Muscle wasting in disease: molecular mechanisms and promising therapies

Key Points

  • Muscle wasting is a debilitating condition that develops with ageing and more rapidly with inactivity (bed rest) and in various systemic diseases (for example, cancer, renal failure, chronic obstructive pulmonary disease, sepsis, HIV and trauma). Fibre atrophy primarily results from an acceleration of protein degradation, often combined with reduced protein synthesis. Treatments that prevent this activation of proteolysis or increase protein synthesis offer considerable promise to combat this debilitating process.

  • Various types of rapid muscle wasting develop through a common transcriptional programme involving the induction of a set of atrophy-related genes (atrogenes) by forkhead box protein O (FOXO) transcription factors and reduced signalling by the PI3K–AKT–mTOR pathway.

  • The resulting muscle weakness is a consequence of the degradation of myofibrils, which is catalysed by ubiquitin ligases that target different components of the contractile apparatus for proteasomal degradation. By contrast, the loss of endurance results from the breakdown of mitochondria via autophagy.

  • Myostatin, an autocrine inhibitor of normal muscle growth, and its circulating homologue activin A, also trigger muscle protein loss in various catabolic states via the activation of SMAD2 and SMAD3, which function together with FOXO transcription factors.

  • Antibodies against myostatin or activin A, or agents that block their receptor — activin A receptor, type IIB (ActRIIB) — in muscle could be a promising approach to combat muscle loss caused by cancer-associated cachexia, renal failure and ageing. Indeed, these treatments helped to preserve muscle and prolong longevity in tumour-bearing mice, and several of these treatments are currently in clinical trials.

  • Glucocorticoids and various circulating inflammatory mediators, such as tumour necrosis factor-α (TNFα) and interleukin-6 (IL-6), have also been implicated in excessive muscle proteolysis in cachexia, but their roles in different catabolic states remain uncertain and controversial.

  • Recent studies have increased our understanding of the biochemical mechanisms of atrophy and have identified many intracellular proteins that are crucial in muscle wasting (for example, SMADs, tripartate motif-containing protein 32 (TRIM32), nuclear factor-κB (NF-κB)) or that combat this process (for example, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), sirtuin1 (SIRT1) and JUNB). Their manipulation by small molecules offers many opportunities for the rational design of new treatments for this condition.

Abstract

Atrophy occurs in specific muscles with inactivity (for example, during plaster cast immobilization) or denervation (for example, in patients with spinal cord injuries). Muscle wasting occurs systemically in older people (a condition known as sarcopenia); as a physiological response to fasting or malnutrition; and in many diseases, including chronic obstructive pulmonary disorder, cancer-associated cachexia, diabetes, renal failure, cardiac failure, Cushing syndrome, sepsis, burns and trauma. The rapid loss of muscle mass and strength primarily results from excessive protein breakdown, which is often accompanied by reduced protein synthesis. This loss of muscle function can lead to reduced quality of life, increased morbidity and mortality. Exercise is the only accepted approach to prevent or slow atrophy. However, several promising therapeutic agents are in development, and major advances in our understanding of the cellular mechanisms that regulate the protein balance in muscle include the identification of several cytokines, particularly myostatin, and a common transcriptional programme that promotes muscle wasting. Here, we discuss these new insights and the rationally designed therapies that are emerging to combat muscle wasting.

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Figure 1: Signalling pathways leading to muscle atrophy.
Figure 2: Mechanisms of myofibril breakdown and atrophy.

References

  1. 1

    Jackman, R. W. & Kandarian, S. C. The molecular basis of skeletal muscle atrophy. Am. J. Physiol. Cell Physiol. 287, C834–C843 (2004).

    CAS  Google Scholar 

  2. 2

    Lecker, S. H., Goldberg, A. L. & Mitch, W. E. Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J. Am. Soc. Nephrol. 17, 1807–1819 (2006).

    CAS  Google Scholar 

  3. 3

    Zhou, X. et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142, 531–543 (2010). This article demonstrates that targeting of the myostatin–activin pathway is a promising option in reducing cachexia and its associated morbidity.

    CAS  Google Scholar 

  4. 4

    Mitch, W. E. & Goldberg, A. L. Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N. Engl. J. Med. 335, 1897–1905 (1996). This review first established the importance of excessive proteolysis by the UPS in diverse disease.

    CAS  Google Scholar 

  5. 5

    Lecker, S. H., Solomon, V., Mitch, W. E. & Goldberg, A. L. Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. J. Nutr. 129, 227S–237S (1999).

    CAS  Google Scholar 

  6. 6

    Jagoe, R. T., Lecker, S. H., Gomes, M. & Goldberg, A. L. Patterns of gene expression in atrophying skeletal muscles: response to food deprivation. FASEB J. 16, 1697–1712 (2002).

    CAS  Google Scholar 

  7. 7

    Lecker, S. H. et al. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 18, 39–51 (2004).

    CAS  Google Scholar 

  8. 8

    Gomes, M. D., Lecker, S. H., Jagoe, R. T., Navon, A. & Goldberg, A. L. Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc. Natl Acad. Sci. USA 98, 14440–14445 (2001).

    CAS  Google Scholar 

  9. 9

    Sacheck, J. M. et al. Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases. FASEB J. 21, 140–155 (2007).

    CAS  Google Scholar 

  10. 10

    Zhao, J. et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 6, 472–483 (2007).

    CAS  Google Scholar 

  11. 11

    Mammucari, C. et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 6, 458–471 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Bodine, S. C. et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294, 1704–1708 (2001). References 6–12 identify and define atrophy-related genes.

    CAS  Google Scholar 

  13. 13

    Cohen, S. et al. During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. J. Cell Biol. 185, 1083–1095 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Cohen, S., Zhai, B., Gygi, S. P. & Goldberg, A. L. Ubiquitylation by Trim32 causes coupled loss of desmin, Z-bands, and thin filaments in muscle atrophy. J. Cell Biol. 198, 575–589 (2012). References 13 and 14 describe the mechanism for myofibril disassembly during muscle atrophy.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Clarke, B. A. et al. The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle. Cell Metab. 6, 376–385 (2007).

    CAS  Google Scholar 

  16. 16

    Lagirand-Cantaloube, J. et al. The initiation factor eIF3-f is a major target for atrogin1/MAFbx function in skeletal muscle atrophy. EMBO J. 27, 1266–1276 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Latres, E. et al. Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. J. Biol. Chem. 280, 2737–2744 (2005).

    CAS  Google Scholar 

  18. 18

    Bonaldo, P. & Sandri, M. Cellular and molecular mechanisms of muscle atrophy. Dis. Model. Mech. 6, 25–39 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Schiaffino, S. & Mammucari, C. Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skelet. Muscle 1, 4 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Glass, D. J. Skeletal muscle hypertrophy and atrophy signaling pathways. Int. J. Biochem. Cell Biol. 37, 1974–1984 (2005).

    CAS  Google Scholar 

  21. 21

    Sandri, M. et al. FoxO transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117, 399–412 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Sartori, R. et al. Smad2 and 3 transcription factors control muscle mass in adulthood. American journal of physiology. Cell Physiol. 296, C1248–C1257 (2009). This study established the critical role of FOXO proteins in causing atrophy.

