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Substrate availability limits human skeletal muscle oxidative ATP regeneration at the onset of ischemic exercise.

Abstract
We have demonstrated previously that dichloroacetate can attenuate skeletal muscle fatigue by up to 35% in a canine model of peripheral ischemia (Timmons, J.A., S.M. Poucher, D. Constantin-Teodosiu, V. Worrall, I.A. Macdonald, and P.L. Greenhaff. 1996. J. Clin. Invest. 97:879-883). This was thought to be a consequence of dichloroacetate increasing acetyl group availability early during contraction. In this study we characterized the metabolic effects of dichloroacetate in a human model of peripheral muscle ischemia. On two separate occasions (control-saline or dichloroacetate infusion), nine subjects performed 8 min of single-leg knee extension exercise at an intensity aimed at achieving volitional exhaustion in approximately 8 min. During exercise each subject's lower limbs were exposed to 50 mmHg of positive pressure, which reduces blood flow by approximately 20%. Dichloroacetate increased resting muscle pyruvate dehydrogenase complex activation status by threefold and elevated acetylcarnitine concentration by fivefold. After 3 min of exercise, phosphocreatine degradation and lactate accumulation were both reduced by approximately 50% after dichloroacetate pretreatment, when compared with control conditions. However, after 8 min of exercise no differences existed between treatments. Therefore, it would appear that dichloroacetate can delay the accumulation of metabolites which lead to the development of skeletal muscle fatigue during ischemia but does not alter the metabolic profile when a maximal effort is approached.
AuthorsJ A Timmons, T Gustafsson, C J Sundberg, E Jansson, E Hultman, L Kaijser, J Chwalbinska-Moneta, D Constantin-Teodosiu, I A Macdonald, P L Greenhaff
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 101 Issue 1 Pg. 79-85 (Jan 01 1998) ISSN: 0021-9738 [Print] United States
PMID9421469 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Blood Glucose
  • Pyruvate Dehydrogenase Complex
  • Phosphocreatine
  • Lactic Acid
  • Acetylcarnitine
  • Adenosine Triphosphate
  • Glycogen
  • Dichloroacetic Acid
Topics
  • Acetylcarnitine (metabolism)
  • Adenosine Triphosphate (metabolism)
  • Adult
  • Blood Glucose (metabolism)
  • Cardiovascular Physiological Phenomena
  • Dichloroacetic Acid (pharmacology)
  • Exercise (physiology)
  • Glycogen (metabolism)
  • Humans
  • Lactic Acid (metabolism)
  • Male
  • Muscle, Skeletal (blood supply, drug effects, metabolism)
  • Phosphocreatine (metabolism)
  • Pyruvate Dehydrogenase Complex (metabolism)
  • Time Factors

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