The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet
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 d...
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sg-ntu-dr.10356-1037852022-02-16T16:28:50Z The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet Pérez-Schindler, Joaquín Svensson, Kristoffer Vargas-Fernández, Elyzabeth Santos, Gesa Wahli, Walter Handschin, Christoph Lee Kong Chian School of Medicine (LKCMedicine) DRNTU::Science::Biological sciences 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. Accepted version 2015-01-13T07:17:41Z 2019-12-06T21:20:12Z 2015-01-13T07:17:41Z 2019-12-06T21:20:12Z 2014 2014 Journal Article Pérez-Schindler, J., Svensson, K., Vargas-Fernández, E., Santos, G., Wahli, W., & Handschin, C. (2014). The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet. Diabetologia, 57(11), 2405-2412. https://hdl.handle.net/10356/103785 http://hdl.handle.net/10220/24594 10.1007/s00125-014-3352-3 25116175 en Diabetologia © 2014 Springer-Verlag Berlin Heidelberg. This is the author created version of a work that has been peer reviewed and accepted for publication by Diabetologia, Springer-Verlag Berlin Heidelberg. It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [http://dx.doi.org/10.1007/s00125-014-3352-3]. 38 p. application/pdf |
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DRNTU::Science::Biological sciences Pérez-Schindler, Joaquín Svensson, Kristoffer Vargas-Fernández, Elyzabeth Santos, Gesa Wahli, Walter Handschin, Christoph The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet |
description |
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. |
author2 |
Lee Kong Chian School of Medicine (LKCMedicine) |
author_facet |
Lee Kong Chian School of Medicine (LKCMedicine) Pérez-Schindler, Joaquín Svensson, Kristoffer Vargas-Fernández, Elyzabeth Santos, Gesa Wahli, Walter Handschin, Christoph |
format |
Article |
author |
Pérez-Schindler, Joaquín Svensson, Kristoffer Vargas-Fernández, Elyzabeth Santos, Gesa Wahli, Walter Handschin, Christoph |
author_sort |
Pérez-Schindler, Joaquín |
title |
The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet |
title_short |
The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet |
title_full |
The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet |
title_fullStr |
The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet |
title_full_unstemmed |
The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet |
title_sort |
coactivator pgc-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor pparβ/δ in sedentary mice fed a regular chow diet |
publishDate |
2015 |
url |
https://hdl.handle.net/10356/103785 http://hdl.handle.net/10220/24594 |
_version_ |
1725985654177792000 |