Cellular mechanism of immobilization-induced muscle atrophy: A mini review

Abstract

It is well-established that regular contraction maintains morphological and functional integrity of skeletal muscle, whereas rigorous exercise training can upregulate muscle metabolic and contractile function. However, when muscles stop contraction, such as during immobilization (IM) and denervation, withdrawal of IGF/Akt/mTOR signaling allows FoxO-controlled protein degradation pathways to dominate. Mitochondria play an important role in regulating both protein synthesis and degradation via several redox sensitive signaling pathways such as mitochondrial biogenesis, fusion and fission dynamics, ubiquitin-proteolysis, autophagy/mitophagy, and apoptosis. During prolonged IM, downregulation of PGC-1α and increased mitochondrial oxidative damage facilitate fission protein and inflammatory cytokine production and activate mitophagic process, leading to a vicious cycle of protein degradation. This “mitostasis theory of muscle atrophy” is the opposite pathway of hormesis, which defines enhanced muscle function with contractile overload. The demonstration that PGC-1α overexpression via transgene or in vivo DNA transfection can successfully restore mitochondrial homeostasis and reverse myocyte atrophy supports such a proposition. Understanding the mechanism governing mitostasis can be instrumental to the treatment of muscle atrophy associated with bedrest, cancer cachexia and sarcopenia.

Keywords

Atrophy / Immobilization / Mitochondria / Muscle

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This work was supported in part by a grant-in-aid by the University of Minnesota Office of the Vice President for Research. There is not conflict of interest to be declared.