Sex Differences in Skeletal Muscle Mitochondrial Function in Rats Fed a High-Fat/High-Sucrose Diet

Women maintain their metabolic health at greater body mass indexes compared with men, delaying the onset of type 2 diabetes (T2D). Skeletal muscle is responsible for the bulk of glucose uptake and oxidation; these functions are impaired in T2D. Skeletal muscle mitochondria support muscle bioenergetics balancing oxidative phosphorylation of ATP with the production of reactive oxygen species. We hypothesized that skeletal muscle mitochondria in females would be protected from the oxidative metabolic stress of high-fat/high-sucrose (HFHS) diet compared with males. Wistar rats fed a chow or HFHS diet for 14 weeks were sacrificed at 18 weeks. HFHS fed males gained more body weight compared with females (P < 0.0001), yet fat mass was greater with HFHS diet in both sexes when controlled for body mass (P < 0.0001). Glucose was greater in males and HFHS fed rats (P < 0.001). Insulin resistance (HOMA-IR) was greater in males (P = 0.01) but unaffected by diet. HFHS fed males had greater mitochondrial respiration compared with females (P < 0.01 diet by sex interaction). Nutrient stress can induce reactive oxygen species. Hydrogen peroxide (H2O2) production measured with Amplex Red at this respiration steady state was 34% greater in HFHS fed males compared with 11% in females. ADP titration revealed a greater area under the curve for HFHS fed males for both oxygen (P = 0.02) and H2O2 flux (P = 0.07). Protein content of mitochondrial complexes I and III, the sites of electron leak and generation of mitochondrial reactive oxygen species, were greater in males (P < 0.02), and complex V, the site of ATP production, was greater in females (P = 0.01). These data suggest that males respond to an obesogenic challenge with greater mitochondrial respiration and accompanying oxidant production whereas females with similar fat mass accrual are protected from excess oxidant production in this setting. Sex-specific adaptation to nutrient excess may play a role in a higher obesity threshold for women compared to men at risk for T2D. Disclosure L.Knaub: None. S.Hull: None. N.A.Hulett: None. A.C.Keller: None. J.E.B.Reusch: Advisory Panel; Medtronic. R.L.Scalzo: None. Funding U.S. Department of Veterans Affairs (BX004533-01, BX002046); National Institutes of Health (5T32AG000279-20)