    CAS  Google Scholar 

  23. 23

    Menconi, M. et al. Role of glucocorticoids in the molecular regulation of muscle wasting. Crit. Care Med. 35, S602–S608 (2007).

    CAS  Google Scholar 

  24. 24

    Cai, D. et al. IKKβ/NF-κB activation causes severe muscle wasting in mice. Cell 119, 285–298 (2004).

    CAS  Google Scholar 

  25. 25

    Mourkioti, F. et al. Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration. J. Clin. Invest. 116, 2945–2954 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Allen, D. L. & Unterman, T. G. Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors. Am.J. Physiol. Cell Physiol. 292, C188–C199 (2007).

    CAS  Google Scholar 

  27. 27

    Glass, D. J. PI3 kinase regulation of skeletal muscle hypertrophy and atrophy. Curr. Top. Microbiol. Immunol. 346, 267–278 (2010).

    CAS  Google Scholar 

  28. 28

    Scott, R. C., Schuldiner, O. & Neufeld, T. P. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev. Cell 7, 167–178 (2004).

    CAS  Google Scholar 

  29. 29

    Shimizu, N. et al. Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle. Cell Metab. 13, 170–182 (2011).

    CAS  Google Scholar 

  30. 30

    Sacheck, J. M., Ohtsuka, A., McLary, S. C. & Goldberg, A. L. IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. Am. J. Physiol. Endocrinol. Metab. 287, E591–E601 (2004).

    CAS  Google Scholar 

  31. 31

    Lai, K. M. et al. Conditional activation of akt in adult skeletal muscle induces rapid hypertrophy. Mol. Cell. Biol. 24, 9295–9304 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Han, H. Q., Zhou, X., Mitch, W. E. & Goldberg, A. L. Myostatin/activin pathway antagonism: Molecular basis and therapeutic potential. Int. J. Biochem. Cell Biol. 45, 2333–2347 (2013).

    CAS  Google Scholar 

  33. 33

    Trendelenburg, A. U. et al. Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am. J. Physiol. Cell Physiol. 296, C1258–C1270 (2009).

    CAS  Google Scholar 

  34. 34

    Raffaello, A. et al. JunB transcription factor maintains skeletal muscle mass and promotes hypertrophy. J. Cell Biol. 191, 101–113 (2010). This study demonstrates the crucial role of JUNB in maintaining muscle mass.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Piechaczyk, M. & Farras, R. Regulation and function of JunB in cell proliferation. Biochem. Soc. Trans. 36, 864–867 (2008).

    CAS  Google Scholar 

  36. 36

    Sandri, M. et al. PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc. Natl Acad. Sci. USA 103, 16260–16265 (2006).

    CAS  Google Scholar 

  37. 37

    Brault, J. J., Jespersen, J. G. & Goldberg, A. L. Peroxisome proliferator-activated receptor γ coactivator 1α or 1β overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. J. Biol. Chem. 285, 19460–19471 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Ruas, J. L. et al. A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 151, 1319–1331 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Handschin, C. & Spiegelman, B. M. The role of exercise and PGC1α in inflammation and chronic disease. Nature 454, 463–469 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Vega, R. B., Huss, J. M. & Kelly, D. P. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor α in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol. Cell. Biol. 20, 1868–1876 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Yamazaki, Y. et al. The cathepsin L gene is a direct target of FOXO1 in skeletal muscle. Biochem. J. 427, 171–178 (2010).

    CAS  Google Scholar 

  42. 42

    Waddell, D. S. et al. The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene. Am. J. Physiol. Endocrinol. Metab. 295, E785–E797 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Smith, I. J. et al. Sepsis increases the expression and activity of the transcription factor Forkhead Box O1 (FOXO1) in skeletal muscle by a glucocorticoid-dependent mechanism. Int. J. Biochem. Cell Biol. 42, 701–711 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Wei, B. et al. MST1, a key player, in enhancing fast skeletal muscle atrophy. BMC Biol. 11, 12 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Greer, E. L. et al. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr. Biol. 17, 1646–1656 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Greer, E. L. et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J. Biol. Chem. 282, 30107–30119 (2007).

    CAS  Google Scholar 

  47. 47

    Lee, D. & Goldberg, A. L. SIRT1 by blocking the activities of FoxO1 and 3 inhibits muscle atrophy and promotes muscle growth. J. Biol. Chem. 288, 30515–30526 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Bertaggia, E., Coletto, L. & Sandri, M. Posttranslational modifications control FoxO3 activity during denervation. American journal of physiology. Cell Physiol. 302, C587–C596 (2012).

    CAS  Google Scholar 

  49. 49

    Hunter, R. B. & Kandarian, S. C. Disruption of either the Nfkb1 or the Bcl3 gene inhibits skeletal muscle atrophy. J. Clin. Invest. 114, 1504–1511 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Reed, S. A., Senf, S. M., Cornwell, E. W., Kandarian, S. C. & Judge, A. R. Inhibition of IκB kinase α (IKKα) or IKKβ (IKKβ) plus forkhead box O (Foxo) abolishes skeletal muscle atrophy. Biochem. Biophys. Res. Commun. 405, 491–496 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Guttridge, D. C., Mayo, M. W., Madrid, L. V., Wang, C. Y. & Baldwin, A. S. Jr. NF-κB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 289, 2363–2366 (2000).

    CAS  Google Scholar 

  52. 52

    Sriram, S. et al. Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF-κB. Aging Cell 10, 931–948 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Paul, P. K. et al. The E3 ubiquitin ligase TRAF6 intercedes in starvation-induced skeletal muscle atrophy through multiple mechanisms. Mol. Cell. Biol. 32, 1248–1259 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Reid, M. B. & Li, Y. P. Tumor necrosis factor-α and muscle wasting: a cellular perspective. Respir. Res. 2, 269–272 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Yamaki, T. et al. Rel A/p65 is required for cytokine-induced myotube atrophy. Am. J. Physiol. Cell Physiol. 303, C135–C142 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Dogra, C. et al. TNF-related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle-wasting cytokine. FASEB J. 21, 1857–1869 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Mittal, A. et al. The TWEAK-Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice. J. Cell Biol. 188, 833–849 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Burke, J. R. et al. BMS-345541 is a highly selective inhibitor of IκB kinase that binds at an allosteric site of the enzyme and blocks NF-κB-dependent transcription in mice. J. Biol. Chem. 278, 1450–1456 (2003).

    CAS  PubMed  Google Scholar 

  59. 59

    Sharma, V., Lansdell, T. A., Peddibhotla, S. & Tepe, J. J. Sensitization of tumor cells toward chemotherapy: enhancing the efficacy of camptothecin with imidazolines. Chem. Biol. 11, 1689–1699 (2004).

    CAS  Google Scholar 

  60. 60

    Dewey, A., Baughan, C., Dean, T., Higgins, B. & Johnson, I. Eicosapentaenoic acid (EPA, an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia. Cochrane Database Syst Rev, CD004597 (2007).

  61. 61

    Karin, M., Yamamoto, Y. & Wang, Q. M. The IKK NF-κB system: a treasure trove for drug development. Nature Rev. Drug Discov. 3, 17–26 (2004).

