mTOR-autophagy axis regulation by intermittent fasting promotes skeletal muscle growth and differentiation

Abstract Intermittent fasting (IF) as a dietary intervention with potential health benefits has garnered significant attention in recent years. This study investigated the effects of varying fasting intensities on skeletal muscle growth using mouse models. Compared to the normal-diet (ND) control group, short-term fasting induced feeding amount-dependent alterations in skeletal muscle autophagy markers, characterized by elevated LC3B expression, reduced p62 levels, and decreased p-mTOR/mTOR ratio. Notably, short-term mild fasting (sMF) significantly upregulated myogenic (MYH, MyoD) and adipogenic (LPL, PPARγ) differentiation markers, whereas short-term severe fasting (sSF) suppressed myogenic markers without significantly affecting adipogenic factors. Pharmacological modulation using 3-methyladenine (3-MA) and rapamycin (RAPA) confirmed the critical role of autophagy in myogenic and adipogenic processes. Multi-cycle IF studies revealed that intermittent mild fasting (IMF) enhanced metabolic efficiency (evidenced by increased feed conversion ratio), elevated organ indices of gastrocnemius and quadriceps femoris muscles, and reduced groin fat. IMF also promoted intramuscular adipogenesis and myofiber remodeling. In contrast, intermittent severe fasting (ISF) impaired glucose tolerance, decreased triglyceride levels and aspartate aminotransferase (AST) activity, inhibited myofiber growth, and exhibited no significant effect on intramuscular adipogenesis. Our findings demonstrate that IMF enhances skeletal muscle mass and reduces visceral adiposity through mTOR-autophagy axis, providing an optimized fasting regimen for metabolic health and body composition regulation.