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

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.

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.

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.

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.

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.