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

Kristian Kiilerich; Helle Adser; Anne Hviid Jakobsen; Per Amstrup Pedersen; David Grahame Hardie; Jørgen Wojtaszewski; Henriette Pilegaard

doi:10.1152/ajpregu.00400.2010

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

Kristian Kiilerich, Helle Adser, Anne Hviid Jakobsen, Per Amstrup Pedersen, David Grahame Hardie, Jørgen Wojtaszewski, Henriette Pilegaard

Molecular Integrative Physiology

22 Citations (Scopus)

Abstract

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.

Original language	English
Journal	American Journal of Physiology: Regulatory, Integrative and Comparative Physiology
Volume	299
Issue number	5
Pages (from-to)	R1350-R1359
Number of pages	10
ISSN	0363-6119
DOIs	https://doi.org/10.1152/ajpregu.00400.2010
Publication status	Published - Nov 2010

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PGC-1{alpha} increases PDH content but does not change acute PDH regulation in mouse skeletal muscle. / Kiilerich, Kristian; Adser, Helle; Jakobsen, Anne Hviid et al.

In: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, Vol. 299, No. 5, 11.2010, p. R1350-R1359.

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title = "PGC-1{alpha} increases PDH content but does not change acute PDH regulation in mouse skeletal muscle",

abstract = "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.",

author = "Kristian Kiilerich and Helle Adser and Jakobsen, {Anne Hviid} and Pedersen, {Per Amstrup} and Hardie, {David Grahame} and J{\o}rgen Wojtaszewski and Henriette Pilegaard",

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doi = "10.1152/ajpregu.00400.2010",

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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 Hviid

AU - Pedersen, Per Amstrup

AU - Hardie, David Grahame

AU - Wojtaszewski, Jørgen

AU - Pilegaard, Henriette

N1 - CURIS 2010 5200 104

PY - 2010/11

Y1 - 2010/11

N2 - 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.

AB - 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.

U2 - 10.1152/ajpregu.00400.2010

DO - 10.1152/ajpregu.00400.2010

M3 - Journal article

C2 - 20720174

SN - 0363-6119

VL - 299

SP - R1350-R1359

JO - American Journal of Physiology - Regulatory Integrative and Comparative Physiology

JF - American Journal of Physiology - Regulatory Integrative and Comparative Physiology

IS - 5

ER -

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

Abstract

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