SUBSTRATE AVAILABILITY LIMITS HUMAN SKELETAL-MUSCLE OXIDATIVE ATP REGENERATION AT THE ONSET OF ISCHEMIC EXERCISE

We have demonstrated previously that dichloroacetate can attenuate ske letal muscle fatigue by up to 35% in a canine model of peripheral isch emia (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 c haracterized the metabolic effects of dichloroacetate in a human model of peripheral muscle ischemia, On two separate occasions (control-sal ine or dichloroacetate infusion), nine subjects performed 8 min of sin gle-leg knee extension exercise at an intensity aimed at achieving vol itional exhaustion in similar to 8 min, During exercise each subject's lower limbs were exposed to 50 mmHg of positive pressure, which reduc es blood flow by similar to 20%, Dichloroacetate increased resting mus cle pyruvate dehydrogenase complex activation status by threefold and elevated acetylcarnitine concentration by fivefold, After 3 min of exe rcise, phosphocreatine degradation and lactate accumulation were both reduced by similar to 50% after dichloroacetate pretreatment, when com pared with control conditions, However, after 8 min of exercise no dif ferences existed between treatments. Therefore, it would appear that d ichloroacetate can delay the accumulation of metabolites which lead to the development of skeletal muscle fatigue during ischemia but does n ot alter the metabolic profile when a maximal effort is approached.