Sex-specific skeletal muscle fiber atrophy and reduced macrophage inflammation in a rodent transverse aortic constriction model.

Heart failure is associated with systemic skeletal muscle remodeling, where sex-specific differences suggest differential peripheral involvement in disease progression. Skeletal muscle macrophages regulate angiogenesis and tissue remodeling and may contribute to early alterations in muscle structure and function during cardiac pressure overload. We tested whether chronic pressure-overload induces sex-specific skeletal muscle remodeling and alters macrophage abundance and paracrine signaling in male and female Sprague Dawley rats that underwent transverse aortic constriction (TAC) or sham surgery at 4 weeks of age and were studied after 40 wk. TAC induced 12% greater heart mass (p = 0.049) and 17% greater heart-to-body mass ratio (p = 0.018) in males, while females showed minimal cardiac remodeling. In extensor digitorum longus (EDL) muscle, TAC males exhibited ~ 10% smaller fiber perimeter corresponding with higher capillary-to-fiber perimeter exchange (p < 0.05 for both), while female TAC rats had no difference in fiber size and 17% lower capillary-to-fiber ratio than female sham (p = 0.033). In soleus muscle, TAC rats had higher capillarization indices (p < 0.05) regardless of sex. Muscle macrophage abundance was 19% lower in TAC males than sham males (p = 0.005). TAC macrophages secreted less MCP-1 (- 35%, p = 0.0058), IL-1β (- 16%, p = 0.0167), TNF-α (- 16%, p = 0.0337), and VEGF-A (- 16%, p = 0.0120) and produced less complex endothelial networks (18% larger mesh size, p = 0.001). These findings indicate that TAC is associated with skeletal muscle remodeling and macrophage immunosuppression, with some changes occurring in a sex-specific manner. This suggests the potential for immune-microvascular coupling in peripheral adaptations to cardiac pressure overload.