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Am J Physiol Cell Physiol 292: C729-C739, 2007. First published October 18, 2006; doi:10.1152/ajpcell.00311.2006
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SPECIAL SECTION ON MITOCHONDRIAL MODELING AND FUNCTION

Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism

¹Departments of Nutritional Sciences and Internal Medicine, University of Missouri and Division of Research, Harry S. Truman VA Hospital, Columbia, Missouri; ²Metabolism Unit, Shriner's Burns Institute and Department of Surgery, University of Texas Medical Branch, Galveston, Texas; ³Department of Physiology, Brody School of Medicine, East Carolina University, Greenville; and ⁴Departments of Medicine and Pharmacology and Cancer Biology, and Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina

Submitted 5 June 2006 ; accepted in final form 11 October 2006

Acute exercise can reverse muscle insulin resistance, but the mechanism(s) of action are unknown. With the use of a hindlimb perfusion model, we have found that acute contraction restores insulin-stimulated glucose uptake in muscle of obese Zucker rats to levels witnessed in lean controls. Previous reports have suggested that obesity-related insulin resistance stems from lipid oversupply and tissue accumulation of toxic lipid intermediates that impair insulin signaling. We reasoned that contraction might activate hydrolysis and oxidation of intramuscular lipids, thus alleviating "lipotoxicity" and priming the muscle for enhanced insulin action. Indeed, analysis of mitochondrial-derived acyl-carnitine esters suggested that contraction caused robust increases in -oxidative flux and mitochondrial oxidation. As predicted, contraction decreased intramuscular triacylglycerol content; however, diacylglycerol and long chain acyl-CoAs, lipid intermediates presumed to trigger insulin resistance, were either unchanged or increased. In muscles from obese animals, insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 remained impaired after contraction, whereas phosphorylation of the downstream signaling protein, AS160, was partially restored. These results suggest that acute exercise enables diabetic muscle to circumvent upstream defects in insulin signal transduction via mechanisms that are more tightly coupled to increased mitochondrial energy metabolism than the lowering of diacylglycerol and long chain acyl-CoA.

skeletal muscle; intramuscular lipids; signaling; exercise

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