title: Exercise performance and peripheral vascular insufficiency improve with AMPK activation in high-fat diet-fed mice.
abstract: Intermittent claudication is a form of exercise intolerance characterized by muscle pain during walking in patients with peripheral artery disease (PAD). Endothelial cell and muscle dysfunction are thought to be important contributors to the etiology of this disease, but a lack of preclinical models that incorporate these elements and measure exercise performance as a primary end point has slowed progress in finding new treatment options for these patients. We sought to develop an animal model of peripheral vascular insufficiency in which microvascular dysfunction and exercise intolerance were defining features. We further set out to determine if pharmacological activation of 5'-AMP-activated protein kinase (AMPK) might counteract any of these functional deficits. Mice aged on a high-fat diet demonstrate many functional and molecular characteristics of PAD, including the sequential development of peripheral vascular insufficiency, increased muscle fatigability, and progressive exercise intolerance. These changes occur gradually and are associated with alterations in nitric oxide bioavailability. Treatment of animals with an AMPK activator, R118, increased voluntary wheel running activity, decreased muscle fatigability, and prevented the progressive decrease in treadmill exercise capacity. These functional performance benefits were accompanied by improved mitochondrial function, the normalization of perfusion in exercising muscle, increased nitric oxide bioavailability, and decreased circulating levels of the endogenous endothelial nitric oxide synthase inhibitor asymmetric dimethylarginine. These data suggest that aged, obese mice represent a novel model for studying exercise intolerance associated with peripheral vascular insufficiency, and pharmacological activation of AMPK may be a suitable treatment for intermittent claudication associated with PAD.
authors.affiliation: Rigel Pharmaceuticals Incorporated, South San Francisco, California.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Baltgalvis
authors.forename: Kathy
authors.initials: K
authors.lastname: White
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Mark D
authors.initials: MD
authors.lastname: Claypool
authors.forename: Wayne
authors.initials: W
authors.lastname: Lang
authors.forename: Raniel
authors.initials: R
authors.lastname: Alcantara
authors.forename: Baljit K
authors.initials: BK
authors.lastname: Singh
authors.forename: Annabelle M
authors.initials: AM
authors.lastname: Friera
authors.forename: John
authors.initials: J
authors.lastname: McLaughlin
authors.forename: Derek
authors.initials: D
authors.lastname: Hansen
authors.forename: Kelly
authors.initials: K
authors.lastname: McCaughey
authors.forename: Henry
authors.initials: H
authors.lastname: Nguyen
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Smith
authors.forename: Guillermo
authors.initials: G
authors.lastname: Godinez
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Shaw
authors.forename: Dane
authors.initials: D
authors.lastname: Goff
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.forename: Vadim
authors.initials: V
authors.lastname: Markovtsov
authors.forename: Tian-Qiang
authors.initials: TQ
authors.lastname: Sun
authors.forename: Yonchu
authors.initials: Y
authors.lastname: Jenkins
authors.forename: Gerald
authors.initials: G
authors.lastname: Uy
authors.forename: Yingwu
authors.initials: Y
authors.lastname: Li
authors.forename: Alison
authors.initials: A
authors.lastname: Pan
authors.forename: Tarikere
authors.initials: T
authors.lastname: Gururaja
authors.forename: David
authors.initials: D
authors.lastname: Lau
authors.forename: Gary
authors.initials: G
authors.lastname: Park
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Hitoshi
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.forename: Todd M
authors.initials: TM
authors.lastname: Kinsella
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000375:Aging; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D000077407:Cilostazol; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000008:administration & dosage*; D006801:Humans; D007383:Intermittent Claudication / Q000150:complications / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018763:Muscle Fatigue / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000150:complications*; D016491:Peripheral Vascular Diseases / Q000209:etiology / Q000503:physiopathology*; D058987:Phosphodiesterase 3 Inhibitors / Q000008:administration & dosage; D005082:Physical Exertion / Q000502:physiology*; D013777:Tetrazoles / Q000008:administration & dosage; D014665:Vasodilator Agents
chemical_list: D001057:Apolipoproteins E; D020536:Enzyme Activators; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D014665:Vasodilator Agents; C487735:dimethylarginine; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases; D000077407:Cilostazol
keywords: 5′-AMP-activated protein kinase; exercise; intermittent claudication; nitric oxide; obesity