Pyruvate suppresses PGC1α expression and substrate utilization despite increased respiratory chain content in C2C12 myotubes

Philp A, Perez-Schindler J, Green C, Hamilton DL, Baar K. Pyruvate suppresses PGC1 alpha expression and substrate utilization despite increased respiratory chain content in C2C12 myotubes. Am J Physiol Cell Physiol 299: C240-C250, 2010. First published April 21, 2010; doi: 10.1152/ajpcell.00438.2009.-Sodium pyruvate can increase mitochondrial biogenesis in C2C12 myoblasts in a peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1 alpha)-independent manner. The present study examined the effect of 72-h treatment with sodium pyruvate (5-50 mM) or sodium chloride (50 mM) as an osmotic control on the regulation of mitochondrial substrate metabolism and biogenesis in C2C12 myotubes. Pyruvate (50 mM) increased the levels of fatty acid oxidation enzymes (CD36, 61%, and beta-oxidative enzyme 3-hydroxyacyl-CoA dehydrogenase, 54%) and the expression of cytochrome-c oxidase subunit I (220%) and cytochrome c (228%), consistent with its previous described role as a promoter of mitochondrial biogenesis. However, in contrast, pyruvate treatment reduced glucose transporter 4 (42%), phosphofructokinase (57%), and PGC1 alpha (72%) protein content as well as PGC1 alpha (48%) and PGC1 beta (122%) mRNA. The decrease in PGC1 alpha was compensated for by an increase in the PGC1 alpha-related coactivator (PRC; 187%). Pyruvate treatment reduced basal and insulin-stimulated glucose uptake (41% and 31%, respectively) and palmitate uptake and oxidation (24% and 31%, respectively). The addition of the pyruvate dehydrogenase activator dichloroacetate (DCA) and the TCA precursor glutamine increased PGC1 alpha expression (368%) and returned PRC expression to basal. Glucose uptake increased by 4.2-fold with DCA and glutamine and palmitate uptake increased by 18%. Coupled to this adaptation was an 80% increase in oxygen consumption. The data suggest that supraphysiological doses of pyruvate decrease mitochondrial function despite limited biogenesis and that anaplerotic agents can reverse this effect.