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

Feb 14, 1998The Journal of clinical investigation

Limited fuel reduces muscle energy production during the start of exercise with blocked blood flow

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Abstract

Dichloroacetate increased resting muscle pyruvate dehydrogenase complex activation status by threefold in a human model of peripheral muscle ischemia.

Dichloroacetate elevated acetylcarnitine concentration by fivefold during the study.
Phosphocreatine degradation and lactate accumulation were both reduced by approximately 50% after 3 minutes of exercise following dichloroacetate pretreatment.
No differences in metabolic profile were observed after 8 minutes of exercise between dichloroacetate and control conditions.
Dichloroacetate may delay the accumulation of metabolites that lead to skeletal muscle fatigue during ischemia.

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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.

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

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