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

Abstract

-We examined the effects of increasing acetylcarnitine and acetyl-CoA availability at rest, independent of pyruvate dehydrogenase complex (PDC) activation, on energy production and tension development during the rest-to-work transition in canine skeletal muscle. We aimed to elucidate whether the lag in PDC-derived acetyl-CoA delivery toward the TCA cycle at the onset of exercise can be overcome by increasing acetyl group availability independently of PDC activation or is intimately dependent on PDCderived acetyl-CoA. Gracilis muscle pretreated with saline or sodium acetate (360 mg/kg body mass) (both n ϭ 6) was sampled repeatedly during 5 min of ischemic contraction. Acetate increased acetylcarnitine and acetyl-CoA availability (both P Ͻ 0.01) above control at rest and throughout contraction (P Ͻ 0.05), independently of differences in resting PDC activation between treatments. Acetate reduced oxygen-independent ATP resynthesis ϳ40% (P Ͻ 0.05) during the first minute of contraction. No difference in oxygen-independent ATP resynthesis existed between treatments from 1 to 3 min of contraction; however, energy production via this route increased ϳ25% (P Ͻ 0.05) above control in the acetate-treated group during the final 2 min of contraction. Tension development was ϳ20% greater after 5-min contraction after acetate treatment than in control (P Ͻ 0.05). In conclusion, at the immediate onset of contraction, when PDC was largely inactive, increasing cellular acetyl group availability overcame inertia in mitochondrial ATP regeneration. However, after the first minute, when PDC was near maximally activated in both groups, it appears that PDC-derived acetyl-CoA, rather than increased cellular acetyl group availability per se, dictated mitochondrial ATP resynthesis.acetylcarnitine; oxygen deficit; oxidative phosphorylation; phosphocreatine; sodium acetate THE READJUSTMENT of oxidative (mitochondrial) ATP production to meet the increase in muscular energy demand during the transition from rest to exercise, or the step increase from one workload to another, is delayed and follows an approximately exponential time course (for review, see Ref. 37). During this period of latency, the transient shortfall in mitochondrial ATP production, classically termed the "oxygen deficit" (21, 30), is supplemented by ATP resynthesis from non-oxygen-dependent routes [i.e., ATP and phosphocreatine (PCr) breakdown and glycolysis]. Although ATP production from oxygen-independent routes enables rapid rates of ATP turnover to be achieved, it has only a finite capacity and also results in the accumulation of metabolic byproducts that are deleterious to muscular contractile function (hydrogen ions, lactate ions, and inorganic phosphate; see Ref. 8). Indeed, without the progressive increase in mitochondrial ATP production at the onset of contraction, the onset of muscular fatigue would be markedly accelerated. Classically, the lag in oxidative ATP production and resulting oxygen deficit have been attributed to a lag in muscle blood flow and thereby m...

In vivo enzymatic activity of acetylCoA synthetase in skeletal muscle revealed by 13C turnover from hyperpolarized [1-13C]acetate to [1-13C]acetylcarnitine

“…The tissue concentrations used in the present study (0.12-1.00 mM) were approximately an order of magnitude lower than those used to maximally acetylate free carnitine and CoA in canine skeletal muscle [15] and human skeletal muscle at rest [42][43][44]. This indicates that the observed acetylcarnitine formation was not hindered Acetate Acetylcarnitine Model Fit Fig.…”

“…In rat skeletal muscle, 98% to 99% of extra acetylCoA produced is buffered by acetylcarnitine [14]. Since the mitochondrial inner membrane is impermeable to acetylCoA, CAT is essential in the metabolism of acetate, as was shown in canine skeletal muscle [15]. After transformation to acetylcarnitine it traverses the inner mitochondrial membrane via acetylcarnitine translocase (ATL) where a mitochondrial CAT transfers the acetyl group back to CoASH upon which acetylCoA can enter the TCA cycle.…”

Linear relation between time constant of oxygen uptake kinetics, total creatine, and mitochondrial content in vitro

“…In addition, Kindig et al (31) reported much faster J o kinetics in isolated myocytes in the presence of a CK inhibitor. It is important to note, however, that elevating cellular TCr, via dietary Cr supplementation, failed to slow J o kinetics in exercising human muscle (29), as the Meyer model would predict.A different conceptual approach to what accounts for the sluggish cellular adjustment to ATP demand describes the response as "metabolic inertia" (18,22,26,50). In this view, a lag in the availability of oxidative substrate accounts for the delay in the matching of oxidative phosphorylation to ATP demand (22,26,50,55).…”

No acetyl group deficit is evident at the onset of exercise at 90% of maximal oxygen uptake in humans

“…The studies by Bangsbo et al (Bangsbo et al 2002), Rossiter et al (Rossiter et al 2003) and Jones et al (Jones et al 2004) failed to make concurrent measurement of both acetyl group availability and pyruvate dehydrogenase complex activation status before and during exercise. Accurate measures of both of these factors are necessary when evaluating the acetyl group deficit (Roberts et al 2002;Roberts, Loxham, Poucher, Constantin-Teodosiu, & Greenhaff, 2005). In addition, Savasi et al (Savasi et al 2002) and Jones et al (Jones et al 2004) utilised intermittent exercise protocols, which are likely to blunt the effects of dichloroacetate infusion, since prior exercise causes activation of the pyruvate dehydrogenase complex.…”