Effect of moderate-intensity aerobic exercise on early oxidative stress and muscle atrophy in SAMP8 mice through modulation of the DAO/SRR and Nrf2/Keap1 pathways.
Age-related muscle atrophy is closely associated with oxidative stress imbalance. This study investigated the molecular mechanisms by which moderate-intensity aerobic exercise alleviates early oxidative stress and muscle atrophy in senescence-accelerated mouse prone 8 (SAMP8) mice via modulation of the D-amino acid oxidase (DAO)-nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathways. 3-month-old male SAMP8 mice and senescence-accelerated mouse resistant 1 (SAMR1) controls were randomised into four groups (n = 10/group): SAMR1-Sed, SAMR1-Ex, SAMP8-Sed, and SAMP8-Ex. The exercise groups performed 12 weeks of moderate-intensity treadmill running. Gastrocnemius muscle morphology was assessed by hematoxylin and eosin (HE), Masson's trichrome, and toluidine blue (TB) staining; oxidative stress markers were measured using biochemical assays; and expression of DAO, serine racemase (SRR), and Nrf2/Keap1 pathway components was quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Moderate-intensity aerobic exercise significantly increased muscle fibre cross-sectional area, reduced collagen deposition and mast cell degranulation, lowered hydrogen peroxide (H₂O₂), malondialdehyde (MDA), and protein carbonylation levels, and enhanced superoxide dismutase (SOD) activity and glutathione (GSH) content in SAMP8 mice. It downregulated DAO and SRR expression while activating Nrf2, inhibiting Keap1, and upregulating downstream antioxidant genes (Hmox1, Nqo1, Gclc). These findings suggest that moderate-intensity aerobic exercise alleviates early oxidative stress and muscle atrophy by inhibiting the pro-oxidant DAO/SRR pathway and activating the Nrf2/Keap1 antioxidant axis, thereby providing evidence for the molecular mechanisms underlying the attenuation of age-related skeletal muscle degeneration.