title: Increasing muscle mass improves vascular function in obese (db/db) mice.
abstract: BACKGROUND
  A sedentary lifestyle is an independent risk factor for cardiovascular disease and exercise has been shown to ameliorate this risk. Inactivity is associated with a loss of muscle mass, which is also reversed with isometric exercise training. The relationship between muscle mass and vascular function is poorly defined. The aims of the current study were to determine whether increasing muscle mass by genetic deletion of myostatin, a negative regulator of muscle growth, can influence vascular function in mesenteric arteries from obese db/db mice.
  
  
  RESULTS
  Myostatin expression was elevated in skeletal muscle of obese mice and associated with reduced muscle mass (30% to 50%). Myostatin deletion increased muscle mass in lean (40% to 60%) and obese (80% to 115%) mice through increased muscle fiber size (P<0.05). Myostatin deletion decreased adipose tissue in lean mice, but not obese mice. Markers of insulin resistance and glucose tolerance were improved in obese myostatin knockout mice. Obese mice demonstrated an impaired endothelial vasodilation, compared to lean mice. This impairment was improved by superoxide dismutase mimic Tempol. Deletion of myostatin improved endothelial vasodilation in mesenteric arteries in obese, but not in lean, mice. This improvement was blunted by nitric oxide (NO) synthase inhibitor l-NG-nitroarginine methyl ester (l-NAME). Prostacyclin (PGI2)- and endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilation were preserved in obese mice and unaffected by myostatin deletion. Reactive oxygen species) was elevated in the mesenteric endothelium of obese mice and down-regulated by deletion of myostatin in obese mice. Impaired vasodilation in obese mice was improved by NADPH oxidase inhibitor (GKT136901). Treatment with sepiapterin, which increases levels of tetrahydrobiopterin, improved vasodilation in obese mice, an improvement blocked by l-NAME.
  
  
  CONCLUSIONS
  Increasing muscle mass by genetic deletion of myostatin improves NO-, but not PGI2- or EDHF-mediated vasodilation in obese mice; this vasodilation improvement is mediated by down-regulation of superoxide.
authors: Vascular Biology Center and Department of Physiology, Georgia Regents University, Augusta, GA, Germany (S.Q., J.D.M., C.D.S., W.H., A.G., F.C., Y.Y., Y.S., D.J.F., D.W.S.).
authors: Shuiqing
authors: S
authors: Qiu
authors: Vascular Biology Center and Department of Physiology, Georgia Regents University, Augusta, GA, Germany (S.Q., J.D.M., C.D.S., W.H., A.G., F.C., Y.Y., Y.S., D.J.F., D.W.S.).
authors: James D
authors: JD
authors: Mintz
authors: Vascular Biology Center and Department of Physiology, Georgia Regents University, Augusta, GA, Germany (S.Q., J.D.M., C.D.S., W.H., A.G., F.C., Y.Y., Y.S., D.J.F., D.W.S.).
authors: Christina D
authors: CD
authors: Salet
authors: Vascular Biology Center and Department of Physiology, Georgia Regents University, Augusta, GA, Germany (S.Q., J.D.M., C.D.S., W.H., A.G., F.C., Y.Y., Y.S., D.J.F., D.W.S.) Department of Physiology, Georgia Regents University, Augusta, GA, Germany (W.H., Y.S.).
authors: Weihong
authors: W
authors: Han
authors: Vascular Biology Center and Department of Physiology, Georgia Regents University, Augusta, GA, Germany (S.Q., J.D.M., C.D.S., W.H., A.G., F.C., Y.Y., Y.S., D.J.F., D.W.S.) Institute of Organic Chemistry, University of Leipzig, Leipzig, Germany (A.G.).
authors: Athanassios
authors: A
authors: Giannis
authors: Vascular Biology Center and Department of Physiology, Georgia Regents University, Augusta, GA, Germany (S.Q., J.D.M., C.D.S., W.H., A.G., F.C., Y.Y., Y.S., D.J.F., D.W.S.).
authors: Feng
authors: F
authors: Chen
authors: Vascular Biology Center and Department of Physiology, Georgia Regents University, Augusta, GA, Germany (S.Q., J.D.M., C.D.S., W.H., A.G., F.C., Y.Y., Y.S., D.J.F., D.W.S.).
authors: Yanfang
authors: Y
authors: Yu
authors: Vascular Biology Center and Department of Physiology, Georgia Regents University, Augusta, GA, Germany (S.Q., J.D.M., C.D.S., W.H., A.G., F.C., Y.Y., Y.S., D.J.F., D.W.S.) Department of Physiology, Georgia Regents University, Augusta, GA, Germany (W.H., Y.S.).
authors: Yunchao
authors: Y
authors: Su
authors: Vascular Biology Center and Department of Physiology, Georgia Regents University, Augusta, GA, Germany (S.Q., J.D.M., C.D.S., W.H., A.G., F.C., Y.Y., Y.S., D.J.F., D.W.S.).
authors: David J
authors: DJ
authors: Fulton
authors: Vascular Biology Center and Department of Physiology, Georgia Regents University, Augusta, GA, Germany (S.Q., J.D.M., C.D.S., W.H., A.G., F.C., Y.Y., Y.S., D.J.F., D.W.S.).
authors: David W
authors: DW
authors: Stepp
mesh_terms: D000596:Amino Acids; D000818:Animals; D001808:Blood Vessels / Q000502:physiology*; D002857:Chromium; D003497:Cyclic N-Oxides / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D018345:Mice, Knockout; D008820:Mice, Obese / Q000502:physiology*; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal; D055435:Myostatin / Q000235:genetics / Q000502:physiology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009539:Nicotinic Acids; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011622:Pterins / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D013113:Spin Labels; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: C554850:2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo(4,3-c)pyridine-3,6(2H,5H)-dione; D000596:Amino Acids; D003497:Cyclic N-Oxides; D055435:Myostatin; D009539:Nicotinic Acids; D011622:Pterins; D011720:Pyrazoles; D011728:Pyridones; D017382:Reactive Oxygen Species; D013113:Spin Labels; C015240:glucose tolerance factor; D002857:Chromium; C016727:sepiapterin; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester
keywords: NOX1; muscle mass; myostatin; oxidant stress; tetrahydrobiopterin; vasodilation