title: GSNOR Deficiency Enhances In Situ Skeletal Muscle Strength, Fatigue Resistance, and RyR1 S-Nitrosylation Without Impacting Mitochondrial Content and Activity.
abstract: Nitric oxide (NO) plays important, but incompletely defined roles in skeletal muscle. NO exerts its regulatory effects partly though S-nitrosylation, which is balanced by denitrosylation by enzymes such as S-nitrosoglutathione reductase (GSNOR), whose functions in skeletal muscle remain to be fully deciphered.
  
  
  
  GSNOR null (GSNOR-/-) tibialis anterior (TA) muscles showed normal growth and were stronger and more fatigue resistant than controls in situ. However, GSNOR-/-lumbrical muscles showed normal contractility and Ca2+handling in vitro, suggesting important differences in GSNOR function between muscles or between in vitro and in situ environments. GSNOR-/-TA muscles exhibited normal mitochondrial content, and capillary densities, but reduced type IIA fiber content. GSNOR inhibition did not impact mitochondrial respiratory complex I, III, or IV activities. These findings argue that enhanced GSNOR-/-TA contractility is not driven by changes in mitochondrial content or activity, fiber type, or blood vessel density. However, loss of GSNOR led to RyR1 hypernitrosylation, which is believed to increase muscle force output under physiological conditions. cGMP synthesis by soluble guanylate cyclase (sGC) was decreased in resting GSNOR-/-muscle and was more responsive to agonist (DETANO, BAY 41, and BAY 58) stimulation, suggesting that GSNOR modulates cGMP production in skeletal muscle.
  
  
  
  GSNOR may act as a "brake" on skeletal muscle contractile performance under physiological conditions by modulating nitrosylation/denitrosylation balance.
  
  
  
  GSNOR may play important roles in skeletal muscle contractility, RyR1 S-nitrosylation, fiber type specification, and sGC activity. Antioxid. Redox Signal. 26, 165-181.
authors.affiliation: 1 Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine , Miami, Florida.
authors.forename: Younghye
authors.initials: Y
authors.lastname: Moon
authors.affiliation: 1 Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine , Miami, Florida.|2 The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine , Miami, Florida.
authors.forename: Yenong
authors.initials: Y
authors.lastname: Cao
authors.affiliation: 1 Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine , Miami, Florida.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: 3 Department of Physiology and Biophysics, University of Miami Miller School of Medicine , Miami, Florida.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: 2 The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine , Miami, Florida.|4 Department of Medicine, University of Miami Miller School of Medicine , Miami, Florida.
authors.forename: Wayne
authors.initials: W
authors.lastname: Balkan
authors.affiliation: 5 Department of Anesthesia, Critical Care and Pain Medicine, Anesthesia Center for Critical Care Research , Harvard Medical School, Massachusetts General Hospital Boston, Boston, Massachusetts.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.affiliation: 6 Department of Neurology, University of Miami Miller School of Medicine , Miami, Florida.
authors.forename: Francisca
authors.initials: F
authors.lastname: Diaz
authors.affiliation: 3 Department of Physiology and Biophysics, University of Miami Miller School of Medicine , Miami, Florida.
authors.forename: W Glenn
authors.initials: WG
authors.lastname: Kerrick
authors.affiliation: 1 Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine , Miami, Florida.|2 The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine , Miami, Florida.|4 Department of Medicine, University of Miami Miller School of Medicine , Miami, Florida.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
authors.affiliation: 1 Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine , Miami, Florida.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Percival
mesh_terms: D000426:Alcohol Dehydrogenase / Q000172:deficiency*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis; D005838:Genotype; D006984:Hypertrophy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000235:genetics* / Q000378:metabolism*; D018763:Muscle Fatigue / Q000235:genetics*; D053580:Muscle Strength / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology*; D018919:Neovascularization, Physiologic; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; C483598:Adh5 protein, mouse; D000426:Alcohol Dehydrogenase; D006152:Cyclic GMP; D002118:Calcium
keywords: GSNOR; S-nitrosylation; fatigue; mitochondria; nitric oxide; sGC