Review Article | Published:

Muscle wasting in disease: molecular mechanisms and promising therapies

Nature Reviews Drug Discovery volume 14, pages 5874 (2015) | Download Citation

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.

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.

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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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Affiliations

  1. Faculty of Biology, Technion Institute of Technology, Haifa, 32000, Israel.

    • Shenhav Cohen
  2. Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, CB2 0XY, UK.

    • James A. Nathan
  3. Department of Cell Biology, 240 Longwood Ave., Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Alfred L. Goldberg

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Shenhav Cohen or Alfred L. Goldberg.

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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https://doi.org/10.1038/nrd4467

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