    CAS  Google Scholar 

  62. 62

    McCroskery, S., Thomas, M., Maxwell, L., Sharma, M. & Kambadur, R. Myostatin negatively regulates satellite cell activation and self-renewal. J. Cell Biol. 162, 1135–1147 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Wagner, K. R., Liu, X., Chang, X. & Allen, R. E. Muscle regeneration in the prolonged absence of myostatin. Proc. Natl Acad. Sci. USA 102, 2519–2524 (2005).

    CAS  Google Scholar 

  64. 64

    Hittel, D. S. et al. Myostatin decreases with aerobic exercise and associates with insulin resistance. Med. Sci. Sports Exerc. 42, 2023–2029 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Watts, R., McAinch, A. J., Dixon, J. B., O'Brien, P. E. & Cameron-Smith, D. Increased Smad signaling and reduced MRF expression in skeletal muscle from obese subjects. Obesity (Silver Spring) 21, 525–528 (2013).

    CAS  Google Scholar 

  66. 66

    Lang, C. H., Silvis, C., Nystrom, G. & Frost, R. A. Regulation of myostatin by glucocorticoids after thermal injury. FASEB J. 15, 1807–1809 (2001).

    CAS  Google Scholar 

  67. 67

    Schakman, O., Gilson, H. & Thissen, J. P. Mechanisms of glucocorticoid-induced myopathy. J. Endocrinol. 197, 1–10 (2008).

    CAS  Google Scholar 

  68. 68

    Lach-Trifilieff, E. et al. An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy. Mol. Cell. Biol. 34, 606–618 (2014).

    PubMed  PubMed Central  Google Scholar 

  69. 69

    Lee, S. J. & McPherron, A. C. Regulation of myostatin activity and muscle growth. Proc. Natl Acad. Sci. USA 98, 9306–9311 (2001).

    CAS  Google Scholar 

  70. 70

    Lipina, C., Kendall, H., McPherron, A. C., Taylor, P. M. & Hundal, H. S. Mechanisms involved in the enhancement of mammalian target of rapamycin signalling and hypertrophy in skeletal muscle of myostatin-deficient mice. FEBS Lett. 584, 2403–2408 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Sartori, R. et al. BMP signaling controls muscle mass. Nature Genet. 45, 1309–1318 (2013).

    CAS  Google Scholar 

  72. 72

    Shan, T., Liang, X., Bi, P. & Kuang, S. Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1α-Fndc5 pathway in muscle. FASEB J. 27, 1981–1989 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Fielitz, J. et al. Myosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3. J. Clin. Invest. 117, 2486–2495 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Kudryashova, E., Kudryashov, D., Kramerova, I. & Spencer, M. J. Trim32 is a ubiquitin ligase mutated in limb girdle muscular dystrophy type 2H that binds to skeletal muscle myosin and ubiquitinates actin. J. Mol. Biol. 354, 413–424 (2005).

    CAS  Google Scholar 

  75. 75

    Frosk, P. et al. Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. Am. J. Hum. Genet. 70, 663–672 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Kudryashova, E., Wu, J., Havton, L. A. & Spencer, M. J. Deficiency of the E3 ubiquitin ligase TRIM32 in mice leads to a myopathy with a neurogenic component. Hum. Mol. Genet. 18, 1353–1367 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Kudryashova, E., Kramerova, I. & Spencer, M. J. Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H. J. Clin. Invest. 122, 1764–1776 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Cohen, S., Lee, D., Zhai, B., Gygi, S. P. & Goldberg, A. L. Trim32 reduces PI3K-Akt-FoxO signaling in muscle atrophy by promoting plakoglobin-PI3K dissociation. J. Cell Biol. 204, 747–758 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Sandri, M. Signaling in muscle atrophy and hypertrophy. Physiology 23, 160–170 (2008).

    CAS  Google Scholar 

  80. 80

    Rabinovich, E., Kerem, A., Frohlich, K. U., Diamant, N. & Bar-Nun, S. AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol. Cell. Biol. 22, 626–634 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Piccirillo, R. & Goldberg, A. L. The p97/VCP ATPase is critical in muscle atrophy and the accelerated degradation of muscle proteins. EMBO J. 31, 3334–3350 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Chou, T. F. et al. Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways. Proc. Natl Acad. Sci. USA 108, 4834–4839 (2011).

    CAS  Google Scholar 

  83. 83

    Magnaghi, P. et al. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nature Chem. Biol. 9, U548–U544 (2013).

    Google Scholar 

  84. 84

    Watts, G. D. et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nature Genet. 36, 377–381 (2004).

    CAS  Google Scholar 

  85. 85

    Johnson, J. O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857–864 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Goldberg, A. L. Development of proteasome inhibitors as research tools and cancer drugs. J. Cell Biol. 199, 583–588 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Jamart, C., Raymackers, J. M., Li An, G., Deldicque, L. & Francaux, M. Prevention of muscle disuse atrophy by MG132 proteasome inhibitor. Muscle Nerve 43, 708–716 (2011).

    CAS  Google Scholar 

  88. 88

    Caron, A. Z. et al. The proteasome inhibitor MG132 reduces immobilization-induced skeletal muscle atrophy in mice. BMC Musculoskelet. Disord. 12, 185 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Supinski, G. S., Vanags, J. & Callahan, L. A. Effect of proteasome inhibitors on endotoxin-induced diaphragm dysfunction. Am. J. Physiol. Lung Cell. Mol. Physiol. 296, L994–L1001 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Evans, W. J. et al. Cachexia: a new definition. Clin. Nutr. 27, 793–799 (2008).

    CAS  Google Scholar 

  91. 91

    Baracos, V. E., DeVivo, C., Hoyle, D. H. & Goldberg, A. L. Activation of the ATP-ubiquitin-proteasome pathway in skeletal muscle of cachectic rats bearing a hepatoma. Am. J. Physiol. 268, E996–E1006 (1995).

    CAS  Google Scholar 

  92. 92

    Bossola, M. et al. Increased muscle proteasome activity correlates with disease severity in gastric cancer patients. Ann. Surg. 237, 384–389 (2003).

    PubMed  PubMed Central  Google Scholar 

  93. 93

    Williams, A., Sun, X., Fischer, J. E. & Hasselgren, P. O. The expression of genes in the ubiquitin-proteasome proteolytic pathway is increased in skeletal muscle from patients with cancer. Surgery 126, 744–749 (1999).

    CAS  Google Scholar 

  94. 94

    Oliff, A. et al. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell 50, 555–563 (1987).

    CAS  Google Scholar 

  95. 95

    Bhatnagar, S. et al. Tumor necrosis factor-α regulates distinct molecular pathways and gene networks in cultured skeletal muscle cells. PLoS ONE 5, e13262 (2010).

    PubMed  PubMed Central  Google Scholar 

  96. 96

    Costelli, P. et al. Tumor necrosis factor-α mediates changes in tissue protein turnover in a rat cancer cachexia model. J. Clin. Invest. 92, 2783–2789 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Llovera, M. et al. Anti-TNF treatment reverts increased muscle ubiquitin gene expression in tumour-bearing rats. Biochem. Biophys. Res. Commun. 221, 653–655 (1996).

