Pyruvate suppresses PGC1 alpha expression and substrate utilization despite increased respiratory chain content in C2C12 myotubes

Citation

Philp A, Perez-Schindler J, Green C, Hamilton DL & Baar K (2010) Pyruvate suppresses PGC1 alpha expression and substrate utilization despite increased respiratory chain content in C2C12 myotubes. American Journal of Physiology - Cell Physiology, 299 (2), pp. C240-C250. https://doi.org/10.1152/ajpcell.00438.2009

Abstract
Sodium pyruvate can increase mitochondrial biogenesis in C2C12 myoblasts in a peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α)-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 β-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 PGC1α (72%) protein content as well as PGC1α (48%) and PGC1β (122%) mRNA. The decrease in PGC1α was compensated for by an increase in the PGC1α-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 PGC1α 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.

Keywords
glutamine; glucose metabolism; Type 2 diabetes; peroxisome proliferator-activated receptor-gamma coactivator-1 alpha; Diabetes Mellitus, Type 2 therapy; Evidence-Based Medicine

Journal
American Journal of Physiology - Cell Physiology: Volume 299, Issue 2