffield-Moore M,

administration to older men improves muscle function: Molecular and physiological mechanisms. American Journal of Physiology. Endocrinology and Metabolism. 2002;**282**:E601-E607. DOI: 10.1152/ajpendo.00362.2001

[13] Bakhshi V, Elliott M, Gentili A, Godschalk M, Mulligan T. Testosterone improves rehabilitation outcomes in ill older men. Journal of the American Geriatrics Society. 2000;**48**:550-553. DOI: 10.1111/j.1532-5415.2000.

testosterone supplementation for 3 years on muscle performance and physical function in older men. The Journal of Clinical Endocrinology and Metabolism.

Yeckel CW, et al. Testosterone

jcb.200909117

febs.12253

tb05002.x

jc.2016-2771

[14] Storer TW, Basaria S, Traustadottir T, et al. Effects of

2017;**102**:583-593. DOI: 10.1210/

10.1677/joe.0.1700027

[2] Lecker SH, Goldberg AL, Mitch WE. Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. Journal of the American Society of Nephrology: JASN. 2006;**17**:1807-1819. DOI: 10.1681/

[3] Scott D. Sarcopenia in older adults. Journal of Clinical Medicine. 2019;**8**: 1844. DOI: 10.3390/jcm8111844

[4] Dupont-Versteegden EE. Apoptosis in muscle atrophy: Relevance to

sarcopenia. Experimental Gerontology. 2005;**40**:473-481. DOI: 10.1016/j.

[5] Biolo G, Cederholm T, Muscaritoli M.

Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: From sarcopenic obesity to cachexia. Clinical Nutrition (Edinburgh,

Scotland). 2014;**33**:737-748. DOI: 10.1016/j.clnu.2014.03.007

[7] Llovera M, Carbó N, López-Soriano J, et al. Different cytokines modulate ubiquitin gene expression in rat skeletal muscle. Cancer Letters.

1998;**133**:83-87. DOI: 10.1016/ s0304-3835(98)00216-x

[8] Mittal A, Bhatnagar S, Kumar A, et al. The TWEAK-Fn14 system is a critical regulator of denervationinduced skeletal muscle atrophy in

[6] Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: An international consensus. The Lancet Oncology. 2011;**12**:489-495. DOI: 10.1016/s1470-2045(10)70218-7

**References**

ajpcell.00579.2003

asn.2006010083

exger.2005.04.003

*Drugs for the Treatment of Muscle Atrophy DOI: http://dx.doi.org/10.5772/intechopen.93503*

## **References**

*Background and Management of Muscular Atrophy*

for muscle atrophy treatment are needed.

The authors declare no conflict of financial interest.

**Acknowledgements**

**Conflict of interest**

(No. 81873042 and 81872494).

Due to the multifactorial pathogenesis of muscle atrophy, combining new drugs with multimodal transport interventions including exercise methods and nutritional interventions may be the most promising approach; however, few clinical trials have investigated this approach. In this light, a better understanding of the contributing factors and underlying mechanisms of muscle atrophy is essential for the development of targeted therapies, and new methods of combination therapy

This work was supported by the National Natural Science Foundation of China

**92**

**Author details**

University, Shanghai, China

provided the original work is properly cited.

Linlin Chen, Hong Zhang, Mengyi Chi, Quanjun Yang\* and Cheng Guo\*

Department of Pharmacy, Shanghai Sixth People's Hospital, Shanghai Jiao Tong

\*Address all correspondence to: myotime@sjt.edu.cn and guopharm@126.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Jackman RW, Kandarian SC. The molecular basis of skeletal muscle atrophy. American Journal of Physiology. Cell Physiology. 2004;**287**:C834-C843. DOI: 10.1152/ ajpcell.00579.2003

[2] Lecker SH, Goldberg AL, Mitch WE. Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. Journal of the American Society of Nephrology: JASN. 2006;**17**:1807-1819. DOI: 10.1681/ asn.2006010083

[3] Scott D. Sarcopenia in older adults. Journal of Clinical Medicine. 2019;**8**: 1844. DOI: 10.3390/jcm8111844

[4] Dupont-Versteegden EE. Apoptosis in muscle atrophy: Relevance to sarcopenia. Experimental Gerontology. 2005;**40**:473-481. DOI: 10.1016/j. exger.2005.04.003

[5] Biolo G, Cederholm T, Muscaritoli M. Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: From sarcopenic obesity to cachexia. Clinical Nutrition (Edinburgh, Scotland). 2014;**33**:737-748. DOI: 10.1016/j.clnu.2014.03.007

[6] Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: An international consensus. The Lancet Oncology. 2011;**12**:489-495. DOI: 10.1016/s1470-2045(10)70218-7