    CAS  Google Scholar 

  98. 98

    Kettelhut, I. C. & Goldberg, A. L. Tumor necrosis factor can induce fever in rats without activating protein breakdown in muscle or lipolysis in adipose tissue. J. Clin. Invest. 81, 1384–1389 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Kettelhut, I. C., Fiers, W. & Goldberg, A. L. The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors. Proc. Natl Acad. Sci. USA 84, 4273–4277 (1987).

    CAS  Google Scholar 

  100. 100

    Jatoi, A. et al. A placebo-controlled double blind trial of etanercept for the cancer anorexia/weight loss syndrome: results from N00C1 from the North Central Cancer Treatment Group. Cancer 110, 1396–1403 (2007).

    CAS  Google Scholar 

  101. 101

    Jatoi, A. et al. A placebo-controlled, double-blind trial of infliximab for cancer-associated weight loss in elderly and/or poor performance non-small cell lung cancer patients (N01C9). Lung Cancer 68, 234–239 (2010).

    Google Scholar 

  102. 102

    Catalano, M. G. et al. Selective up-regulation of tumor necrosis factor receptor I in tumor-bearing rats with cancer-related cachexia. Int. J. Oncol. 23, 429–436 (2003).

    CAS  Google Scholar 

  103. 103

    Ebrahimi, B., Tucker, S. L., Li, D., Abbruzzese, J. L. & Kurzrock, R. Cytokines in pancreatic carcinoma: correlation with phenotypic characteristics and prognosis. Cancer 101, 2727–2736 (2004).

    CAS  Google Scholar 

  104. 104

    Kuroda, K. et al. Interleukin 6 is associated with cachexia in patients with prostate cancer. Urology 69, 113–117 (2007).

    Google Scholar 

  105. 105

    Oka, M. et al. Relationship between serum levels of interleukin 6, various disease parameters and malnutrition in patients with esophageal squamous cell carcinoma. Cancer Res. 56, 2776–2780 (1996).

    CAS  Google Scholar 

  106. 106

    Scott, H. R., McMillan, D. C., Crilly, A., McArdle, C. S. & Milroy, R. The relationship between weight loss and interleukin 6 in non-small-cell lung cancer. Br. J. Cancer 73, 1560–1562 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Strassmann, G., Fong, M., Kenney, J. S. & Jacob, C. O. Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J. Clin. Invest. 89, 1681–1684 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Bayliss, T. J., Smith, J. T., Schuster, M., Dragnev, K. H. & Rigas, J. R. A humanized anti-IL-6 antibody (ALD518) in non-small cell lung cancer. Expert Opin. Biol. Ther. 11, 1663–1668 (2011).

    CAS  Google Scholar 

  109. 109

    Benny Klimek, M. E. et al. Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. Biochem. Biophys. Res. Commun. 391, 1548–1554 (2010).

    CAS  Google Scholar 

  110. 110

    Busquets, S. et al. Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance. J. Cachexia Sarcopenia Muscle 3, 37–43 (2012).

    Google Scholar 

  111. 111

    Murphy, K. T. et al. Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R716–R726 (2011). References 109–111 describe several approaches to inhibit myostatin signalling and cachexia in tumour-bearing mice.

    CAS  Google Scholar 

  112. 112

    Bolton, C. F. et al. Critically ill polyneuropathy: electrophysiological studies and differentiation from Guillain-Barre syndrome. J. Neurol. Neurosurg. Psychiatry 49, 563–573 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    de Letter, M. A. et al. Risk factors for the development of polyneuropathy and myopathy in critically ill patients. Crit. Care Med. 29, 2281–2286 (2001).

    CAS  Google Scholar 

  114. 114

    Larsson, L. Acute quadriplegic myopathy: an acquired “myosinopathy”. Adv. Exp. Med. Biol. 642, 92–98 (2008).

    CAS  Google Scholar 

  115. 115

    Hund, E. Myopathy in critically ill patients. Crit. Care Med. 27, 2544–2547 (1999).

    CAS  Google Scholar 

  116. 116

    Helliwell, T. R. et al. Muscle fibre atrophy in critically ill patients is associated with the loss of myosin filaments and the presence of lysosomal enzymes and ubiquitin. Neuropathol. Appl. Neurobiol. 24, 507–517 (1998).

    CAS  Google Scholar 

  117. 117

    Levine, S. et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N. Engl. J. Med. 358, 1327–1335 (2008).

    CAS  Google Scholar 

  118. 118

    Castillero, E., Alamdari, N., Aversa, Z., Gurav, A. & Hasselgren, P. O. PPARβ/δ regulates glucocorticoid- and sepsis-induced FOXO1 activation and muscle wasting. PLoS ONE 8, e59726 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Nystrom, G. J. & Lang, C. H. Sepsis and AMPK activation by AICAR differentially regulate FoxO-1, -3 and -4 mRNA in striated muscle. Int. J. Clin. Exp. Med. 1, 50–63 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Proserpio, V., Fittipaldi, R., Ryall, J. G., Sartorelli, V. & Caretti, G. The methyltransferase SMYD3 mediates the recruitment of transcriptional cofactors at the myostatin and c-Met genes and regulates skeletal muscle atrophy. Genes Dev. 27, 1299–1312 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Dong, Y., Pan, J. S. & Zhang, L. Myostatin suppression of Akirin1 mediates glucocorticoid-induced satellite cell dysfunction. PLoS ONE 8, e58554 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Qin, J. et al. Dexamethasone-induced skeletal muscle atrophy was associated with upregulation of myostatin promoter activity. Res. Vet. Sci. 94, 84–89 (2013).

    CAS  Google Scholar 

  123. 123

    Lang, C. H., Huber, D. & Frost, R. A. Burn-induced increase in atrogin-1 and MuRF-1 in skeletal muscle is glucocorticoid independent but downregulated by IGF-I. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R328–R336 (2007).

    CAS  Google Scholar 

  124. 124

    Pickering, W. P. et al. Glucocorticoid antagonist RU38486 fails to block acid-induced muscle wasting in vivo or in vitro. Nephrol. Dial. Transplant 18, 1475–1484 (2003).

    CAS  Google Scholar 

  125. 125

    Smith, I. J., Aversa, Z., Alamdari, N., Petkova, V. & Hasselgren, P. O. Sepsis downregulates myostatin mRNA levels without altering myostatin protein levels in skeletal muscle. J. Cell Biochem. 111, 1059–1073 (2010).

    CAS  Google Scholar 

  126. 126

    Coats, A. J. Origin of symptoms in patients with cachexia with special reference to weakness and shortness of breath. Int. J. Cardiol. 85, 133–139 (2002).

    Google Scholar 

  127. 127

    Workeneh, B. T. & Mitch, W. E. Review of muscle wasting associated with chronic kidney disease. Am. J. Clin. Nutr. 91, 1128S–1132S (2010).

    CAS  Google Scholar 

  128. 128

    Marquis, K. et al. Midthigh muscle cross-sectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 166, 809–813 (2002).

    Google Scholar 

  129. 129

    Swallow, E. B. et al. Quadriceps strength predicts mortality in patients with moderate to severe chronic obstructive pulmonary disease. Thorax 62, 115–120 (2007).

