Inorganic Nitrate Mimics Exercise-Stimulated Muscular Fiber-Type Switching and Myokine and γ-Aminobutyric Acid Release

Exercise is an effective intervention for the prevention and treatment of type 2 diabetes. Skeletal muscle combines multiple signals that contribute to the beneficial effects of exercise on cardiometabolic health. Inorganic nitrate increases exercise efficiency, tolerance, and performance. The transcriptional regulator peroxisome proliferator-activated receptor y coactivator 1 alpha (PGC1 alpha) coordinates the exercise-stimulated skeletal muscle fiber-type switch from glycolytic fast-twitch (type 11b) to oxidative slow-twitch (type I) and intermediate (type 11a) fibers, an effect reversed in insulin resistance and diabetes. We found that nitrate induces PGC1 alpha expression and a switch toward type I and Ila fibers in rat muscle and myotubes in vitro. Nitrate induces the release of exercise/PGC1 alpha-dependent myokine FNDC5/ irisin and beta-aminoisobutyric acid from myotubes and muscle in rats and humans. Both exercise and nitrate stimulated PGC1 alpha-mediated gamma-aminobutyric acid (GABA) secretion from muscle. Circulating GABA concentrations were increased in exercising mice and nitrate-treated rats and humans; thus, GABA may function as an exercise/PGC1 alpha-mediated myokine-like small molecule. Moreover, nitrate increased circulating growth hormone levels in humans and rodents. Nitrate induces physiological responses that mimic exercise training and may underlie the beneficial effects of this metabolite on exercise and cardiometabolic health.