Sex-dependent effects of aging and insulin resistance on skeletal muscle function and structure in rats

Skeletal muscle function is determinant for maintaining functional performance and independence in older adults. Muscle is a primary target of aging and insulin resistance (IR)—two conditions associated with functional decline. Sex-related differences may influence these effects at structural and functional levels. We aimed to evaluate the individual and combined effects of aging and IR on the function and structure of extensor digitorum longus (EDL) and soleus muscles in male and female rats. Animals aged 3 and 20 months were studied, with IR induced by 8 weeks of 20% fructose in drinking water. Muscle contractility was assessed alongside histological and hormonal analyses. In males, aging impaired EDL and soleus contractile force, free testosterone levels, and muscle mass. IR decreased muscle function only in young animals. In females, aging led to muscle loss without affecting contractile strength, but the combination of aging and IR reduced muscle contraction, decreased estradiol and exacerbated muscle loss. Both sexes showed aging-related loss of EDL glycolytic fibers, altered regenerative capacity, and increased fibrosis. IR alone reduced glycolytic fibers in young animals of both sexes but increased fibrosis only in males. These results highlight sex-specific effects of aging and IR on muscle function, relevant for targeted strategies to prevent and treat age- and IR-related muscle function decline.