    Google Scholar 

  130. 130

    Vestbo, J. et al. Body mass, fat-free body mass, and prognosis in patients with chronic obstructive pulmonary disease from a random population sample: findings from the Copenhagen City Heart Study. Am. J. Respir. Crit. Care Med. 173, 79–83 (2006).

    Google Scholar 

  131. 131

    Crul, T. et al. Gene expression profiling in vastus lateralis muscle during an acute exacerbation of COPD. Cell. Physiol. Biochem. 25, 491–500 (2010).

    CAS  Google Scholar 

  132. 132

    Doucet, M. et al. Atrophy and hypertrophy signalling of the quadriceps and diaphragm in COPD. Thorax 65, 963–970 (2010).

    Google Scholar 

  133. 133

    Testelmans, D. et al. Atrophy and hypertrophy signalling in the diaphragm of patients with COPD. Eur. Respir. J. 35, 549–556 (2010).

    CAS  Google Scholar 

  134. 134

    Thomas, S. S. & Mitch, W. E. Mechanisms stimulating muscle wasting in chronic kidney disease: the roles of the ubiquitin-proteasome system and myostatin. Clin. Exp. Nephrol. 17, 174–182 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Mitch, W. E. et al. Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting. Am. J. Physiol. 276, C1132–C1138 (1999).

    CAS  Google Scholar 

  136. 136

    Hu, Z., Wang, H., Lee, I. H., Du, J. & Mitch, W. E. Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice. J. Clin. Invest. 119, 3059–3069 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Du, J. et al. Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. J. Clin. Invest. 113, 115–123 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Workeneh, B. T. et al. Development of a diagnostic method for detecting increased muscle protein degradation in patients with catabolic conditions. J. Am. Soc. Nephrol. 17, 3233–3239 (2006).

    CAS  Google Scholar 

  139. 139

    Solomon, V., Baracos, V., Sarraf, P. & Goldberg, A. L. Rates of ubiquitin conjugation increase when muscles atrophy, largely through activation of the N-end rule pathway. Proc. Natl Acad. Sci. USA 95, 12602–12607 (1998).

    CAS  Google Scholar 

  140. 140

    Solomon, V., Lecker, S. H. & Goldberg, A. L. The N-end rule pathway catalyzes a major fraction of the protein degradation in skeletal muscle. J. Biol. Chem. 273, 25216–25222 (1998).

    CAS  Google Scholar 

  141. 141

    Wang, X. H. et al. Caspase-3 cleaves specific 19 S proteasome subunits in skeletal muscle stimulating proteasome activity. J. Biol. Chem. 285, 21249–21257 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Plant, P. J., Bain, J. R., Correa, J. E., Woo, M. & Batt, J. Absence of caspase-3 protects against denervation-induced skeletal muscle atrophy. J. Appl. Physiol. 107, 224–234 (2009).

    CAS  Google Scholar 

  143. 143

    Hu, J. et al. XIAP reduces muscle proteolysis induced by CKD. J. Am. Soc. Nephrol. 21, 1174–1183 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Demontis, F., Piccirillo, R., Goldberg, A. L. & Perrimon, N. Mechanisms of skeletal muscle aging: insights from Drosophila and mammalian models. Dis. Model. Mech. 6, 1339–1352 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Lozano, R. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2095–2128 (2012).

    Google Scholar 

  146. 146

    de Man, F. S. et al. Diaphragm muscle fiber weakness in pulmonary hypertension. Am. J. Respir. Crit. Care Med. 183, 1411–1418 (2011).

    Google Scholar 

  147. 147

    Mainguy, V. et al. Peripheral muscle dysfunction in idiopathic pulmonary arterial hypertension. Thorax 65, 113–117 (2010).

    Google Scholar 

  148. 148

    Batt, J., Shadly Ahmed, S., Correa, J., Bain, A. & Granton, J. Skeletal muscle dysfunction in idiopathic pulmonary arterial hypertension. Am. J. Respir. Cell. Mol. Biol. 50, 74–86 (2013).

    Google Scholar 

  149. 149

    Sillau, A. H. & Banchero, N. Effects of hypoxia on capillary density and fiber composition in rat skeletal muscle. Pflugers Arch. 370, 227–232 (1977).

    CAS  Google Scholar 

  150. 150

    Chaudhary, P. et al. Chronic hypobaric hypoxia mediated skeletal muscle atrophy: role of ubiquitin-proteasome pathway and calpains. Mol. Cell Biochem. 364, 101–113 (2012).

    CAS  Google Scholar 

  151. 151

    Howald, H. & Hoppeler, H. Performing at extreme altitude: muscle cellular and subcellular adaptations. Eur. J. Appl. Physiol. 90, 360–364 (2003).

    Google Scholar 

  152. 152

    Zattara-Hartmann, M. C., Badier, M., Guillot, C., Tomei, C. & Jammes, Y. Maximal force and endurance to fatigue of respiratory and skeletal muscles in chronic hypoxemic patients: the effects of oxygen breathing. Muscle Nerve 18, 495–502 (1995).

    CAS  Google Scholar 

  153. 153

    von Haehling, S., Lainscak, M., Springer, J. & Anker, S. D. Cardiac cachexia: a systematic overview. Pharmacol. Ther. 121, 227–252 (2009).

    CAS  Google Scholar 

  154. 154

    Sharma, M. et al. Myostatin, a transforming growth factor-β superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct. J. Cell. Physiol. 180, 1–9 (1999).

    CAS  Google Scholar 

  155. 155

    Heineke, J. et al. Genetic deletion of myostatin from the heart prevents skeletal muscle atrophy in heart failure. Circulation 121, 419–425 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Loffredo, F. S. et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153, 828–839 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Muscaritoli, M. et al. Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) “cachexia-anorexia in chronic wasting diseases” and “nutrition in geriatrics”. Clin. Nutr. 29, 154–159 (2010).

    CAS  Google Scholar 

  158. 158

    Cosqueric, G. et al. Sarcopenia is predictive of nosocomial infection in care of the elderly. Br. J. Nutr. 96, 895–901 (2006).

    CAS  Google Scholar 

  159. 159

    Keller, J. N., Hanni, K. B. & Markesbery, W. R. Possible involvement of proteasome inhibition in aging: implications for oxidative stress. Mech. Ageing Dev. 113, 61–70 (2000).

    CAS  Google Scholar 

  160. 160

    Altun, M. et al. Muscle wasting in aged, sarcopenic rats is associated with enhanced activity of the ubiquitin proteasome pathway. J. Biol. Chem. 285, 39597–39608 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Combaret, L. et al. Skeletal muscle proteolysis in aging. Curr. Opin. Clin. Nutr. Metab. Care 12, 37–41 (2009).

    Google Scholar 

  162. 162

    Whitman, S. A., Wacker, M. J., Richmond, S. R. & Godard, M. P. Contributions of the ubiquitin-proteasome pathway and apoptosis to human skeletal muscle wasting with age. Pflugers Arch. 450, 437–446 (2005).

