PGC-1α increases PDH content but does not change acute PDH regulation in mouse skeletal muscle

Kiilerich K, Adser H, Jakobsen AH, Pedersen PA, Hardie DG, Wojtaszewski JFP, Pilegaard H. PGC-1 alpha increases PDH content but does not change acute PDH regulation in mouse skeletal muscle. Am J Physiol Regul Integr Comp Physiol 299: R1350-R1359, 2010. First published August 18, 2010; doi:10.1152/ajpregu.00400.2010.- The aim of this study was to test whether the transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)1 alpha regulates the content of pyruvate dehydrogenase (PDH)-E1 alpha and influences PDH activity through regulation of pyruvate dehydrogenase kinase-4 (PDK4) expression and subsequently PDH phosphorylation. PGC-1 alpha whole body knockout (KO), muscle-specific PGC-1 alpha overexpressing mice (MCK PGC-1 alpha), and littermate wild-type (WT) mice underwent two interventions known to affect PDH. Quadriceps muscles were removed from fed and 24-h fasted mice as well as at 6 h of recovery after 1-h running and from mice that did not run acutely. PDH-E1 alpha protein content and PDH-E1 alpha phosphorylation were lower in PGC-1 alpha KO and higher in MCK PGC-1 alpha mice at rest, but, while MCK PGC-1 alpha had higher PDK4 protein content, KO of PGC-1 alpha had no effect on PDK4 protein content. The differences in phosphorylation partly vanished when expressing phosphorylation relative to the PDH-E1 alpha content with only a maintained elevated phosphorylation in MCK PGC-1 alpha mice. Fasting upregulated PDK4 protein in PGC-1 alpha KO, MCK PGC-1 alpha and WT mice, but this was not consistently associated with increased PDH-E1 alpha phosphorylation. Downregulation of the activity of PDH in the active form (PDHa) at 6-h recovery from exercise in both the PGC-1 alpha KO and MCK PGC-1 alpha mice and the association between PDH-E1 alpha phosphorylation and PDHa activity in PGC-1 alpha KO mice indicate that PGC-1 alpha is not required for these responses. In conclusion, PGC-1 alpha regulates PDH-E1 alpha protein content in parallel with mitochondrial oxidative proteins, but does not seem to influence PDH regulation in mouse skeletal muscle in response to fasting and in recovery from exercise.