Intrinsic exercise capacity is associated with skeletal muscle clock gene and IGF-1 signaling in aged low- and high-running capacity rats

BACKGROUND: Intrinsic exercise capacity is a strong predictor of health and longevity and is independently associated with aging- and disease-related outcomes. Although previous studies using low- and high-capacity runner (LCR and HCR) rats have demonstrated organ-specific patterns of epigenetic aging, the molecular mechanisms linking intrinsic aerobic capacity to skeletal muscle signaling remain incompletely understood. OBJECTIVE: This study investigated whether intrinsic exercise capacity is associated with alterations in skeletal muscle clock gene expression and insulin-like growth factor-1 (IGF-1)-related signaling pathways. METHODS: Female LCR and HCR rats (23-24 months old, 44th generation) underwent maximal oxygen uptake (VO₂max) testing, followed by molecular analyses of plantaris and soleus muscles using quantitative PCR and Western blotting. RESULTS: VO₂max was significantly higher in HCR rats. In skeletal muscle, LCR rats exhibited higher mRNA expression levels of Cry1, Bmal1, Igf1, and Igf1Ec measured at ZT2-ZT3, whereas expression of Cry2, Pdk4, and MuRF-1 did not differ between phenotypes. Despite increased Igf1 expression in LCR rats, the phosphorylated-to-total JAK2 ratio was reduced, while STAT5 phosphorylation was unchanged. Correlation analyses demonstrated significant negative associations between VO₂max and Igf1, Igf1Ec, Cry1, and Bmal1 expression. CONCLUSION: These findings indicate that low intrinsic exercise capacity is associated with coordinated alterations in skeletal muscle clock gene expression and IGF-1- related signaling, suggesting altered IGF-1-related signaling balance in aging skeletal muscle. These results provide mechanistic insight into how intrinsic aerobic capacity may influence muscle biology and health trajectories during aging.