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

• Published in: Nutrients 2023-10, Vol.15 (20), p.4438
• Main Authors: Hulett, Nicholas A, Knaub, Leslie A, Hull, Sara E, Pott, Gregory B, Peelor, Rick, Miller, Benjamin F, Shankar, Kartik, Rudolph, Michael C, Reusch, Jane E B, Scalzo, Rebecca L
• Format: Article
• Language: English
• Subjects: Animals; Biosynthesis; Blood sugar; Body mass index; Carbohydrates; Cytochrome; Diabetes; Diabetes Mellitus, Type 2 - metabolism; Diet; Diet, High-Fat - adverse effects; Dietary Fats - metabolism; Female; Females; Gender differences; Glucose; Health aspects; Homeostasis; Humans; Insulin; Insulin resistance; Insulin Resistance - physiology; Kinases; Male; Males; Metabolism; mitochondrial respiration; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Phosphatidylinositol 3-Kinases - metabolism; Proteins; Rats; Rats, Wistar; Respiration; Sex Characteristics; sex differences; skeletal muscle; Sucrose; Sucrose - metabolism; Type 2 diabetes
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu15204438

Men are diagnosed with type 2 diabetes at lower body mass indexes than women; the role of skeletal 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 address mechanistic differences underlying this sex disparity, we investigated skeletal muscle mitochondrial 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, transcriptional patterns, and protein profiles. Fat mass was greater with the HFHS diet in both sexes when controlled for body mass ( < 0.0001). Blood glucose and insulin resistance were greater in males ( = 0.01) and HFHS-fed rats ( < 0.001). HFHS-fed males had higher mitochondrial respiration compared with females ( < 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 respiration sex/diet interaction. However, transcriptomic analyses indicate sex differences in nutrient handling. Sex-specific differences occurred in PI3K/AKT signaling, PPARα/RXRα, and triacylglycerol 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 resistance.