Physical exercise mitigates amyloid beta-driven muscle degeneration in Alzheimer's disease

Introduction: Alzheimer's disease (AD) is increasingly recognized as a systemic disorder, with skeletal muscle dysfunction contributing substantially to frailty and functional decline. Although amyloid-beta (Aβ) has been detected in peripheral tissues, including skeletal muscle, how it drives muscle degeneration and whether exercise can counteract this process remain to be elucidated.

Objectives: This study aimed to define the molecular mechanisms underlying Aβ-induced skeletal muscle degeneration in AD and assess the potential of high-intensity interval training (HIIT) to alleviate muscle dysfunction and related pathology.

Methods: We employed a small-scale exploratory clinical cohort and the 5 × FAD mouse model, integrating transcriptomic and metabolomic profiling with in vitro and in vivo functional assays to dissect Aβ-induced muscle pathology and the protective mechanisms of HIIT.

Results: AD patients in the exploratory cohort showed a trend toward reduced handgrip strength, mirroring the progressive muscle weakness, myofiber atrophy, and intramuscular Aβ accumulation observed in 5 × FAD mice. Mechanistically, Aβ activated RAGE/NF-κB signaling, driving inflammation and oxidative stress in myofibers. HIIT reversed these pathological changes and concomitantly lowered Aβ levels. Transcriptomic profiling identified Fibroblast Growth Factor 10 (FGF10) as a key exercise-induced mediator: FGF10 activated the FGFR2-AKT-ADAM10 axis to promote RAGE ectodomain shedding, generating soluble RAGE that suppressed Aβ-mediated inflammatory and injury signaling.

Conclusion: Our findings define an Aβ-RAGE axis driving AD-associated muscle degeneration and reveal an exercise-responsive FGF10-RAGE protective pathway, reframing AD as a brain-muscle axis disorder and highlighting FGF10 as a promising target for systemic therapeutic intervention.