Regular contractile activity plays a critical role in maintaining skeletal muscle morphological integrity and physiological function. If the muscle is forced to stop contraction, such as during limb immobilization (IM), the IGF/Akt/mTOR signaling pathway that normally stimulates protein synthesis and inhibits proteolysis will be suppressed, whereas the FoxO-controlled protein degradation pathways such as ubiquitin-proteolysis and autophagy/mitophagy will be activated and dominate. Research evidence suggests that mitochondria occupy a central position in regulating both protein synthesis and degradation via several redox sensitive pathways including PGC-1α, mitochondrial fusion and fission dynamics, mitophagy, and sirtuins. Prolonged IM downregulates PGC-1α due to AMPK and FoxO activation thus decreasing mitochondrial biogenesis and causing oxidative damage. Decline of mitochondrial inner membrane potential ((∆Ψm) and increased mitochondrial fission can trigger cascades of mitophagic process leading to loss of mitochondrial homeostasis (mitostasis), inflammation, and apoptosis. The phenotypic outcome of these disorders is compromised muscle function and fiber atrophy. Recent research suggests that overexpression of PGC-1α via transgene and in vivo DNA transfection with electroporation ameliorate mitostasis and reduce IM-induced muscle atrophy. Nutritional supplementation of select amino acids and phytochemicals can also provide mechanistic and practical insights into the prevention of muscle disuse atrophy.
