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|120||PGC-1alpha 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 JF; Pilegaard H
Am J Physiol Regul Integr Comp Physiol 2010; 299(5): R1350-9
PubMed ID: 20720174
The aim of this study was to test whether the transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)1alpha regulates the content of pyruvate dehydrogenase (PDH)-E1alpha and influences PDH activity through regulation of pyruvate dehydrogenase kinase-4 (PDK4) expression and subsequently PDH phosphorylation. PGC-1alpha whole body knockout (KO), muscle-specific PGC-1alpha overexpressing mice (MCK PGC-1alpha), 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-E1alpha protein content and PDH-E1alpha phosphorylation were lower in PGC-1alpha KO and higher in MCK PGC-1alpha mice at rest, but, while MCK PGC-1alpha had higher PDK4 protein content, KO of PGC-1alpha had no effect on PDK4 protein content. The differences in phosphorylation partly vanished when expressing phosphorylation relative to the PDH-E1alpha content with only a maintained elevated phosphorylation in MCK PGC-1alpha mice. Fasting upregulated PDK4 protein in PGC-1alpha KO, MCK PGC-1alpha and WT mice, but this was not consistently associated with increased PDH-E1alpha phosphorylation. Downregulation of the activity of PDH in the active form (PDHa) at 6-h recovery from exercise in both the PGC-1alpha KO and MCK PGC-1alpha mice and the association between PDH-E1alpha phosphorylation and PDHa activity in PGC-1alpha KO mice indicate that PGC-1alpha is not required for these responses. In conclusion, PGC-1alpha regulates PDH-E1alpha 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.