[7] Llovera M, Carbó N, López-Soriano J, et al. Different cytokines modulate ubiquitin gene expression in rat skeletal muscle. Cancer Letters. 1998;**133**:83-87. DOI: 10.1016/ s0304-3835(98)00216-x

[8] Mittal A, Bhatnagar S, Kumar A, et al. The TWEAK-Fn14 system is a critical regulator of denervationinduced skeletal muscle atrophy in

mice. The Journal of Cell Biology. 2010;**188**:833-849. DOI: 10.1083/ jcb.200909117

[9] Frost RA, Lang CH. Protein kinase B/Akt: A nexus of growth factor and cytokine signaling in determining muscle mass. Journal of Applied Physiology (Bethesda, MD: 1985). 2007;**103**:378-387. DOI: 10.1152/ japplphysiol.00089.2007

[10] Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M. Mechanisms regulating skeletal muscle growth and atrophy. The FEBS Journal. 2013;**280**:4294-4314. DOI: 10.1111/ febs.12253

[11] Bhasin S, Woodhouse L, Storer TW. Proof of the effect of testosterone on skeletal muscle. The Journal of Endocrinology. 2001;**170**:27-38. DOI: 10.1677/joe.0.1700027

[12] Ferrando AA, Sheffield-Moore M, Yeckel CW, et al. Testosterone administration to older men improves muscle function: Molecular and physiological mechanisms. American Journal of Physiology. Endocrinology and Metabolism. 2002;**282**:E601-E607. DOI: 10.1152/ajpendo.00362.2001

[13] Bakhshi V, Elliott M, Gentili A, Godschalk M, Mulligan T. Testosterone improves rehabilitation outcomes in ill older men. Journal of the American Geriatrics Society. 2000;**48**:550-553. DOI: 10.1111/j.1532-5415.2000. tb05002.x

[14] Storer TW, Basaria S, Traustadottir T, et al. Effects of testosterone supplementation for 3 years on muscle performance and physical function in older men. The Journal of Clinical Endocrinology and Metabolism. 2017;**102**:583-593. DOI: 10.1210/ jc.2016-2771

[15] Iellamo F, Volterrani M, Caminiti G, et al. Testosterone therapy in women with chronic heart failure: A pilot double-blind, randomized, placebocontrolled study. Journal of the American College of Cardiology. 2010;**56**:1310- 1316. DOI: 10.1016/j.jacc.2010.03.090

[16] Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: Effects on sexual function, body composition, muscle performance and physical function in a randomized trial. Menopause (New York, NY). 2014;**21**:612-623. DOI: 10.1097/ gme.0000000000000093

[17] Singh R, Bhasin S, Braga M, et al. Regulation of myogenic differentiation by androgens: Cross talk between androgen receptor/beta-catenin and follistatin/transforming growth factorbeta signaling pathways. Endocrinology. 2009;**150**:1259-1268. DOI: 10.1210/ en.2008-0858

[18] Mendler L, Baka Z, Kovács-Simon A, Dux L. Androgens negatively regulate myostatin expression in an androgen-dependent skeletal muscle. Biochemical and Biophysical Research Communications. 2007;**361**:237-242. DOI: 10.1016/j.bbrc.2007.07.023

[19] Ferrando AA, Sheffield-Moore M, Paddon-Jones D, Wolfe RR, Urban RJ. Differential anabolic effects of testosterone and amino acid feeding in older men. The Journal of Clinical Endocrinology and Metabolism. 2003;**88**:358-362. DOI: 10.1210/ jc.2002-021041

[20] Khoo TK. Adverse events associated with testosterone administration. The New England Journal of Medicine. 2010;**363**:1865-1866; author reply 1866- 1867. DOI: 10.1056/NEJMc1009326

[21] Curran MJ, Bihrle W III. Dramatic rise in prostate-specific antigen after

androgen replacement in a hypogonadal man with occult adenocarcinoma of the prostate. Urology. 1999;**53**:423-424. DOI: 10.1016/s0090-4295(98)00348-3

[22] Mohler ML, Bohl CE, Jones A, et al. Nonsteroidal selective androgen receptor modulators (SARMs): Dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. Journal of Medicinal Chemistry. 2009;**52**:3597- 3617. DOI: 10.1021/jm900280m

[23] Kim J, Wu D, Hwang DJ, Miller DD, Dalton JT. The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl) propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators. The Journal of Pharmacology and Experimental Therapeutics. 2005;**315**:230-239. DOI: 10.1124/jpet.105.088344

[24] Dobs AS, Boccia RV, Croot CC, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: A double-blind, randomised controlled phase 2 trial. The Lancet Oncology. 2013;**14**:335-345. DOI: 10.1016/s1470-2045(13)70055-x

