Journal
DIABETOLOGIA
Volume 57, Issue 11, Pages 2405-2412Publisher
SPRINGER
DOI: 10.1007/s00125-014-3352-3
Keywords
Coregulators; Exercise; Nuclear receptors; Skeletal muscle metabolism
Categories
Funding
- Swiss National Science Foundation
- Muscular Dystrophy Association USA (MDA)
- SwissLife 'Jubilaumsstiftung fur Volksgesundheit und medizinische Forschung'
- Swiss Society for Research on Muscle Diseases (SSEM)
- Swiss Diabetes Association
- Roche Research Foundation
- United Mitochondrial Disease Foundation (UMDF)
- Association Francaise contre les Myopathies (AFM)
- Neuromuscular Research Association Basel (NeRAB)
- Gebert-Ruf Foundation 'Rare Diseases' Program
- University of Basel
- Biozentrum
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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)gamma coactivator-1 alpha (PGC-1 alpha) and the nuclear receptor PPAR beta/delta 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-1 alpha muscle-specific transgenic (mTg) mice, PPAR beta/delta muscle-specific knockout (mKO) mice and the combination PPAR beta/delta mKO + PGC-1 alpha mTg mice were studied under basal conditions and following PPAR beta/delta 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 PPAR beta/delta activation was only disrupted by PPAR beta/delta knockout. We also found that the disruption of the PGC-1 alpha-PPAR beta/delta axis did not affect whole-body metabolism under basal conditions. As expected, PGC-1 alpha mTg mice exhibited higher exercise performance, peak oxygen consumption and lower blood lactate levels following exercise, though PPAR beta/delta mKO + PGC-1 alpha mTg mice showed a similar phenotype. Similarly, we found that PPAR beta/delta was dispensable for PGC-1 alpha-mediated enhancement of an oxidative phenotype in skeletal muscle. Conclusions/interpretation Collectively, these results indicate that PPAR beta/delta is not an essential partner of PGC-1 alpha in the control of skeletal muscle energy metabolism.
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