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Diabetologia

, Volume 57, Issue 11, pp 2405–2412 | Cite as

The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet

  • Joaquín Pérez-Schindler
  • Kristoffer Svensson
  • Elyzabeth Vargas-Fernández
  • Gesa Santos
  • Walter Wahli
  • Christoph Handschin
Article

Abstract

Aims/hypothesis

Physical activity improves oxidative capacity and exerts therapeutic beneficial effects, particularly in the context of metabolic diseases. The peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC-1α) and the nuclear receptor PPARβ/δ have both been independently discovered to play a pivotal role in the regulation of oxidative metabolism in skeletal muscle, though their interdependence remains unclear. Hence, our aim was to determine the functional interaction between these two factors in mouse skeletal muscle in vivo.

Methods

Adult male control mice, PGC-1α muscle-specific transgenic (mTg) mice, PPARβ/δ muscle-specific knockout (mKO) mice and the combination PPARβ/δ mKO + PGC-1α mTg mice were studied under basal conditions and following PPARβ/δ agonist administration and acute exercise. Whole-body metabolism was assessed by indirect calorimetry and blood analysis, while magnetic resonance was used to measure body composition. Quantitative PCR and western blot were used to determine gene expression and intracellular signalling. The proportion of oxidative muscle fibre was determined by NADH staining.

Results

Agonist-induced PPARβ/δ activation was only disrupted by PPARβ/δ knockout. We also found that the disruption of the PGC-1α–PPARβ/δ axis did not affect whole-body metabolism under basal conditions. As expected, PGC-1α mTg mice exhibited higher exercise performance, peak oxygen consumption and lower blood lactate levels following exercise, though PPARβ/δ mKO + PGC-1α mTg mice showed a similar phenotype. Similarly, we found that PPARβ/δ was dispensable for PGC-1α-mediated enhancement of an oxidative phenotype in skeletal muscle.

Conclusions/interpretation

Collectively, these results indicate that PPARβ/δ is not an essential partner of PGC-1α in the control of skeletal muscle energy metabolism.

Keywords

Coregulators Exercise Nuclear receptors Skeletal muscle metabolism 

Abbreviations

AMPK

AMP-activated protein kinase

CON

Control mice

GTT

Glucose tolerance test

IMTG

Intramyocellular triacylglycerol

ITT

Insulin tolerance test

mKO

Muscle-specific knockout

mTg

Muscle-specific transgenic

PGC

PPARγ coactivator

PPAR

Peroxisome proliferator-activated receptor

qPCR

Quantitative PCR

RER

Respiratory exchange ratio

TBP

TATA binding protein

UCP3

Uncoupling protein 3

\( \overset{\cdot }{V}{\mathrm{O}}_{2\mathrm{peak}} \)

Peak oxygen consumption

Notes

Funding

This project was funded by the Swiss National Science Foundation, the Muscular Dystrophy Association USA (MDA), the SwissLife ‘Jubiläumsstiftung für Volksgesundheit und medizinische Forschung’, the Swiss Society for Research on Muscle Diseases (SSEM), the Swiss Diabetes Association, the Roche Research Foundation, the United Mitochondrial Disease Foundation (UMDF), the Association Française contre les Myopathies (AFM), the Neuromuscular Research Association Basel (NeRAB), the Gebert-Rüf Foundation ‘Rare Diseases’ Program, the University of Basel and the Biozentrum.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

JPS, WW and CH contributed to the study conception and design, being responsible for the integrity of the work as a whole. All the authors contributed to the acquisition of data or analysis and interpretation of data, in addition to drafting the article, and approved its final version.

Supplementary material

125_2014_3352_MOESM1_ESM.pdf (614 kb)
ESM Fig. 1 (PDF 614 kb)
125_2014_3352_MOESM2_ESM.pdf (259 kb)
ESM Fig. 2 (PDF 259 kb)
125_2014_3352_MOESM3_ESM.pdf (96 kb)
ESM Table 1 (PDF 95 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Joaquín Pérez-Schindler
    • 1
    • 2
  • Kristoffer Svensson
    • 1
  • Elyzabeth Vargas-Fernández
    • 1
  • Gesa Santos
    • 1
  • Walter Wahli
    • 3
    • 4
  • Christoph Handschin
    • 1
  1. 1.BiozentrumUniversity of BaselBaselSwitzerland
  2. 2.School of Sport, Exercise and Rehabilitation SciencesUniversity of BirminghamBirminghamUK
  3. 3.Center for Integrative Genomics, National Research Center Frontiers in GeneticsUniversity of LausanneLausanneSwitzerland
  4. 4.Lee Kong Chian School of MedicineNanyang Technological UniversitySingaporeRepublic of Singapore

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