Exercise-Induced Activation of IGF-1/mTOR Signaling and Hippocampal BDNF/PGC-1α Expression Reverses Age-Related Motor Decline

Purpose: Aging is associated with a progressive decline in skeletal muscle function and motor coordination, contributing to reduced mobility and quality of life. While exercise is a well-established intervention to counteract age-related deterioration, the underlying molecular mechanisms in both muscle and the brain remain incompletely understood.Methods: Young (4 months) and aged (20 months) male C57BL/6N mice were assigned to control or treadmill exercise groups. After 8 weeks of training, the grip strength, muscle histology, rotarod performance, and molecular markers related to muscle hypertrophy and brain plasticity were analyzed.Results: Treadmill exercise significantly increased grip strength in both young and aged mice without changes in muscle fiber size, indicating improved muscle quality. Molecular analysis revealed upregulation of insulin-like growth factor 1/AKT/mammalian target of rapamycin (mTOR) and mTOR/p70 ribosomal protein S6 kinase signaling in both young and aged mice. Exercise also modulated myogenic markers in an age-dependent manner, increasing paired box 3 (Pax3) and myogenic differentiation 1 in aged mice and Pax7 in young mice. Rotarod performance significantly improved over time, suggesting enhanced motor coordination and learning. These functional gains were accompanied by elevated hippocampal brain-derived neurotrophic factor and peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression.Conclusions: Eight weeks of treadmill exercise enhances muscle strength and motor performance in both young and aged mice. These benefits occur independently of muscle hypertrophy and are associated with favorable molecular adaptations in muscle and the brain. These findings underscore the potential of exercise to preserve neuromuscular function during aging through peripheral and central mechanisms.