[25] Crawford J, Prado CM, Johnston MA, et al. Study design and rationale for the phase 3 clinical development program of enobosarm, a selective androgen receptor modulator, for the prevention and treatment of muscle wasting in cancer patients (POWER trials). Current Oncology Reports. 2016;**18**:37. DOI: 10.1007/s11912-016-0522-0

[26] Basaria S, Collins L, Dillon EL, et al. The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men. The Journals of Gerontology Series A Biological Sciences and Medical Sciences. 2013;**68**:87-95. DOI: 10.1093/ gerona/gls078

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> lung adenocarcinoma in mice. European Journal of Pharmacology. 2014;**743**:1-10. DOI: 10.1016/j.ejphar.2014.09.025

> [34] Nagaya N, Moriya J, Yasumura Y, et al. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation. 2004;**110**:3674-3679. DOI: 10.1161/01.

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pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: A randomised, placebo-controlled, double-blind, double-crossover study. British Journal of Cancer. 2008;**98**:300- 308. DOI: 10.1038/sj.bjc.6604148

Cir.0000149746.62908.Bb

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s13539-014-0159-5

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10.1007/s12603-013-0335-x

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chest.128.3.1187

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10.1172/jci39920

jcsm.12023

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[29] Nagaya N, Itoh T, Murakami S, et al. Treatment of cachexia with ghrelin in patients with COPD. Chest. 2005;**128**:1187-1193. DOI: 10.1378/

[30] Barazzoni R, Zhu X, Deboer M, et al. Combined effects of ghrelin and higher food intake enhance skeletal muscle mitochondrial oxidative capacity

and AKT phosphorylation in rats with chronic kidney disease. Kidney International. 2010;**77**:23-28. DOI:

[31] Porporato PE, Filigheddu N, Reano S, et al. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice. The Journal of Clinical Investigation. 2013;**123**:611-622. DOI:

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[33] Tsubouchi H, Yanagi S, Miura A, Matsumoto N, Kangawa K, Nakazato M.

Ghrelin relieves cancer cachexia associated with the development of *Drugs for the Treatment of Muscle Atrophy DOI: http://dx.doi.org/10.5772/intechopen.93503*

*Background and Management of Muscular Atrophy*

androgen replacement in a hypogonadal man with occult adenocarcinoma of the prostate. Urology. 1999;**53**:423-424. DOI: 10.1016/s0090-4295(98)00348-3

[22] Mohler ML, Bohl CE, Jones A, et al. Nonsteroidal selective androgen receptor modulators (SARMs): Dissociating the anabolic and

androgenic activities of the androgen receptor for therapeutic benefit. Journal of Medicinal Chemistry. 2009;**52**:3597-

[23] Kim J, Wu D, Hwang DJ, Miller DD, Dalton JT. The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl) propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators. The Journal of Pharmacology and Experimental Therapeutics. 2005;**315**:230-239. DOI:

3617. DOI: 10.1021/jm900280m

10.1124/jpet.105.088344

[24] Dobs AS, Boccia RV, Croot CC, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: A double-blind, randomised controlled phase 2 trial. The Lancet Oncology. 2013;**14**:335-345. DOI:

10.1016/s1470-2045(13)70055-x

10.1007/s11912-016-0522-0

gerona/gls078

[26] Basaria S, Collins L, Dillon EL, et al. The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men. The Journals of Gerontology Series A Biological Sciences and Medical Sciences. 2013;**68**:87-95. DOI: 10.1093/

[25] Crawford J, Prado CM, Johnston MA, et al. Study design and rationale for the phase 3 clinical development program of enobosarm, a selective androgen receptor modulator, for the prevention and treatment of muscle wasting in cancer patients (POWER trials). Current Oncology Reports. 2016;**18**:37. DOI:

[15] Iellamo F, Volterrani M, Caminiti G, et al. Testosterone therapy in women with chronic heart failure: A pilot double-blind, randomized, placebocontrolled study. Journal of the American College of Cardiology. 2010;**56**:1310- 1316. DOI: 10.1016/j.jacc.2010.03.090

[16] Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: Effects on sexual function, body composition, muscle performance and physical function in a randomized trial. Menopause (New York, NY). 2014;**21**:612-623. DOI: 10.1097/ gme.0000000000000093

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[18] Mendler L, Baka Z, Kovács-

Simon A, Dux L. Androgens negatively regulate myostatin expression in an androgen-dependent skeletal muscle. Biochemical and Biophysical Research Communications. 2007;**361**:237-242. DOI: 10.1016/j.bbrc.2007.07.023

