title: Increased acetyl group availability enhances contractile function of canine skeletal muscle during ischemia.
abstract: 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 resting metabolism, on canine gracilis muscle contractile function during constant flow ischemia. Pretreatment with dichloroacetate increased resting pyruvate dehydrogenase complex activity and resting acetylcarnitine concentration by approximately 4- and approximately 10-fold, respectively. After 20-min contraction the control group had demonstrated an approximately 40% reduction in isomeric tension whereas the dichloroacetate group had fatigued by approximately 25% (P < 0.05). Dichloroacetate resulted in less lactate accumulation (10.3 +/- 3.0 vs 58.9 +/- 10.5 mmol.kg-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. Acetylcarnitine concentration fell during contraction by 5.4 +/- 1.8 mmol.kg-1 dm in the dichloroacetate group but increased by 10.0 +/- 1.9 mmol.kg-1 dm in the control group. In conclusion, dichloroacetate enhanced contractile function during ischemia, independently of blood flow, such that it appears oxidative ATP regeneration is limited by pyruvate dehydrogenase complex activity and acetyl group availability.
authors.affiliation: Department of Physiology and Pharmacology, University Medical School, Queens Medical Center, Nottingham, United Kingdom.
authors.forename: J A
authors.initials: JA
authors.lastname: Timmons
authors.forename: S M
authors.initials: SM
authors.lastname: Poucher
authors.forename: D
authors.initials: D
authors.lastname: Constantin-Teodosiu
authors.forename: V
authors.initials: V
authors.lastname: Worrall
authors.forename: I A
authors.initials: IA
authors.lastname: Macdonald
authors.forename: P L
authors.initials: PL
authors.lastname: Greenhaff
mesh_terms: D000108:Acetylcarnitine / Q000032:analysis; D000255:Adenosine Triphosphate / Q000378:metabolism; D000332:Aerobiosis; D000693:Anaerobiosis; D000818:Animals; D050260:Carbohydrate Metabolism; D002331:Carnitine / Q000032:analysis; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004285:Dogs; D004558:Electric Stimulation; D004789:Enzyme Activation; D005260:Female; D066298:In Vitro Techniques; D007511:Ischemia / Q000378:metabolism*; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D009119:Muscle Contraction / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology; D016491:Peripheral Vascular Diseases / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000187:drug effects*
chemical_list: D007773:Lactates; D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D000108:Acetylcarnitine; D000255:Adenosine Triphosphate; D003999:Dichloroacetic Acid; D002331:Carnitine