    CAS  Google Scholar 

  163. 163

    Ibebunjo, C. et al. Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia. Mol. Cell. Biol. 33, 194–212 (2013). This study identifies the transcriptional changes that occur during sarcopenia.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Deschenes, M. R., Roby, M. A., Eason, M. K. & Harris, M. B. Remodeling of the neuromuscular junction precedes sarcopenia related alterations in myofibers. Exp. Gerontol. 45, 389–393 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Chai, R. J., Vukovic, J., Dunlop, S., Grounds, M. D. & Shavlakadze, T. Striking denervation of neuromuscular junctions without lumbar motoneuron loss in geriatric mouse muscle. PLoS ONE 6, e28090 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Vermeulen, A. Clinical review 24: Androgens in the aging male. J. Clin. Endocrinol. Metab. 73, 221–224 (1991).

    CAS  Google Scholar 

  167. 167

    Khosla, S. et al. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J. Clin. Endocrinol. Metab. 83, 2266–2274 (1998).

    CAS  Google Scholar 

  168. 168

    Hermann, M. & Berger, P. Hormonal changes in aging men: a therapeutic indication? Exp. Gerontol. 36, 1075–1082 (2001).

    CAS  Google Scholar 

  169. 169

    Zadik, Z. et al. The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals. J. Clin. Endocrinol. Metab. 60, 513–516 (1985).

    CAS  Google Scholar 

  170. 170

    Brill, K. T. et al. Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men. J. Clin. Endocrinol. Metab. 87, 5649–5657 (2002).

    CAS  Google Scholar 

  171. 171

    Srinivas-Shankar, U. et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 95, 639–650.

    CAS  Google Scholar 

  172. 172

    Siriett, V. et al. Prolonged absence of myostatin reduces sarcopenia. J. Cell. Physiol. 209, 866–873 (2006).

    CAS  Google Scholar 

  173. 173

    Siriett, V. et al. Antagonism of myostatin enhances muscle regeneration during sarcopenia. Mol. Ther. 15, 1463–1470 (2007).

    CAS  Google Scholar 

  174. 174

    Baccarelli, A. et al. Activin A serum levels and aging of the pituitary-gonadal axis: a cross-sectional study in middle-aged and elderly healthy subjects. Exp. Gerontol. 36, 1403–1412 (2001).

    CAS  Google Scholar 

  175. 175

    Yarasheski, K. E., Bhasin, S., Sinha-Hikim, I., Pak-Loduca, J. & Gonzalez-Cadavid, N. F. Serum myostatin-immunoreactive protein is increased in 60–92 year old women and men with muscle wasting. J. Nutr. Health Aging 6, 343–348 (2002).

    CAS  Google Scholar 

  176. 176

    LeBrasseur, N. K. et al. Myostatin inhibition enhances the effects of exercise on performance and metabolic outcomes in aged mice. J. Gerontol. A Biol. Sci. Med. Sci. 64, 940–948 (2009).

    Google Scholar 

  177. 177

    Murphy, K. T. et al. Antibody-directed myostatin inhibition in 21-mo-old mice reveals novel roles for myostatin signaling in skeletal muscle structure and function. FASEB J. 24, 4433–4442 (2010).

    CAS  Google Scholar 

  178. 178

    Adams, G. R., Haddad, F., Bodell, P. W., Tran, P. D. & Baldwin, K. M. Combined isometric, concentric, and eccentric resistance exercise prevents unloading-induced muscle atrophy in rats. J. Appl. Physiol. 103, 1644–1654 (2007).

    CAS  Google Scholar 

  179. 179

    Gielen, S. et al. Exercise training attenuates MuRF-1 expression in the skeletal muscle of patients with chronic heart failure independent of age: the randomized Leipzig Exercise Intervention in Chronic Heart Failure and Aging catabolism study. Circulation 125, 2716–2727 (2012).

    CAS  Google Scholar 

  180. 180

    Hurst, J. E. & Fitts, R. H. Hindlimb unloading-induced muscle atrophy and loss of function: protective effect of isometric exercise. J. Appl. Physiol. 95, 1405–1417 (2003).

    CAS  Google Scholar 

  181. 181

    Vissing, K. et al. Effect of resistance exercise contraction mode and protein supplementation on members of the STARS signalling pathway. J. Physiol. 591, 3749–3763 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182

    Ferrara, N. et al. Exercise training promotes SIRT1 activity in aged rats. Rejuven. Res. 11, 139–150 (2008).

    CAS  Google Scholar 

  183. 183

    Lin, J. et al. Transcriptional co-activator PGC-1 α drives the formation of slow-twitch muscle fibres. Nature 418, 797–801 (2002).

    CAS  Google Scholar 

  184. 184

    Arany, Z. et al. The transcriptional coactivator PGC-1β drives the formation of oxidative type IIX fibers in skeletal muscle. Cell Metab. 5, 35–46 (2007).

    CAS  Google Scholar 

  185. 185

    Shao, D. et al. PGC-1 β-regulated mitochondrial biogenesis and function in myotubes is mediated by NRF-1 and ERR α. Mitochondrion 10, 516–527 (2010).

    CAS  Google Scholar 

  186. 186

    Wallace, M. A. et al. Striated muscle activator of Rho signalling (STARS) is a PGC-1α/oestrogen-related receptor-α target gene and is upregulated in human skeletal muscle after endurance exercise. J. Physiol. 589, 2027–2039 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

    McGee, S. L. & Hargreaves, M. Exercise and myocyte enhancer factor 2 regulation in human skeletal muscle. Diabetes 53, 1208–1214 (2004).

    CAS  Google Scholar 

  188. 188

    Russell, A. P. PGC-1α and exercise: important partners in combating insulin resistance. Curr. Diabetes Rev. 1, 175–181 (2005).

    CAS  Google Scholar 

  189. 189

    Arany, Z. et al. The transcriptional coactivator PGC-1β drives the formation of oxidative type IIX fibers in skeletal muscle. Cell Metab. 5, 35–46 (2007).

    CAS  Google Scholar 

  190. 190

    Wenz, T., Rossi, S. G., Rotundo, R. L., Spiegelman, B. M. & Moraes, C. T. Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging. Proc. Natl Acad. Sci. USA 106, 20405–20410 (2009).

    CAS  Google Scholar 

  191. 191

    Rera, M. et al. Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metab. 14, 623–634 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Jager, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).

    Google Scholar 

  193. 193

    Narkar, V. A. et al. AMPK and PPARδ agonists are exercise mimetics. Cell 134, 405–415 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194

    Nakashima, K. & Yakabe, Y. AMPK activation stimulates myofibrillar protein degradation and expression of atrophy-related ubiquitin ligases by increasing FOXO transcription factors in C2C12 myotubes. Biosci. Biotechnol. Biochem. 71, 1650–1656 (2007).

    CAS  Google Scholar 

  195. 195

    Krawiec, B. J., Nystrom, G. J., Frost, R. A., Jefferson, L. S. & Lang, C. H. AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C2C12 cells. Am. J. Physiol. Endocrinol. Metab. 292, E1555–E1567 (2007).

    CAS  Google Scholar 

  196. 196

    Meder, B. et al. JunB-CBFβ signaling is essential to maintain sarcomeric Z-disc structure and when defective leads to heart failure. J. Cell Sci. 123, 2613–2620 (2010).

