Abstract
During aerobic exercise (>65% of VO2max) the primary source of acetyl-CoA to fuel oxidative ATP synthesis in muscle is the pyruvate dehydrogenase (PDH) reaction. This study investigated how regulation of PDH activity affects muscle energetics by determining whether activation of PDH with dichloroacetate (DCA) alters the dynamics of the phosphate potential of rat gastrocnemius muscle during contraction. Twitch contractions were induced in vivo over a broad range of intensities to sample submaximal and maximal aerobic workloads. Muscle phosphorus metabolites were measured in vivo before and after DCA treatment using phosphorus nuclear magnetic resonance spectroscopy. At rest, DCA increased PDH activation compared to control (90±12 vs 23±3%, p<0.05) with parallel decreases in inorganic phosphate (Pi) of 17% (1.4±0.2 vs 1.7±0.1 mM, p<0.05) and an increase in the free energy of ATP hydrolysis (ΔGATP) (-66.2±0.3 vs -65.6±0.2 kJ/mol, p<0.05). During stimulation DCA increased steady state phosphocreatine (PCr) and ΔGATP with concomitant reduction in Pi and ADP concentrations. These effects were not due to kinetic alterations in PCr hydrolysis, resynthesis, or glycolytic ATP production and altered the flow force relationship between mitochondrial ATP synthesis rate (JMITO) and ΔGATP. DCA had no significant effect at 1.0-2.0 Hz stimulation, because physiological mechanisms at these high stimulation levels cause maximal activation of PDH. These data support a role of PDH activation in the regulation of the energetic steady state by altering the thermodynamic set point of the phosphate potential (ΔGATP) at rest and during contraction and do not support kinetic limitations to mitochondria as previously suggested.