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

Abstract

Aims/hypothesis-Physical activity improves oxidative capacity and exerts therapeutic beneficial effects, particularly in the context of metabolic diseases. The peroxisome proliferatoractivated receptor γ (PPARγ) 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 remain 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 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 signaling. Proportion of oxidative muscle fiber 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 does 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 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 acquisition of data or analysis and interpretation of data, in addition to drafting the article and the approval of its final version. Duality of interestThe authors declare that there is no duality of interest associated with this manuscript. PPARβ/δ was dispensable for PGC-1α-mediated enhancement of an oxidative phenotype in skeletal muscle. Europe PMC Funders GroupConclusions/interpretation-Collectively, these results indicate that PPARβ/δ is not an essential partner of PGC-1α in the control of skeletal muscle energy metabolism.

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