Midlife time-restricted feeding preserves skeletal muscle insulin responsiveness and function during aging

Primary sarcopenia, the progressive loss of skeletal muscle mass and function during aging, is partly driven by anabolic resistance, a reduced ability of aged muscle to activate protein synthesis in response to nutrients and hormones. We compared 12-week time-restricted feeding (TRF) and alternate-day fasting (ADF) interventions initiated at 3, 12, 15, or 18 months of age in male C57BL/6J mice (analyzed at 6, 15, 18, or 21 months, respectively). The effects of intermittent fasting on skeletal muscle were strongly age dependent. Midlife (15 months of age) TRF preserved lean mass, improved glucose tolerance, and increased insulin-stimulated glucose uptake in isolated muscle, whereas ADF induced broader metabolic remodeling but was associated with lean-tissue loss when initiated later in life. Muscle aging was accompanied by reduced membrane abundance of insulin receptor-plakoglobin-dystrophin glycoprotein complex (DGC) signaling assembly. However, midlife TRF was associated with greater abundance of these protein modules and enhanced postprandial AKT signaling. These findings identify midlife as a responsive window for nutritional timing interventions and link improved muscle insulin responsiveness and maintenance with diet-associated differences in sarcolemmal protein abundance and organization, although targeted perturbation studies are required to establish causality.