Sex Differences in the Skeletal Muscle Response to a High Fat, High Sucrose Diet in Rats

Men are diagnosed with type 2 diabetes at lower body mass indexes than women; the role of skel-etal muscle in this sex difference is poorly understood. Type 2 diabetes impacts skeletal muscle, particularly in females who demonstrate a lower oxidative capacity compared to males. To ad-dress mechanistic differences underlying this sex disparity, we investigated skeletal muscle mito-chondrial respiration in female and male rats in response to chronic high-fat, high-sugar (HFHS) diet consumption. Four-week-old Wistar Rats were fed a standard chow or HFHS diet for 14 weeks to identify sex-specific adaptations in mitochondrial respirometry and characteristics, transcrip-tional patterns, and protein profiles. Fat mass was greater with the HFHS diet in both sexes when controlled for body mass (p < 0.0001). Blood glucose and insulin resistance were greater in males (p = 0.01) and HFHS-fed rats (p < 0.001). HFHS-fed males had higher mitochondrial respiration compared with females (p < 0.01 sex/diet interaction). No evidence of a difference by sex or diet was found for mitochondrial synthesis, dynamics, or quality to support the mitochondrial respi-ration sex/diet interaction. However, transcriptomic analyses indicate sex differences in nutrient handling. Sex-specific differences occurred in PI3K/AKT signaling, PPARa/RXRa, and triacyl-glycerol degradation. These findings may provide insight into the clinical sex differences in body mass index threshold for diabetes development and tissue-specific progression of insulin re-sistance. Overall design: Differential gene expression profiling analysis of RNA-seq data for gastronemius of male and female Wistar rats given chow or high fat/high sugar diet