Cellular and molecular mechanisms of muscle atrophy

Abstract

Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.

Fig. 1.

Ubiquitin-proteasome systems in muscle homeostasis. E1 enzymes activate ubiquitin proteins after the cleavage of ATP. The ubiquitin is then moved from E1 to members of the E2 enzyme class. The final ubiquitylation reaction is catalyzed by members of the E3 enzyme class. E3 binds to E2 and the protein substrate, inducing the transfer of ubiquitin from E2 to the substrate. Once the substrate is polyubiquitylated, it is docked to the proteasome for degradation. Note that polyubiquitin chains can be removed by de-ubiquitylating enzymes [ubiquitin-specific processing proteases (USPs)]. The components of this system that contribute to muscle wasting are depicted. ZNF216 is involved in the recognition and delivery to the proteasome of ubiquitylated proteins during muscle atrophy. Atrogin-1 regulates the half-life of the MyoD transcription factor and of eIF3f, which is crucial for protein synthesis. Fbxo40 regulates the half-life of IRS1, an essential factor for IGF1/insulin signaling, whereas MuRF1 regulates the half-life of several sarcomeric proteins. E3 ubiquitin ligases are depicted in green, with arrows pointing to their substrates. Note that ubiquitin ligases can have different cellular localizations and can shuttle into the nucleus. IRS1, insulin receptor substrate 1; Ub, ubiquitin.

Fig. 2.

Macroautophagy, microautophagy and chaperone-mediated autophagy (CMA), and their contribution to protein degradation and organelle removal in skeletal muscle. (A) Macroautophagy is triggered by the activation of a regulatory complex (containing Vps34, Beclin 1, Vps15, Ambra1 and Atg14) that induces LC3 recruitment to the nascent autophagosome (isolation membrane). Selective removal of mitochondria (mitophagy; a specific form of macroautophagy) requires the PINK1-parkin complex and Bnip3 factors. Proteins that are committed for lysosomal degradation (including BAG3 and filamin, shown here) are labeled by polyubiquitin chains and delivered to the autophagosome by the p62 scaffold protein. (B) Microautophagy involves the direct engulfment of small portions of cytoplasm into lysosomes. Glycogen (Glyc) is reportedly taken up and broken down by microautophagy in skeletal muscle. (C) In CMA, proteins that are damaged by different agents, such as reactive oxygen species (ROS), expose a specific amino acid sequence (the KFERQ motif) that is recognized by the Hsc70 chaperone, which in turn delivers them to the lysosome via interaction with Lamp2a receptors. Dotted lines depict pathways whose molecular mechanisms and roles in adult skeletal muscle have not yet been fully defined.

Fig. 3.

Major pathways that control muscle fiber size. Protein synthesis and degradation are regulated by several different stimuli, which activate multiple signaling pathways, many of which converge at common intermediates and/or crosstalk with one another. Many of the components shown here could be promising therapeutic targets. See the main text for further details. Dotted lines depict pathways whose molecular mechanisms and role in adult skeletal muscle have yet to be completely defined. GR, glucocorticoid receptor.