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

Exercise is an effective intervention for prevention and treatment of type 2 diabetes. Skeletal muscle combines multiple signals contributing to the beneficial effects of exercise on cardiometabolic health. Inorganic nitrate increases exercise efficiency, tolerance and performance. The transcriptional regulator peroxisome proliferator-activated receptorγ coactivator1α (PGC1α) coordinates the exercise-stimulated skeletal muscle fiber-type switch from glycolytic fast-twitch (type IIb) to oxidative slow-twitch (type I) and intermediate (type IIa) fibers; an effect reversed in insulin resistance and diabetes. We find that nitrate induces PGC1α expression and a switch towards type I and IIa fibers in rat muscle and myotubes in vitro Nitrate induces the release of exercise/PGC1α-dependent myokine FNDC5/irisin, and β-aminoisobutyric acid from myotubes, and muscle in rats and humans. Both exercise and nitrate stimulated, PGC1α-mediated, γ-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/PGC1α-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.