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

TY - JOUR

T1 - PGC-1 alpha increases PDH content but does not change acute PDH regulation in mouse skeletal muscle

AU - Kiilerich, Kristian

AU - Adser, Helle

AU - Jakobsen, Anne H.

AU - Pedersen, Per A.

AU - Hardie, D. Grahame

AU - Wojtaszewski, Jorgen F. P.

AU - Pilegaard, Henriette

PY - 2010/11

Y1 - 2010/11

N2 - 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.

AB - 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.

KW - pyruvate dehydrogenase kinase

KW - PYRUVATE-DEHYDROGENASE COMPLEX

KW - TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA

KW - GENE-EXPRESSION

KW - METABOLIC GENES

KW - KINASE-ACTIVITY

KW - ISOFORM EXPRESSION

KW - ENERGY-METABOLISM

KW - CARBOHYDRATE DIET

KW - EXERCISE

KW - PHOSPHORYLATION

U2 - 10.1152/ajpregu.00400.2010

DO - 10.1152/ajpregu.00400.2010

M3 - Article

C2 - 20720174

SN - 0363-6119

VL - 299

SP - R1350-R1359

JO - American Journal of Physiology - Regulatory, Integrative and Comparative Physiology (AJP - Regulatory, Integrative and Comparative Physiology)

JF - American Journal of Physiology - Regulatory, Integrative and Comparative Physiology (AJP - Regulatory, Integrative and Comparative Physiology)

IS - 5

ER -