INCREASED ACETYL GROUP AVAILABILITY ENHANCES CONTRACTILE FUNCTION OF CANINE SKELETAL-MUSCLE DURING ISCHEMIA

Skeletal muscle contractile function is impaired during acute ischemia such as that experienced by peripheral vascular disease patients. We therefore, examined the effects of dichloroacetate, which can alter re sting metabolism, on canine gracilis muscle contractile function durin g constant flow ischemia. Pretreatment with dichloroacetate increased resting pyruvate dehydrogenase complex activity and resting acetylcarn itine concentration by similar to 4- and similar to 10-fold, respectiv ely. After 20-min contraction the control group had demonstrated an si milar to 40% reduction in isometric tension whereas the dichloroacetat e group had fatigued by similar to 25% (P < 0.05). Dichloroacetate res ulted in less lactate accumulation (10.3+/-3.0 vs 58.9+/-10.5 mmol . k g(-1) dry muscle [dm], P < 0.05) and phosphocreatine hydrolysis (15.6/-6.3 vs 33.8+/-9.0 mmol . kg(-1) dm, P < 0.05) during contraction. Ac etylcarnitine concentration fell during contraction by 5.4+/-1.8 mmol . kg(-1) dm in the dichloroacetate group but increased by 10.0+/-1.9 m mol . kg(-1) dm in the control group. In conclusion, dichloroacetate e nhanced contractile function during ischemia, independently of blood f low, such that it appears oxidative ATP regeneration is limited by pyr uvate dehydrogenase complex activity and acetyl group availability.