[19] Ferrando AA, Sheffield-Moore M, Paddon-Jones D, Wolfe RR, Urban RJ. Differential anabolic effects of testosterone and amino acid feeding in older men. The Journal of Clinical Endocrinology and Metabolism. 2003;**88**:358-362. DOI: 10.1210/

[20] Khoo TK. Adverse events associated with testosterone administration. The New England Journal of Medicine. 2010;**363**:1865-1866; author reply 1866- 1867. DOI: 10.1056/NEJMc1009326

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en.2008-0858

jc.2002-021041

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[27] Papanicolaou DA, Ather SN, Zhu H, et al. A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia. The Journal of Nutrition, Health and Aging. 2013;**17**:533-543. DOI: 10.1007/s12603-013-0335-x

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[31] Porporato PE, Filigheddu N, Reano S, et al. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice. The Journal of Clinical Investigation. 2013;**123**:611-622. DOI: 10.1172/jci39920

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[113] Kurzrock R, Hickish T, Wyrwicz L, et al. Interleukin-1 receptor antagonist levels predict favorable outcome after bermekimab, a first-in-class true human interleukin-1α antibody, in a phase III randomized study of advanced colorectal cancer. Oncoimmunology. 2019;**8**:1551651. DOI: 10.1080/2162402x.2018.1551651

[114] Yadava RS, Foff EP, Yu Q, et al. TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy. Human Molecular Genetics. 2015;**24**:2035-2048. DOI: 10.1093/hmg/

[115] Bowerman M, Salsac C, Coque E, et al. Tweak regulates astrogliosis, microgliosis and skeletal muscle atrophy in a mouse model of amyotrophic lateral sclerosis. Human Molecular Genetics. 2015;**24**:3440-3456. DOI: 10.1093/hmg/

[116] Johnston AJ, Murphy KT, Jenkinson L, et al. Targeting of Fn14 prevents cancer-induced cachexia and prolongs survival.

ddu617

ddv094

[104] Granado M, Martín AI, Priego T, López-Calderón A, Villanúa MA. Tumour necrosis factor blockade did not prevent the increase of muscular muscle RING finger-1 and muscle atrophy F-box in arthritic rats. The Journal of Endocrinology. 2006;**191**:319-326. DOI:

[105] Wiedenmann B, Malfertheiner P, Friess H, et al. A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia. The Journal of Supportive Oncology. 2008;**6**:18-25

[106] Subramaniam K, Fallon K, Ruut T, et al. Infliximab reverses inflammatory muscle wasting (sarcopenia) in Crohn's disease. Alimentary Pharmacology & Therapeutics. 2015;**41**:419-428. DOI:

[107] DeBoer MD, Lee AM, Herbert K, et al. Increases in IGF-1 after anti-TNF-α therapy are associated with bone and muscle accrual in pediatric Crohn disease. The Journal of Clinical Endocrinology and Metabolism. 2018;**103**:936-945. DOI: 10.1210/

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10.1097/MPA.0b013e318279b87f

#### *Drugs for the Treatment of Muscle Atrophy DOI: http://dx.doi.org/10.5772/intechopen.93503*

*Background and Management of Muscular Atrophy*

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[105] Wiedenmann B, Malfertheiner P, Friess H, et al. A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia. The Journal of Supportive Oncology. 2008;**6**:18-25

[106] Subramaniam K, Fallon K, Ruut T, et al. Infliximab reverses inflammatory muscle wasting (sarcopenia) in Crohn's disease. Alimentary Pharmacology & Therapeutics. 2015;**41**:419-428. DOI: 10.1111/apt.13058

[107] DeBoer MD, Lee AM, Herbert K, et al. Increases in IGF-1 after anti-TNF-α therapy are associated with bone and muscle accrual in pediatric Crohn disease. The Journal of Clinical Endocrinology and Metabolism. 2018;**103**:936-945. DOI: 10.1210/ jc.2017-01916

[108] Chen CY, Tsai CY, Lee PC, Lee SD. Long-term etanercept therapy favors weight gain and ameliorates cachexia in rheumatoid arthritis patients: Roles of gut hormones and leptin. Current Pharmaceutical Design. 2013;**19**:1956-1964. DOI: 10.2174/1381612811319100014

[109] Wu C, Fernandez SA, Criswell T, et al. Disrupting cytokine signaling in pancreatic cancer: A phase I/II study of etanercept in combination with gemcitabine in patients with advanced disease. Pancreas. 2013;**42**:813-818. DOI: 10.1097/MPA.0b013e318279b87f