    CAS  Google Scholar 

  197. 197

    Finkel, T., Deng, C. X. & Mostoslavsky, R. Recent progress in the biology and physiology of sirtuins. Nature 460, 587–591 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198

    Lavu, S., Boss, O., Elliott, P. J. & Lambert, P. D. Sirtuins—novel therapeutic targets to treat age-associated diseases. Nature Rev. Drug Discov. 7, 841–853 (2008).

    CAS  Google Scholar 

  199. 199

    Haigis, M. C. & Sinclair, D. A. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5, 253–295 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200

    Amat, R. et al. SIRT1 controls the transcription of the peroxisome proliferator-activated receptor-γ Co-activator-1α (PGC-1α) gene in skeletal muscle through the PGC-1α autoregulatory loop and interaction with MyoD. J. Biol. Chem. 284, 21872–21880 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201

    Rathbone, C. R., Booth, F. W. & Lees, S. J. Sirt1 increases skeletal muscle precursor cell proliferation. Eur. J. Cell Biol. 88, 35–44 (2009).

    CAS  Google Scholar 

  202. 202

    McPherron, A. C., Lawler, A. M. & Lee, S. J. Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature 387, 83–90 (1997). This is the classic paper describing myostatin as a factor limiting muscle size.

    CAS  Google Scholar 

  203. 203

    Kota, J. et al. Follistatin gene delivery enhances muscle growth and strength in nonhuman primates. Sci. Transl. Med. 1, 6ra15 (2009).

    PubMed  PubMed Central  Google Scholar 

  204. 204

    Bogdanovich, S. et al. Functional improvement of dystrophic muscle by myostatin blockade. Nature 420, 418–421 (2002).

    CAS  Google Scholar 

  205. 205

    Hamrick, M. W. et al. Recombinant myostatin (GDF-8) propeptide enhances the repair and regeneration of both muscle and bone in a model of deep penetrant musculoskeletal injury. J. Trauma 69, 579–583 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206

    Anderson, S. B., Goldberg, A. L. & Whitman, H. Identification of a novel pool of etracellular pro-myostatin in skeletal muscle. J. Biol. Chem. 283, 7027–7035 (2008).

    CAS  Google Scholar 

  207. 207

    Zhang, L. et al. Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. FASEB J. 25, 1653–1663 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 208

    Zhang, C. et al. Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice. Diabetologia 55, 183–193 (2012).

    CAS  Google Scholar 

  209. 209

    Akpan, I. et al. The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity. Int. J. Obes. (Lond.) 33, 1265–1273 (2009).

    CAS  Google Scholar 

  210. 210

    Wang, Q. & McPherron, A. C. Myostatin inhibition induces muscle fibre hypertrophy prior to satellite cell activation. J. Physiol. 590, 2151–2165 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211

    Gilson, H. et al. Follistatin induces muscle hypertrophy through satellite cell proliferation and inhibition of both myostatin and activin. Am. J. Physiol. Endocrinol. Metab. 297, E157–E164 (2009).

    CAS  Google Scholar 

  212. 212

    Dunshea, F. R., Chung, C. S., Owens, P. C., Ballard, J. F. & Walton, P. E. Insulin-like growth factor-I and analogues increase growth in artificially-reared neonatal pigs. Br. J. Nutr. 87, 587–593 (2002).

    CAS  Google Scholar 

  213. 213

    Creaney, L. & Hamilton, B. Growth factor delivery methods in the management of sports injuries: the state of play. Br. J. Sports Med. 42, 314–320 (2008).

    CAS  Google Scholar 

  214. 214

    Garcia, J. M. & Polvino, W. J. Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers. Growth Horm. IGF Res. 19, 267–273 (2009).

    CAS  Google Scholar 

  215. 215

    Porporato, P. E. et al. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice. J. Clin. Invest. 123, 611–622 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. 216

    Vestergaard, E. T., Moller, N. & Jorgensen, J. O. Acute peripheral tissue effects of ghrelin on interstitial levels of glucose, glycerol, and lactate: a microdialysis study in healthy human subjects. Am. J. Physiol. Endocrinol. Metab. 304, E1273–E1280 (2013).

    CAS  Google Scholar 

  217. 217

    Lynch, G. S. & Ryall, J. G. Role of β-adrenoceptor signaling in skeletal muscle: implications for muscle wasting and disease. Physiol. Rev. 88, 729–767 (2008).

    CAS  Google Scholar 

  218. 218

    Hinkle, R. T. et al. Skeletal muscle hypertrophy and anti-atrophy effects of clenbuterol are mediated by the β2-adrenergic receptor. Muscle Nerve 25, 729–734 (2002).

    CAS  Google Scholar 

  219. 219

    Kline, W. O., Panaro, F. J., Yang, H. & Bodine, S. C. Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol. J. Appl. Physiol. 102, 740–747 (2007) (1985).

    CAS  Google Scholar 

  220. 220

    Busquets, S. et al. Anticachectic effects of formoterol: a drug for potential treatment of muscle wasting. Cancer Res. 64, 6725–6731 (2004).

    CAS  Google Scholar 

  221. 221

    Ryall, J. G., Schertzer, J. D. & Lynch, G. S. Attenuation of age-related muscle wasting and weakness in rats after formoterol treatment: therapeutic implications for sarcopenia. J. Gerontol. A Biol. Sci. Med. Sci. 62, 813–823 (2007).

    Google Scholar 

  222. 222

    Berdeaux, R. & Stewart, R. cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration. Am. J. Physiol. Endocrinol. Metab. 303, E1–E17 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223

    Goncalves, D. A. et al. Clenbuterol suppresses proteasomal and lysosomal proteolysis and atrophy-related genes in denervated rat soleus muscles independently of Akt. Am. J. Physiol. Endocrinol. Metab. 302, E123–E133 (2012).

    CAS  Google Scholar 

  224. 224

    Brett, J., Dawson, A. H. & Brown, J. A. Clenbuterol toxicity: a NSW poisons information centre experience. Med. J. Aust. 200, 219–221 (2014).

    Google Scholar 

  225. 225

    Rabe, K. F. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br. J. Pharmacol. 163, 53–67 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. 226

    Hatzelmann, A. et al. The preclinical pharmacology of roflumilast—a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol. Ther. 23, 235–256 (2010).

    CAS  Google Scholar 

  227. 227

    Endres, S. et al. Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-α and interleukin-1 β by human mononuclear cells. Immunology 72, 56–60 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. 228

    Beghe, B., Rabe, K. F. & Fabbri, L. M. Phosphodiesterase-4 inhibitor therapy for lung diseases. Am. J. Respir. Crit. Care Med. 188, 271–278 (2013). References 225–228 describe the clinical use of PDE4 inhibitors for the treatment of COPD.

    CAS  Google Scholar 

  229. 229

    Combaret, L. et al. Torbafylline (HWA 448) inhibits enhanced skeletal muscle ubiquitin-proteasome-dependent proteolysis in cancer and septic rats. Biochem. J. 361, 185–192 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230

    Vary, T. et al. Pentoxifylline improves insulin action limiting skeletal muscle catabolism after infection. J. Endocrinol. 163, 15–24 (1999).

