Metabolic responses of canine gracilis muscle during contraction with partial ischemia

Abstract

The metabolic effects of partial ischemia on canine skeletal muscle were examined during 20 min of isometric contraction. A reduction in blood flow of approximately 75% resulted in an approximate 40% reduction in contractile function. Muscle lactate accumulation and phosphocreatine (PCr) hydrolysis were greater during ischemia, indicating a greater reliance on anaerobic ATP regeneration. Pyruvate dehydrogenase transformation to its active form (PDCa) during contraction was not affected by ischemia, such that PDCa did not appear to be a determinant of skeletal muscle fatigue. Acetylcarnitine concentration was greater during ischemic contraction and inversely correlated with PCr concentration (r = -0.79, P<0.01). Furthermore, acetylcarnitine accumulation and PCr degradation correlated with the degree of skeletal muscle fatigue (r = 0.56, P<0.05 and r = 0.70, P<0.01, respectively). Thus the greater the acetyl group oxidation, the lesser the contribution from anaerobic ATP provision and, subsequently, the smaller the degree of muscle fatigue observed. The metabolic characteristics of this model of ischemic muscle contraction are indistinguishable from the normal metabolic responses observed with increasing contractile intensity.

Acetyl-CoA provision and the acetyl group deficit at the onset of contraction in ischemic canine skeletal muscle

“…A recent series of studies by our group has demonstrated the existence of metabolic inertia at the onset of contraction (27,28,(33)(34)(35)(36). On the basis of evidence from these studies, we believe that the delay in acetyl-CoA provision at the onset of exercise, which we have termed the "acetyl group deficit" (27), is a principal determinant of the oxygen deficit (27,33,34).…”

“…We have demonstrated that pretreatment of canine skeletal muscle with sodium dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase (32), near maximally activated the PDC and acetylated muscular carnitine and free CoASH pools at rest (27,34,35,36). During subsequent submaximal ischemic contraction (blood flow and, hence, oxygen availability held at its resting state), dichloroacetate overcame the acetyl group deficit, reduced ATP resynthesis from oxygen-independent routes, and improved the maintenance of contractile function over the course of contraction compared with control (27,34,35,36).…”

“…Classically, the lag in oxidative ATP production and resulting oxygen deficit have been attributed to a lag in muscle blood flow and thereby muscle oxygen delivery, which also follows an approximately exponential time course (21, 30). However, more recently it has been proposed that oxygen availability may not be the sole determinant of the oxygen deficit, at least at submaximal exercise workloads (11,29), such that the delay in mitochondrial energy production must be attributable, at least in part, to a lag in enzyme activation and/or substrate delivery (metabolic inertia) within energy-producing pathways on the initiation of muscular contraction (10,12,18,37).A recent series of studies by our group has demonstrated the existence of metabolic inertia at the onset of contraction (27,28,(33)(34)(35)(36). On the basis of evidence from these studies, we believe that the delay in acetyl-CoA provision at the onset of exercise, which we have termed the "acetyl group deficit" (27), is a principal determinant of the oxygen deficit (27,33,34).…”

Bioenergetics of contracting skeletal muscle after partial reduction of blood flow

“…Timmons et al (28,30) have recently demonstrated that activating the PDC before the initiation of an ischemic contractile period resulted in less depletion of muscle PCr and ATP, lower lactate accumulation, and enhanced subsequent force production compared with the control ischemic situation with no PDC activation. This indicates that when partial ischemia was imposed on contracting muscle at the onset of contractions, substrate availability for oxidative phosphorylation was inadequate and the reduced O 2 availability was not the only factor determining subsequent muscle performance.…”

“…Timmons et al (28)(29)(30) recently demonstrated that substrate availability through the pyruvate dehydrogenase complex (PDC) for carbohydrate oxidation in the tricarboxylic cycle can affect subsequent muscle performance during moderate ischemia. These investigators (30) demonstrated that having the PDC enzyme fully activated at the onset of an ischemic contractile period resulted in significantly less PCr hydrolysis and lactate accumulation and subsequently less fatigue compared with the same ischemic blood flow reduction with PDC starting from the normal resting deactivated state.…”