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

ABSTRACT: Physical activity improves oxidative capacity and exerts therapeutic beneficial effects, particularly in the context of metabolic diseases. The peroxisome proliferator-activated receptor (PPAR) ? coactivator-1? (PGC-1?) and the nuclear receptor PPAR?/? 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.Adult male control mice, PGC-1? muscle-specific transgenic (mTg) mice, PPAR?/? muscle-specific knockout (mKO) mice and the combination PPAR?/? mKO + PGC-1? mTg mice were studied under basal conditions and following PPAR?/? 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.Agonist-induced PPAR?/? activation was only disrupted by PPAR?/? knockout. We also found that the disruption of the PGC-1?-PPAR?/? axis did not affect whole-body metabolism under basal conditions. As expected, PGC-1? mTg mice exhibited higher exercise performance, peak oxygen consumption and lower blood lactate levels following exercise, though PPAR?/? mKO + PGC-1? mTg mice showed a similar phenotype. Similarly, we found that PPAR?/? was dispensable for PGC-1?-mediated enhancement of an oxidative phenotype in skeletal muscle.Collectively, these results indicate that PPAR?/? is not an essential partner of PGC-1? in the control of skeletal muscle energy metabolism.

SUBMITTER: Perez-Schindler J

PROVIDER: S-EPMC4657154 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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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 J Svensson Kristoffer K Vargas-Fernández Elyzabeth E Santos Gesa G Wahli Walter W Handschin Christoph C

Diabetologia 20140813 11

<h4>Aims/hypothesis</h4>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 inter ...[more]

PMID: 25116175

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Project description:BackgroundObesity is a leading risk factor for osteoarthritis (OA). In contrast, calorie restriction (CR) may lessen OA due to improved systemic inflammatory status and reduced weight-bearing. The aim of this study was to determine how CR with regular chow versus a high-fat diet (HFD) alters OA progression using the Hartley guinea pig model of disease.MethodsTwenty-four male guinea pigs were allocated to four groups at 2 months of age: (1) ad libitum regular chow (obese), (2) CR regular chow (lean), (3) ad libitum HFD, and (4) CR HFD. Animals in both HFD groups ate identical amounts and were combined into one HFD group for analyses. At 5 months, hind limbs were harvested for microcomputed tomography (microCT) and histopathologic evaluation of knee OA. Total body, gonad fat, and infrapatellar fat pad (IFP) masses were recorded. IFPs were collected for gene expression analysis. Immunohistochemistry for monocyte chemoattractant protein-1 (MCP-1) was performed on intact joints. Serum was utilized for protein C3 measurement. All data were compared using ordinary one-way ANOVA analyses with Tukey's post-hoc tests.ResultsBody mass in the lean and HFD groups were similar and lower than the obese group. Despite this, gonad fat pads in the HFD group were comparable to the obese group. MicroCT and histologic OA scores were similar in obese and HFD groups; both scores were significantly lower in the lean group. Obese and HFD groups displayed increased gene expression of pro-inflammatory and catabolic mediators in IFPs relative to lean animals. Consistent with this, immunohistochemistry for MCP-1 in knee joints demonstrated strong positive staining in obese and HFD groups but was minimally detected in lean animals. Serum protein C3 levels were also statistically higher.ConclusionsThis study demonstrated that CR with a regular chow diet lessened knee OA in the Hartley guinea pig and was associated with decreased local and systemic inflammation compared to obese animals. HFD animals, although under CR conditions, had OA scores and inflammatory markers similar to obese animals. Thus, diet composition, and not solely body weight, may be a key factor in development of OA.

Dataset Information

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

Publications

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

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