The importance of pyruvate availability to PDC activation and anaplerosis in human skeletal muscle

No studies have singularly investigated the relationship between pyruvate a vailability, pyruvate dehydrogenase complex (PDC) activation, and anapleros is in skeletal muscle. This is surprising given the functional importance a ttributed to these processes in normal and disease states. We investigated the effects of changing pyruvate availability with dichloroacetate (DCA), e pinephrine, and pyruvate infusions on PDC activation and accumulation of ac etyl groups and tricarboxylic acid (TCA) cycle intermediates (TCAI) in huma n muscle. DCA increased resting PDC activity sixfold (P< 0.05) but decrease d the muscle TCAI pool (mmol/kg dry muscle) from 1.174 +/- 0.042 to 0.741 /- 0.055 (P < 0.05). This was probably a result of pyruvate being diverted to acetyl-CoA and acetylcarnitine after near-maximal activation of PDC by D CA. Conversely, neither epinephrine nor pyruvate activated PDC. However, bo th increased the TCAI pool(1.128 +/- 0.076 to 1.614 +/- 0.188, P < 0.05 and 1.098 +/- 0.059 to 1.385 +/- 0.114, P < 0.05, respectively) by providing a readily available pool of pyruvate for anaplerosis. These data support the hypothesis that TCAI pool expansion is principally a reflection of increas ed muscle pyruvate availability and, together with our previous work (J. A Timmons, S. M. Poucher, D. Constantin-Teodosiu, V. Worrall, I. A. Macdonald , and P L. Greenhaff. J. Clin. Invest. 97: 879-883, 1996), indicate that TC A cycle expansion may be of little functional significance to TCA cycle flu x. lt would appear therefore that the primary effect of DCA on oxidative AT P provision is to provide a readily available pool of acetyl groups to the TCA cycle at-the onset of exercise rather than increasing TCA cycle flux by expanding the TCAI peal.