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[113] Kurzrock R, Hickish T, Wyrwicz L, et al. Interleukin-1 receptor antagonist levels predict favorable outcome after bermekimab, a first-in-class true human interleukin-1α antibody, in a phase III randomized study of advanced colorectal cancer. Oncoimmunology. 2019;**8**:1551651. DOI: 10.1080/2162402x.2018.1551651

[114] Yadava RS, Foff EP, Yu Q, et al. TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy. Human Molecular Genetics. 2015;**24**:2035-2048. DOI: 10.1093/hmg/ ddu617

[115] Bowerman M, Salsac C, Coque E, et al. Tweak regulates astrogliosis, microgliosis and skeletal muscle atrophy in a mouse model of amyotrophic lateral sclerosis. Human Molecular Genetics. 2015;**24**:3440-3456. DOI: 10.1093/hmg/ ddv094

[116] Johnston AJ, Murphy KT, Jenkinson L, et al. Targeting of Fn14 prevents cancer-induced cachexia and prolongs survival. Cell. 2015;**162**:1365-1378. DOI: 10.1016/j. cell.2015.08.031

[117] Zhou X, Wang JL, Lu J, et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell. 2010;**142**:531- 543. DOI: 10.1016/j.cell.2010.07.011

[118] Roth SM, Walsh S. Myostatin: A therapeutic target for skeletal muscle wasting. Current Opinion in Clinical Nutrition and Metabolic Care. 2004;**7**:259-263. DOI: 10.1097/00075197-200405000-00004

[119] Benny Klimek ME, Aydogdu T, Link MJ, Pons M, Koniaris LG, Zimmers TA. Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. Biochemical and Biophysical Research Communications. 2010;**391**:1548-1554. DOI: 10.1016/j. bbrc.2009.12.123

[120] Becker C, Lord SR, Studenski SA, et al. Myostatin antibody (LY2495655) in older weak fallers: A proof-ofconcept, randomised, phase 2 trial. The Lancet Diabetes & Endocrinology. 2015;**3**:948-957. DOI: 10.1016/ s2213-8587(15)00298-3

[121] Golan T, Geva R, Richards D, et al. LY2495655, an antimyostatin antibody, in pancreatic cancer: A randomized, phase 2 trial. Journal of Cachexia, Sarcopenia and Muscle. 2018;**9**:871-879. DOI: 10.1002/jcsm.12331

[122] Attie KM, Borgstein NG, Yang Y, et al. A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers. Muscle & Nerve. 2013;**47**:416-423. DOI: 10.1002/ mus.23539

[123] Campbell C, McMillan HJ, Mah JK, et al. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy:

Results of a randomized, placebocontrolled clinical trial. Muscle & Nerve. 2017;**55**:458-464. DOI: 10.1002/ mus.25268

[124] Lach-Trifilieff E, Minetti GC, Sheppard K, et al. An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy. Molecular and Cellular Biology. 2014;**34**:606-618. DOI: 10.1128/mcb.01307-13

[125] Amato AA, Sivakumar K, Goyal N, et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology. 2014;**83**:2239-2246. DOI: 10.1212/wnl.0000000000001070

[126] Rooks D, Praestgaard J, Hariry S, et al. Treatment of sarcopenia with bimagrumab: Results from a phase II, randomized, controlled, proof-ofconcept study. Journal of the American Geriatrics Society. 2017;**65**:1988-1995. DOI: 10.1111/jgs.14927

[127] Polkey MI, Praestgaard J, Berwick A, et al. Activin type II receptor blockade for treatment of muscle depletion in chronic obstructive pulmonary disease. A randomized trial. American Journal of Respiratory and Critical Care Medicine. 2019;**199**:313- 320. DOI: 10.1164/rccm.201802-0286OC

[128] Mori-Yoshimura M, Yamashita S, Suzuki N, et al. Late phase II/III study of BYM338 in patients with sporadic inclusion body myositis (RESILIENT): Japanese cohort data. Rinsho Shinkeigaku (Clinical Neurology). 2019;**59**:806-813. DOI: 10.5692/ clinicalneurol.cn-001325

[129] Pascual López A, Roqué i Figuls M, Urrútia Cuchi G, et al. Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome. Journal of Pain and Symptom Management. 2004;**27**:360-369. DOI: 10.1016/j.jpainsymman.2003.09.007

**103**

*Drugs for the Treatment of Muscle Atrophy DOI: http://dx.doi.org/10.5772/intechopen.93503*

[130] McCarthy HD, Crowder RE, Dryden S, Williams G. Megestrol acetate stimulates food and water intake in the rat: Effects on regional hypothalamic neuropeptide Y concentrations. European Journal of Pharmacology. 1994;**265**:99-102. DOI: 10.1016/0014-2999(94)90229-1

[136] Côté M, Trudel M, Wang C, Fortin A. Improving quality of life with nabilone during radiotherapy treatments for head and neck cancers: A randomized doubleblind placebo-controlled trial. Annals of Otology, Rhinology, and Laryngology. 2016;**125**:317-324. DOI:

10.1177/0003489415612801

[137] Alamdari N, Aversa Z,

bbrc.2011.11.154

Castillero E, et al. Resveratrol prevents dexamethasone-induced expression of the muscle atrophy-related ubiquitin ligases atrogin-1 and MuRF1 in cultured myotubes through a SIRT1 dependent mechanism. Biochemical and Biophysical Research Communications. 2012;**417**:528-533. DOI: 10.1016/j.

