Exercise performance and peripheral vascular insufficiency improve with AMPK activation in high-fat diet-fed mice.
Am J Physiol Heart Circ Physiol
; 306(8): H1128-45, 2014 Apr 15.
Article
en En
| MEDLINE
| ID: mdl-24561866
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Enfermedades Vasculares Periféricas
/
Activadores de Enzimas
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Esfuerzo Físico
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Proteínas Quinasas Activadas por AMP
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Dieta Alta en Grasa
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Obesidad
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
Am J Physiol Heart Circ Physiol
Asunto de la revista:
CARDIOLOGIA
/
FISIOLOGIA
Año:
2014
Tipo del documento:
Article