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

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.

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.

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.

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.

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.