[138] Wang DT, Yin Y, Yang YJ, et al. Resveratrol prevents TNF-α-induced muscle atrophy via regulation of Akt/mTOR/FoxO1 signaling in C2C12 myotubes. International Immunopharmacology. 2014;**19**:206- 213. DOI: 10.1016/j.intimp.2014.02.002

[139] Momken I, Stevens L, Bergouignan A, et al. Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2011;**25**:3646- 3660. DOI: 10.1096/fj.10-177295

[140] Chen X, Wu Y, Yang T, et al. Salidroside alleviates cachexia symptoms in mouse models of cancer cachexia via activating mTOR signalling. Journal of Cachexia,

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[141] Chen L, Chen L, Wan L, et al. Matrine improves skeletal muscle atrophy by inhibiting E3 ubiquitin ligases and activating the Akt/mTOR/ FoxO3α signaling pathway in C2C12

[131] Mantovani G, Macciò A, Massa E, Madeddu C. Managing cancer-related anorexia/cachexia. Drugs. 2001;**61**:499-514. DOI:

10.2165/00003495-200161040-00004

[132] Ronga I, Gallucci F, Riccardi F, Uomo G. Anorexia-cachexia

advms.2013.11.001

jca.28246

annonc/mdq727

syndrome in pancreatic cancer: Recent advances and new pharmacological approach. Advances in Medical Sciences. 2014;**59**:1-6. DOI: 10.1016/j.

[133] Wang J, Wang Y, Tong M, Pan H, Li D. New prospect for cancer cachexia: Medical cannabinoid. Journal of Cancer. 2019;**10**:716-720. DOI: 10.7150/

European Society for Medical Oncology. 2011;**22**:2086-2093. DOI: 10.1093/

[135] Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, et al. The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: A randomized, double-blind clinical trial. Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer. 2018;**26**:3029-3038. DOI: 10.1007/s00520-018-4154-9

[134] Brisbois TD, de Kock IH, Watanabe SM, et al. Delta-9 tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: Results of a randomized, double-blind, placebocontrolled pilot trial. Annals of Oncology: Official Journal of the

*Drugs for the Treatment of Muscle Atrophy DOI: http://dx.doi.org/10.5772/intechopen.93503*

*Background and Management of Muscular Atrophy*

Cell. 2015;**162**:1365-1378. DOI: 10.1016/j.

Results of a randomized, placebocontrolled clinical trial. Muscle & Nerve. 2017;**55**:458-464. DOI: 10.1002/

[124] Lach-Trifilieff E, Minetti GC, Sheppard K, et al. An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy. Molecular and Cellular Biology. 2014;**34**:606-618. DOI:

[125] Amato AA, Sivakumar K, Goyal N, et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology. 2014;**83**:2239-2246. DOI: 10.1212/wnl.0000000000001070

[126] Rooks D, Praestgaard J, Hariry S, et al. Treatment of sarcopenia with bimagrumab: Results from a phase II, randomized, controlled, proof-ofconcept study. Journal of the American Geriatrics Society. 2017;**65**:1988-1995.

10.1128/mcb.01307-13

DOI: 10.1111/jgs.14927

[127] Polkey MI, Praestgaard J, Berwick A, et al. Activin type II receptor blockade for treatment of muscle depletion in chronic obstructive pulmonary disease. A randomized trial. American Journal of Respiratory and Critical Care Medicine. 2019;**199**:313- 320. DOI: 10.1164/rccm.201802-0286OC

[128] Mori-Yoshimura M, Yamashita S, Suzuki N, et al. Late phase II/III study of BYM338 in patients with sporadic inclusion body myositis (RESILIENT):

Japanese cohort data. Rinsho Shinkeigaku (Clinical Neurology). 2019;**59**:806-813. DOI: 10.5692/ clinicalneurol.cn-001325

[129] Pascual López A, Roqué i Figuls M, Urrútia Cuchi G, et al. Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome. Journal of Pain and Symptom Management. 2004;**27**:360-369. DOI: 10.1016/j.jpainsymman.2003.09.007

mus.25268

[117] Zhou X, Wang JL, Lu J, et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell. 2010;**142**:531- 543. DOI: 10.1016/j.cell.2010.07.011

[118] Roth SM, Walsh S. Myostatin: A therapeutic target for skeletal muscle wasting. Current Opinion in Clinical Nutrition and Metabolic

10.1097/00075197-200405000-00004

[119] Benny Klimek ME, Aydogdu T, Link MJ, Pons M, Koniaris LG, Zimmers TA. Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. Biochemical and Biophysical Research Communications. 2010;**391**:1548-1554. DOI: 10.1016/j.

