Skeletal Muscle Disuse Atrophy and the Rehabilitative Role of Protein in Recovery from Musculoskeletal Injury

Abstract

Muscle atrophy and weakness occur as a consequence of disuse after musculoskeletal injury (MSI). The slow recovery and persistence of these deficits even after physical rehabilitation efforts indicate that interventions designed to attenuate muscle atrophy and protect muscle function are necessary to accelerate and optimize recovery from MSI. Evidence suggests that manipulating protein intake via dietary protein or free amino acid-based supplementation diminishes muscle atrophy and/or preserves muscle function in experimental models of disuse (i.e., immobilization and bed rest in healthy populations). However, this concept has rarely been considered in the context of disuse following MSI, which often occurs with some muscle activation during postinjury physical rehabilitation. Given that exercise sensitizes skeletal muscle to the anabolic effect of protein ingestion, early rehabilitation may act synergistically with dietary protein to protect muscle mass and function during postinjury disuse conditions. This narrative review explores mechanisms of skeletal muscle disuse atrophy and recent advances delineating the role of protein intake as a potential countermeasure. The possible synergistic effect of protein-based interventions and postinjury rehabilitation in attenuating muscle atrophy and weakness following MSI is also considered.

Keywords: inactivity; muscle atrophy; orthopedic injury; protein supplementation; protein turnover; rehabilitation.

FIGURE 1

Molecular mechanisms of skeletal muscle disuse atrophy. Declines in muscle protein synthesis (postabsorptive and postprandial) and a possible early increase in muscle protein breakdown underlie the loss of muscle mass with disuse. Intracellular mechanisms responsible for these changes in protein turnover may include impairments in delivery and intracellular transport of amino acids, declines in mechanotransduction, and insulin resistance specific to protein metabolism leading to downstream attenuation anabolic signaling (mTOR-dependent and -independent pathways) and a possible increase in ubiquitin-mediated proteolysis. Solid arrows indicate consistent findings, while broken arrows suggest potential mechanisms. FAK, focal adhesion kinase; FOXO, forkhead box O; GSK-3β, glycogen synthase kinase 3β; IGF-1, insulin-like growth factor 1; LAT1, L-type amino acid transporter 1; MAFbx, muscle atrophy F-box; mTORC1, mammalian target of rapamycin complex 1; MuRF1, muscle ring finger 1; p70S6K, p70 ribosomal protein S6 kinase; PI3K, phosphoinositide-3-kinase; REDD1/2, regulated in development and DNA damage 1/2; SNAT2, sodium-coupled neutral amino acid transporter 2;  TSC1, tuberous sclerosis complex 1; TSC2, tuberous sclerosis complex 2; 4E-BP1, 4E binding protein 1.