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School of Biomedical Sciences, University Medical School, Queen's Medical Center, Nottingham NG7 2UH, United Kingdom
No studies have singularly investigated the
relationship between pyruvate availability, pyruvate dehydrogenase
complex (PDC) activation, and anaplerosis in skeletal muscle. This is
surprising given the functional importance attributed to these
processes in normal and disease states. We investigated the effects of
changing pyruvate availability with dichloroacetate (DCA), epinephrine, and pyruvate infusions on PDC activation and accumulation of acetyl groups and tricarboxylic acid (TCA) cycle intermediates (TCAI) in human
muscle. DCA increased resting PDC activity sixfold
(P < 0.05) but decreased the muscle
TCAI pool (mmol/kg dry muscle) from 1.174 ± 0.042 to 0.747 ± 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 DCA.
Conversely, neither epinephrine nor pyruvate activated PDC. However,
both 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 increased 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 TCA cycle expansion may be of little
functional significance to TCA cycle flux. It would appear therefore
that the primary effect of DCA on oxidative ATP 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 pool.
dichloroacetate; epinephrine; pyruvate dehydrogenase complex; acetylcarnitine
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