Skeletal muscle adaptation to microgravity: how altered mechanical cues drive catabolic signaling

Exposure to microgravity induces rapid and profound skeletal muscle atrophy, yet the mechanisms by which reduced mechanical loading is sensed and translated into coordinated cellular and tissue-level responses remain incompletely understood. Accumulating evidence indicates that muscle adaptation to microgravity arises from disruption of mechanosensing pathways that regulate membrane signaling, cytoskeletal organization, and extracellular matrix (ECM) structure. Here, we integrate findings from spaceflight, bed rest, immobilization, and in vitro models to examine how reduced mechanical loading alters muscle-intrinsic signaling and tissue architecture. We discuss early suppression of anabolic pathways, activation of proteolytic systems, and remodeling of membrane-associated signaling hubs, including ECM composition, stiffness, and integrin-mediated adhesion. We further highlight how coupling between the ECM, cytoskeleton, and the nucleus enables mechanical cues to shape transcriptional programs and metabolic control during unloading. Understanding how skeletal muscle adapts to altered mechanical forces will facilitate the development of therapies for atrophy in spaceflight and terrestrial conditions of disuse, including bed rest, aging, and immobilization.