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

Roberts, Lee D.; Ashmore, Tom; McNally, Ben D.; Murfitt, Steven A.; Fernandez, Bernadette O.; Feelisch, Martin; Lindsay, Ross; Siervo, Mario; Williams, Elizabeth A.; Murray, Andrew J.; Griffin, Julian L.

Abstract

© 2017 by the American Diabetes Association. 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 g coactivator 1a (PGC1a) 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 found that nitrate induces PGC1a expression and a switch toward type I and IIa fibers in rat muscle and myotubes in vitro. Nitrate induces the release of exercise/PGC1a-dependent myokine FNDC5/ irisin and b-Aminoisobutyric acid from myotubes and muscle in rats and humans. Both exercise and nitrate stimulated PGC1a-mediated g-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/PGC1a-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.

Citation

Roberts, L. D., Ashmore, T., McNally, B. D., Murfitt, S. A., Fernandez, B. O., Feelisch, M., Lindsay, R., Siervo, M., Williams, E. A., Murray, A. J., & Griffin, J. L. (2017). Inorganic Nitrate Mimics Exercise-Stimulated Muscular Fiber-Type Switching and Myokine and γ-Aminobutyric Acid Release. Diabetes, 66(3), 674-688. https://doi.org/10.2337/db16-0843

• Journal Article Type: Article
• Acceptance Date: Dec 18, 2016
• Online Publication Date: Dec 27, 2016
• Publication Date: 2017-03
• Deposit Date: Nov 20, 2019
• Journal: Diabetes
• Print ISSN: 0012-1797
• Electronic ISSN: 1939-327X
• Publisher: American Diabetes Association
• Peer Reviewed: Peer Reviewed
• Volume: 66
• Issue: 3
• Pages: 674-688
• DOI: https://doi.org/10.2337/db16-0843
• Keywords: Internal Medicine; Endocrinology, Diabetes and Metabolism
• Public URL: https://nottingham-repository.worktribe.com/output/3344563
• Publisher URL: https://diabetes.diabetesjournals.org/content/66/3/674