Metabolic responses from rest to steady state determine contractile function in ischemic skeletal muscle

Abstract

Skeletal muscle contraction during ischemia, such as that experienced by peripheral vascular disease patients, is characterized by rapid fatigue. Using a canine gracilis model, we tested the hypothesis that a critical factor determining force production during ischemia is the metabolic response during the transition from rest to steady state. Dichloroacetate (DCA) administration before gracilis muscle contraction increased pyruvate dehydrogenase complex activation and resulted in acetylation of 80% of the free carnitine pool to acetylcarnitine. After 1 min of contraction, phosphocreatine (PCr) degradation in the DCA group was approximately 50% lower than in the control group (P < 0.05) during conditions of identical force production. After 6 min of contraction, steady-state force production was approximately 30% higher in the DCA group (P < 0.05), and muscle ATP, PCr, and glycogen degradation and lactate accumulation were lower (P < 0.05 in all cases). It appears, therefore, that an important determinant of contractile function during ischemia is the mechanisms by which ATP regeneration occurs during the period of rest to steady-state transition.

Carbohydrate ingestion prior to exercise augments the exercise-induced activation of the pyruvate dehydrogenase complex in human skeletal muscle

“…At the onset of exercise there is a delay in the activation of PDC and formation of acetyl-CoA which appears to be associated with an increase in the contribution of substrate level phosphorylation to energy metabolism (Timmons et al 1997;Howlett et al 1999). When this delay in PDC activation was circumvented by maximally activating PDC using dichloroacetate (DCA) prior to contraction (Timmons et al 1997(Timmons et al , 1998Howlett et al 1999), a reduction in muscle PCr hydrolysis and lactate formation was observed within the first few minutes of exercise. This finding is in contrast with the 584 Figure 2 Muscle PDC activity and acetylcarnitine concentrations at rest and after 10 min of exercise in the CON and CHO trials.…”

“…Classically, the extent of this anaerobic ATP production through substrate level phosphorylation at the onset of exercise has been attributed to a lag in blood flow and oxygen delivery to the contracting muscle (Margaria et al 1963). More recently, however, it has been demonstrated that the activity of PDC and the availability of acetyl groups to the tricarboxylic acid (TCA) cycle are important determinants of the metabolic responses during the onset of exercise (Timmons et al 1997(Timmons et al , 1998. The PDC controls the rate-limiting step in CHO oxidation, the oxidative decarboxylation of pyruvate to acetyl-CoA.…”

“…When the rate of acetyl-CoA formation by the PDC exceeds its rate of oxidation by the TCA cycle, the excess acetyl-CoA is buffered by carnitine, resulting in the formation of acetylcarnitine (Constantin-Teodosiu et al 1992). However, at the onset of exercise there is a delay in the activation of PDC and provision of acetyl groups to the TCA cycle which seems to be responsible for the increased contribution of substrate level phosphorylation to energy metabolism (Timmons et al 1997;Howlett et al 1999). Both hyperglycaemia and hyperinsulinaemia increase the activity of PDC in resting human skeletal muscle (Mandarino et al 1987(Mandarino et al , 1993.…”

The Experimental Type 2 Diabetes Therapy Glycogen Phosphorylase Inhibition Can Impair Aerobic Muscle Function During Prolonged Contraction

“…Following 60 min of pretreatment with GPi or vehicle, electrically evoked submaximal isometric muscle contractions were induced (1 Hz, 0.3 ms, 2 V) for 60 min according to methods previously described (20,45), and tension development was recorded. At the start of contraction, muscle blood flow was increased twofold from the resting rate (15 ml ⅐ min Ϫ1 ⅐ 100 g muscle tissue Ϫ1 ) to improve oxygen and substrate delivery.…”

Carnitine and Fat Oxidation

“…Whether these improvements in endurance performance are due to glycogen sparing as a result of a carnitine mediated increase in fat oxidation, or the reported effect of carnitine on glucose disposal requires further investigation, but due to the nature of the time trial this seems unlikely. In fact, it is the reduced reliance on non-oxidative ATP production from carbohydrate oxidation (increase acetyl group buffering and reduced lactate accumulation) that is the more likely cause of the increased endurance performance observed [33]. Moreover, with the acetyl-group buffering role of carnitine in mind, increasing muscle carnitine content may also allow a greater stockpiling of acetylcarnitine during a prior 'warm-up' exercise, which would then serve as a useful immediate supply of acetyl groups at the onset of a subsequent high-intensity performance task and again reduce the reliance on non-oxidative ATP production [34].…”