Male mice are more susceptible than females to obesity‐induced muscle atrophy when fed a high‐fat, high‐cholesterol diet

Obesity-related skeletal muscle atrophy poses a significant health burden, with marked sex differences in this condition. However, the mechanisms underlying these sex differences remain poorly understood. This study investigated whether and to what extent skeletal muscle quality was impaired in C57BL/6 mice fed a high-fat, high-cholesterol (HFHC) diet, focusing on sexual dimorphism. Male and female mice were assigned to control or HFHC groups for 40 weeks. The results showed that both sexes fed the HFHC diet developed obesity and dyslipidemia, with males exhibiting a more severe phenotype. Notably, males experienced more pronounced obesity-induced muscle atrophy than females. This study further revealed that HFHC feeding disrupted physiological homeostasis in both sexes, leading to sexual dimorphism in gut microbial composition and short-chain fatty acid levels, with males displaying a diminished capacity to maintain metabolic homeostasis. Furthermore, males exhibited more severe mitochondrial dysfunction and higher oxidative stress levels compared to females, manifesting as reduced muscle strength and upregulated atrophy-related gene expression. Collectively, these findings indicate that long-term HFHC feeding disrupts gut microbiota and glucolipid metabolic homeostasis, further impairing mitochondrial function and exacerbating muscle atrophy preferentially in males, whereas females are relatively protected through superior maintenance of physiological homeostasis, resulting in milder muscle atrophy.