Emerging mechanisms associated with disuse-induced skeletal muscle atrophy

Skeletal muscle atrophy resulting from disuse represents a significant clinical challenge, characterized by reduced myofiber and muscle tissue size, net protein loss, and functional decline. Although several reviews have covered this topic in depth, we aimed to discuss the emerging mechanisms associated with disuse-induced skeletal muscle atrophy. We first discuss certain hallmark adaptations, including changes in protein balance, emphasizing that noncomplicated disuse atrophy in humans is driven in part by suppressed muscle protein synthesis. Although tracer studies have been inconclusive regarding muscle protein breakdown, it is notable that proteolytic systems, including the ubiquitin-proteasome system, calpains, and autophagy, are operative. Moreover, skeletal myosin heavy chain fragmentation coincides with muscle atrophy after 14 days of noncomplicated disuse, as recently reported by our laboratory. Although more research is needed, this may prove to be a novel marker indicative of protein breakdown. In addition to these topics, more novel concepts that are involved in atrophy are discussed, including the role of ribophagy in translational capacity losses, endoplasmic reticulum stress, the unfolded protein response, and the contribution of satellite and stromal cells. Throughout, we emphasize that the magnitude and nature of atrophic responses depend on the model severity, species, and timing of assessment. Moreover, we emphasize the need for continued research in these novel areas to inform targeted countermeasures.