title: Inorganic Nitrate Mimics Exercise-Stimulated Muscular Fiber-Type Switching and Myokine and γ-Aminobutyric Acid Release.
abstract: 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 γ coactivator 1α (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 found that nitrate induces PGC1α expression and a switch toward 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.
authors.affiliation: Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, U.K. l.d.roberts@leeds.ac.uk.|Medical Research Council-Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, U.K.|Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, U.K.
authors.forename: Lee D
authors.initials: LD
authors.lastname: Roberts
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, U.K.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, U.K.
authors.forename: Tom
authors.initials: T
authors.lastname: Ashmore
authors.affiliation: Medical Research Council-Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, U.K.|Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, U.K.
authors.forename: Ben D
authors.initials: BD
authors.lastname: McNally
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, U.K.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Murfitt
authors.affiliation: Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton General Hospital, Southampton, U.K.
authors.forename: Bernadette O
authors.initials: BO
authors.lastname: Fernandez
authors.affiliation: Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton General Hospital, Southampton, U.K.
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, U.K.|Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, U.K.
authors.forename: Ross
authors.initials: R
authors.lastname: Lindsay
authors.affiliation: Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.
authors.forename: Mario
authors.initials: M
authors.lastname: Siervo
authors.affiliation: Human Nutrition Unit, Department of Oncology, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, U.K.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Williams
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, U.K.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murray
authors.affiliation: Medical Research Council-Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, U.K.|Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, U.K.
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000368:Aged; D000621:Aminoisobutyric Acids; D000818:Animals; D027461:Beta vulgaris; D002853:Chromatography, Liquid; D004311:Double-Blind Method; D005260:Female; D005353:Fibronectins / Q000187:drug effects* / Q000378:metabolism; D000067030:Fruit and Vegetable Juices; D008401:Gas Chromatography-Mass Spectrometry; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007333:Insulin Resistance; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009566:Nitrates / Q000494:pharmacology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D010805:Physical Conditioning, Animal; D051381:Rats; D017208:Rats, Wistar; D059467:Transcriptome; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism
chemical_list: D000621:Aminoisobutyric Acids; C577593:FNDC5 protein, human; C571428:FNDC5 protein, mouse; C583676:FNDC5 protein, rat; D005353:Fibronectins; D009566:Nitrates; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D005680:gamma-Aminobutyric Acid; D013006:Growth Hormone; C033435:3-aminoisobutyric acid