    CAS  Google Scholar 

  231. 231

    Baviera, A. M., Zanon, N. M., Carvalho Navegantes, L. C., Migliorini, R. H. & do Carmo Kettelhut, I. Pentoxifylline inhibits Ca2+-dependent and ATP proteasome-dependent proteolysis in skeletal muscle from acutely diabetic rats. Am. J. Physiol. Endocrinol. Metab. 292, E702–E708 (2007).

    CAS  Google Scholar 

  232. 232

    Hinkle, R. T., Dolan, E., Cody, D. B., Bauer, M. B. & Isfort, R. J. Phosphodiesterase 4 inhibition reduces skeletal muscle atrophy. Muscle Nerve 32, 775–781 (2005).

    CAS  Google Scholar 

  233. 233

    Barnette, M. S. & Underwood, D. C. New phosphodiesterase inhibitors as therapeutics for the treatment of chronic lung disease. Curr. Opin. Pulm. Med. 6, 164–169 (2000).

    CAS  Google Scholar 

  234. 234

    Spina, D. Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease. Drugs 63, 2575–2594 (2003).

    CAS  Google Scholar 

  235. 235

    Goncalves, D. A. et al. Mechanisms involved in 3′,5′-cyclic adenosine monophosphate-mediated inhibition of the ubiquitin-proteasome system in skeletal muscle. Endocrinology 150, 5395–5404 (2009).

    CAS  Google Scholar 

  236. 236

    Lira, E. C. et al. Cyclic adenosine monophosphate-phosphodiesterase inhibitors reduce skeletal muscle protein catabolism in septic rats. Shock 27, 687–694 (2007).

    CAS  Google Scholar 

  237. 237

    Lira, E. C. et al. Phosphodiesterase-4 inhibition reduces proteolysis and atrogenes expression in rat skeletal muscles. Muscle Nerve 44, 371–381 (2011).

    CAS  Google Scholar 

  238. 238

    Sinha-Hikim, I. et al. Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. Am. J. Physiol. Endocrinol. Metab. 283, E154–E164 (2002).

    CAS  Google Scholar 

  239. 239

    Griggs, R. C. et al. Effect of testosterone on muscle mass and muscle protein synthesis. J. Appl. Physiol. 66, 498–503 (1989).

    CAS  Google Scholar 

  240. 240

    Sinha-Hikim, I., Roth, S. M., Lee, M. I. & Bhasin, S. Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men. Am. J. Physiol. Endocrinol. Metab. 285, E197–E205 (2003).

    CAS  Google Scholar 

  241. 241

    Curran, M. J. & Bihrle, W. 3rd. Dramatic rise in prostate-specific antigen after androgen replacement in a hypogonadal man with occult adenocarcinoma of the prostate. Urology 53, 423–424 (1999).

    CAS  Google Scholar 

  242. 242

    Bhasin, S. et al. Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nature Clin. Pract. Endocrinol. Metab. 2, 146–159 (2006).

    CAS  Google Scholar 

  243. 243

    Narayanan, R., Mohler, M. L., Bohl, C. E., Miller, D. D. & Dalton, J. T. Selective androgen receptor modulators in preclinical and clinical development. Nucl. Recept. Signal 6, e010 (2008).

    PubMed  PubMed Central  Google Scholar 

  244. 244

    Zilbermint, M. F. & Dobs, A. S. Nonsteroidal selective androgen receptor modulator Ostarine in cancer cachexia. Future Oncol. 5, 1211–1220 (2009). References 242–244 describe the use of SARMs in pharmacological therapy of wasting in several diseases.

    CAS  Google Scholar 

  245. 245

    Murphy, K. T., Cobani, V., Ryall, J. G., Ibebunjo, C. & Lynch, G. S. Acute antibody-directed myostatin inhibition attenuates disuse muscle atrophy and weakness in mice. J. Appl. Physiol. 110, 1065–1072 (2011).

    CAS  Google Scholar 

  246. 246

    Miki, K. et al. Ghrelin treatment of cachectic patients with chronic obstructive pulmonary disease: a multicenter, randomized, double-blind, placebo-controlled trial. PLoS ONE 7, e35708 (2012).

    PubMed  PubMed Central  Google Scholar 

  247. 247

    Garcia, J. M., Friend, J. & Allen, S. Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study. Support Care Cancer 21, 129–137 (2013).

    Google Scholar 

  248. 248

    Dalton, J. T. et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J. Cachexia Sarcopenia Muscle 2, 153–161 (2011).

    PubMed  PubMed Central  Google Scholar 

  249. 249

    Dobs, A. S. et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 14, 335–345 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. 250

    Stewart Coats, A. J. et al. The ACT-ONE trial, a multicentre, randomised, double-blind, placebo-controlled, dose-finding study of the anabolic/catabolic transforming agent, MT-102 in subjects with cachexia related to stage III and IV non-small cell lung cancer and colorectal cancer: study design. J. Cachexia Sarcopenia Muscle 2, 201–207 (2011).

    PubMed  PubMed Central  Google Scholar 

  251. 251

    Basaria, S. et al. The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men. J. Gerontol. A Biol. Sci. Med. Sci. 68, 87–95 (2013).

    CAS  Google Scholar 

  252. 252

    Zhang, L. et al. Stat3 activation links a C/EBPδ to myostatin pathway to stimulate loss of muscle mass. Cell Metab. 18, 368–379 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. 253

    Lee, S.J. et al. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc. Natl. Acad. Sci. USA. 13, 18117–18122 (2005).

    Google Scholar 

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Acknowledgements

The research of A.L.G. is supported in part by grants from the US National Institutes of Health (ARO55255) and the Muscular Dystrophy Association. J.A.N. is supported by a Wellcome Trust Senior Clinical Research Fellowship and S.C. receives a stipend from the International Sephardic Education Foundation (ISEF).

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Glossary

Cachexia

Severe loss of body weight (especially muscle mass), with or without the loss of fat. Cachexia is associated with serious disease, in particular cancer.

Myofibrillar

Consisting of myofibrils. Myofibrils are the organizational units in skeletal muscle composed of aligned filaments that enable contraction. Myofibrils contain mainly myosin in the thick filaments and actin in the thin filaments plus many less abundant regulatory proteins.

Atrogenes

Atrophy-related genes that are similarly induced or suppressed in all types of atrophy in skeletal muscles.

Catabolic diseases

Diseases associated with marked weight loss, particularly loss of muscle mass and strength owing to the accelerated destruction of muscle proteins.

Sarcomere

The repeated structural and contractile unit along the length of a myofibril delimited by the Z-bands.

Z-bands

The boundaries of sarcomeres where desmin filaments are aligned and thin (actin) filaments are anchored.

N-end rule ubiquitylation system

A pathway for ubiquitylation that targets degradation proteins with unusual amino-terminal residues, which may be generated by proteolytic cleavage of normal cell proteins.

Sarcopenia

The gradual loss of skeletal muscle mass seen in aged humans and animals.

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Cohen, S., Nathan, J. & Goldberg, A. Muscle wasting in disease: molecular mechanisms and promising therapies. Nat Rev Drug Discov 14, 58–74 (2015). https://doi.org/10.1038/nrd4467

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