PGC-1alpha increases PDH content but does not change acute PDH regulation in mouse skeletal muscle.
The aim of this study was to test whether the transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)1α regulates the content of pyruvate dehydrogenase (PDH)-E1α and influences PDH activity through regulation of pyruvate dehydrogenase kinase-4 (PDK4) expression and subsequently PDH phosphorylation. PGC-1α whole body knockout (KO), muscle-specific PGC-1α overexpressing mice (MCK PGC-1α), 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-E1α protein content and PDH-E1α phosphorylation were lower in PGC-1α KO and higher in MCK PGC-1α mice at rest, but, while MCK PGC-1α had higher PDK4 protein content, KO of PGC-1α had no effect on PDK4 protein content. The differences in phosphorylation partly vanished when expressing phosphorylation relative to the PDH-E1α content with only a maintained elevated phosphorylation in MCK PGC-1α mice. Fasting upregulated PDK4 protein in PGC-1α KO, MCK PGC-1α and WT mice, but this was not consistently associated with increased PDH-E1α phosphorylation. Downregulation of the activity of PDH in the active form (PDHa) at 6-h recovery from exercise in both the PGC-1α KO and MCK PGC-1α mice and the association between PDH-E1α phosphorylation and PDHa activity in PGC-1α KO mice indicate that PGC-1α is not required for these responses. In conclusion, PGC-1α regulates PDH-E1α 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.
Kiilerich
Kristian
K
Centre of Inflammation and Metabolism, August Krogh Bldg., Dept. of Biology, Universitetsparken 13, 2100 Copenhagen, Denmark. kkiilerich@bio.ku.dk
Adser
Helle
H
Jakobsen
Anne H
AH
Pedersen
Per A
PA
Hardie
D Grahame
DG
Wojtaszewski
Jorgen F P
JF
Pilegaard
Henriette
H
D000818:Animals; D004435:Eating; D005215:Fasting; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006003:Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009119:Muscle Contraction; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism; D052097:Quadriceps Muscle / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D020127:Recovery of Function; D013997:Time Factors; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015854:Up-Regulation
D024101:Mitochondrial Proteins; C000631439:Pdk4 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D006003:Glycogen; D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit; D017346:Protein Serine-Threonine Kinases