[120] Becker C, Lord SR, Studenski SA, et al. Myostatin antibody (LY2495655) in older weak fallers: A proof-ofconcept, randomised, phase 2 trial. The Lancet Diabetes & Endocrinology.

[121] Golan T, Geva R, Richards D, et al. LY2495655, an antimyostatin antibody, in pancreatic cancer: A randomized, phase 2 trial. Journal of Cachexia, Sarcopenia and Muscle. 2018;**9**:871-879.

[122] Attie KM, Borgstein NG, Yang Y, et al. A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers. Muscle & Nerve. 2013;**47**:416-423. DOI: 10.1002/

[123] Campbell C, McMillan HJ, Mah JK, et al. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy:

2015;**3**:948-957. DOI: 10.1016/ s2213-8587(15)00298-3

DOI: 10.1002/jcsm.12331

Care. 2004;**7**:259-263. DOI:

bbrc.2009.12.123

cell.2015.08.031

**102**

mus.23539

[130] McCarthy HD, Crowder RE, Dryden S, Williams G. Megestrol acetate stimulates food and water intake in the rat: Effects on regional hypothalamic neuropeptide Y concentrations. European Journal of Pharmacology. 1994;**265**:99-102. DOI: 10.1016/0014-2999(94)90229-1

[131] Mantovani G, Macciò A, Massa E, Madeddu C. Managing cancer-related anorexia/cachexia. Drugs. 2001;**61**:499-514. DOI: 10.2165/00003495-200161040-00004

[132] Ronga I, Gallucci F, Riccardi F, Uomo G. Anorexia-cachexia syndrome in pancreatic cancer: Recent advances and new pharmacological approach. Advances in Medical Sciences. 2014;**59**:1-6. DOI: 10.1016/j. advms.2013.11.001

[133] Wang J, Wang Y, Tong M, Pan H, Li D. New prospect for cancer cachexia: Medical cannabinoid. Journal of Cancer. 2019;**10**:716-720. DOI: 10.7150/ jca.28246

[134] Brisbois TD, de Kock IH, Watanabe SM, et al. Delta-9 tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: Results of a randomized, double-blind, placebocontrolled pilot trial. Annals of Oncology: Official Journal of the European Society for Medical Oncology. 2011;**22**:2086-2093. DOI: 10.1093/ annonc/mdq727

[135] Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, et al. The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: A randomized, double-blind clinical trial. Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer. 2018;**26**:3029-3038. DOI: 10.1007/s00520-018-4154-9

[136] Côté M, Trudel M, Wang C, Fortin A. Improving quality of life with nabilone during radiotherapy treatments for head and neck cancers: A randomized doubleblind placebo-controlled trial. Annals of Otology, Rhinology, and Laryngology. 2016;**125**:317-324. DOI: 10.1177/0003489415612801

[137] Alamdari N, Aversa Z, Castillero E, et al. Resveratrol prevents dexamethasone-induced expression of the muscle atrophy-related ubiquitin ligases atrogin-1 and MuRF1 in cultured myotubes through a SIRT1 dependent mechanism. Biochemical and Biophysical Research Communications. 2012;**417**:528-533. DOI: 10.1016/j. bbrc.2011.11.154

[138] Wang DT, Yin Y, Yang YJ, et al. Resveratrol prevents TNF-α-induced muscle atrophy via regulation of Akt/mTOR/FoxO1 signaling in C2C12 myotubes. International Immunopharmacology. 2014;**19**:206- 213. DOI: 10.1016/j.intimp.2014.02.002

[139] Momken I, Stevens L, Bergouignan A, et al. Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2011;**25**:3646- 3660. DOI: 10.1096/fj.10-177295

[140] Chen X, Wu Y, Yang T, et al. Salidroside alleviates cachexia symptoms in mouse models of cancer cachexia via activating mTOR signalling. Journal of Cachexia, Sarcopenia and Muscle. 2016;**7**:225-232. DOI: 10.1002/jcsm.12054

