Angiogenesis-independent VEGF signaling enhances exercise capacity by increasing fat oxidation in mice fed sulfur amino acid-restricted diets

Dietary restriction of the sulfur-containing amino acids methionine and cysteine (SAAR) has numerous metabolic benefits including enhanced body composition and insulin sensitivity. Many of these benefits parallel those associated with endurance exercise. How SAAR impacts skeletal muscle remains largely unexplored. Here, we demonstrate that one week of SAAR in sedentary young male mice increases endurance exercise capacity. SAAR increased lipid oxidation at rest, delaying the onset of carbohydrate utilization during exercise. SAAR increased expression of fatty acid catabolism genes, especially in glycolytic muscle, leading to increased fatty acid circulatory turnover flux and muscle β-oxidation. Reducing lipid uptake from circulation through endothelial-cell-specific CD36 deletion attenuated the running phenotype. Inhibition of VEGF signaling prevented improved exercise performance following SAAR, independent of angiogenesis. These results support a role for angiogenesis-independent VEGF signaling and endothelial cell CD36-dependent fatty acid transport in the regulation of endurance exercise capacity by mediating muscle substrate availability.