Low-carbohydrate diets improved glucose homeostasis and physical performance by regulating mitochondrial function via the SIRT3/PGC1α pathway.

This study aimed to analyze the effects of two low-carbohydrate diets (LCDs) on glucose homeostasis and physical performance in sedentary mice. Eighteen C57BL/6J mice were randomly divided into three groups: fed with standard chow (CON), high-fat LCD chow (HF-LCD), and high-protein LCD chow (HP-LCD). After two weeks, body weight (BW), food intake, fasting serum ketone bodies (β-OHB), blood glucose, glucose tolerance, and relative mass of skeletal muscle were measured. The physical performance was assessed using a treadmill endurance test, and the mRNA levels of mitochondrial function (SIRT3 and PGC1α) in the quadriceps were measured by qRT-PCR. Compared with the CON group, the HF-LCD group showed significantly increased fat content, β-OHB, and physical performance; the HP-LCD group showed significantly decreased calorie intake and BW. Compared with the HF-LCD group, the HP-LCD group showed significantly lower calorie intake, BW, fat content, β-OHB, skeletal muscle mass, and physical performance. Mechanistically, the mRNA levels of SIRT3-PGC1α in the HF-LCD group were higher than those in the other group. Both short-term LCDs can maintain glucose homeostasis in mice. However, only HF-LCD can increase β-OHB and physical performance without compromising skeletal muscle mass and strength. The underlying mechanism may involve transcriptional regulation of mitochondrial‑related genes via the SIRT3/PGC1α pathway.