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Inorganic nitrate mimics exercise-stimulated muscular fiber-Type switching and myokine and g-Aminobutyric acid release

Lookup NU author(s): Dr Mario Siervo



This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Diabetes Association Inc., 2017.

For re-use rights please refer to the publisher's terms and conditions.


© 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.

Publication metadata

Author(s): Roberts LD, Ashmore T, McNally BD, Murfitt SA, Fernandez BO, Feelisch M, Lindsay R, Siervo M, Williams EA, Murray AJ, Griffin JL

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2017

Volume: 66

Issue: 3

Pages: 674-688

Print publication date: 01/03/2017

Online publication date: 27/12/2016

Acceptance date: 18/12/2016

Date deposited: 29/01/2020

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association Inc.


DOI: 10.2337/db16-0843


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