[141] Chen L, Chen L, Wan L, et al. Matrine improves skeletal muscle atrophy by inhibiting E3 ubiquitin ligases and activating the Akt/mTOR/ FoxO3α signaling pathway in C2C12

myotubes and mice. Oncology Reports. 2019;**42**:479-494. DOI: 10.3892/ or.2019.7205

[142] Chen L, Xu W, Yang Q, et al. Imperatorin alleviates cancer cachexia and prevents muscle wasting via directly inhibiting STAT3. Pharmacological Research. 2020;**158**:104871. DOI: 10.1016/j.phrs.2020.104871

[143] Yang Q, Wan L, Zhou Z, et al. Parthenolide from *Parthenium integrifolium* reduces tumor burden and alleviate cachexia symptoms in the murine CT-26 model of colorectal carcinoma. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology. 2013;**20**:992-998. DOI: 10.1016/j. phymed.2013.04.020

[144] Yu R, Chen JA, Xu J, et al. Suppression of muscle wasting by the plant-derived compound ursolic acid in a model of chronic kidney disease. Journal of Cachexia, Sarcopenia and Muscle. 2017;**8**:327-341. DOI: 10.1002/ jcsm.12162

[145] Chen L, Yang Q, Zhang H, et al. Cryptotanshinone prevents muscle wasting in CT26-induced cancer cachexia through inhibiting STAT3 signaling pathway. Journal of Ethnopharmacology. 2020;**260**:113066. DOI: 10.1016/j.jep.2020.113066

**105**

**Chapter 6**

**Abstract**

**1. Introduction**

Nutritional Approaches for

Attenuating Muscle Atrophy

Muscle atrophy occurs under a number of different conditions, including disuse and aging accompanied by the onset of sarcopenia. Although muscle mass is reduced by decreased protein synthesis and/or increased protein degradation, the mechanisms of disuse muscle atrophy and sarcopenia differ. Therefore, nutrition strategies need to be customized for each type of muscle atrophy. Difficulties are associated with assessing the efficacy of nutrients for preventing sarcopenia due to uncontrolled factors in human studies. We herein (a) summarize nutritional epidemiology evidence related to sarcopenia from recent systematic reviews, (b) review nutrient supplementation for attenuating sarcopenia through dietary control, and (c) provide evidence for the efficacy of nutrient supplementation for treating disuse muscle atrophy under dietary control. Epidemiological studies have indicated that diets with a sufficient intake of beneficial foods are useful for preventing sarcopenia. Supplementation with vitamin D and leucine-enriched whey protein have been suggested to help attenuate sarcopenia in geriatric patients, particularly those who are unable to exercise. Further studies are needed to clarify the effects of protein and amino acid supplementation on muscle mass and strength. High-quality studies with controlled diets and physical activities are required to clarify the effects of

*Muneshige Shimizu and Kunihiro Sakuma*

nutritional interventions on both types of muscle atrophy.

**Keywords:** diet quality, muscle atrophy, disuse, sarcopenia, epidemiology

Muscle mass and strength have been linked to overall health and mortality [1, 2], and improvements in skeletal muscle properties and the prevention of muscle wasting with disuse/atrophy are essential for all individuals, particularly inactive older adults [3]. Sarcopenia is characterized by the loss of skeletal muscle mass and physical function (muscle strength or physical performance) with advancing age [4–6]. It is associated with physical disability, poor quality of life, and increased mortality in older adults [5]. Although the loss of muscle mass and physical function is associated with aging, rates of decline vary across the population [7]. Therefore, modifiable behavioral factors, such as diet, may influence the development of sarcopenia. Since a poor diet and nutritional status are common among the elderly [8–10], improvements in these factors may contribute to the prevention and treatment of sarcopenia, thereby promoting better health in later life for this population [11]. The term *diet quality* describes how well an individual's diet conforms to dietary recommendations using a principal component or factor analysis [12, 13]. In older adults, a higher quality diet leads to several positive health outcomes, including a

### **Chapter 6**

*Background and Management of Muscular Atrophy*

myotubes and mice. Oncology Reports.

2019;**42**:479-494. DOI: 10.3892/

[142] Chen L, Xu W, Yang Q, et al. Imperatorin alleviates cancer cachexia and prevents muscle wasting via directly inhibiting STAT3. Pharmacological Research. 2020;**158**:104871. DOI: 10.1016/j.phrs.2020.104871

[143] Yang Q, Wan L, Zhou Z, et al. Parthenolide from *Parthenium integrifolium* reduces tumor burden and alleviate cachexia symptoms in the murine CT-26 model of

colorectal carcinoma. Phytomedicine: International Journal of Phytotherapy

and Phytopharmacology. 2013;**20**:992-998. DOI: 10.1016/j.

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