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The transcriptional coregulator PGC-1? controls mitochondrial function and anti-oxidant defence in skeletal muscles.

ABSTRACT: The transcriptional coregulators PGC-1? and PGC-1? modulate the expression of numerous partially overlapping genes involved in mitochondrial biogenesis and energetic metabolism. The physiological role of PGC-1? is poorly understood in skeletal muscle, a tissue of high mitochondrial content to produce ATP levels required for sustained contractions. Here we determine the physiological role of PGC-1? in skeletal muscle using mice, in which PGC-1? is selectively ablated in skeletal myofibres at adulthood (PGC-1?((i)skm-/-) mice). We show that myofibre myosin heavy chain composition and mitochondrial number, muscle strength and glucose homeostasis are unaffected in PGC-1?((i)skm-/-) mice. However, decreased expression of genes controlling mitochondrial protein import, translational machinery and energy metabolism in PGC-1?((i)skm-/-) muscles leads to mitochondrial structural and functional abnormalities, impaired muscle oxidative capacity and reduced exercise performance. Moreover, enhanced free-radical leak and reduced expression of the mitochondrial anti-oxidant enzyme Sod2 increase muscle oxidative stress. PGC-1? is therefore instrumental for skeletal muscles to cope with high energetic demands.

SUBMITTER: Gali Ramamoorthy T

PROVIDER: S-EPMC4703903 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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The transcriptional coregulator PGC-1β controls mitochondrial function and anti-oxidant defence in skeletal muscles.

Gali Ramamoorthy Thanuja T Laverny Gilles G Schlagowski Anna-Isabel AI Zoll Joffrey J Messaddeq Nadia N Bornert Jean-Marc JM Panza Salvatore S Ferry Arnaud A Geny Bernard B Metzger Daniel D

Nature communications 20151217

The transcriptional coregulators PGC-1α and PGC-1β modulate the expression of numerous partially overlapping genes involved in mitochondrial biogenesis and energetic metabolism. The physiological role of PGC-1β is poorly understood in skeletal muscle, a tissue of high mitochondrial content to produce ATP levels required for sustained contractions. Here we determine the physiological role of PGC-1β in skeletal muscle using mice, in which PGC-1β is selectively ablated in skeletal myofibres at adul ...[more]

PMID: 26674215

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Project description:The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1?) is a chief activator of mitochondrial and metabolic programs and protects against atrophy in skeletal muscle (skm). Here we tested whether PGC-1? overexpression could restructure the transcriptome and metabolism of primary cultured human skm cells, which display a phenotype that resembles the atrophic phenotype. An oligonucleotide microarray analysis was used to reveal the effects of PGC-1? on the whole transcriptome. Fifty-three different genes showed altered expression in response to PGC-1?: 42 upregulated and 11 downregulated. The main gene ontologies (GO) associated with the upregulated genes were mitochondrial components and processes and this was linked with an increase in COX activity, an indicator of mitochondrial content. Furthermore, PGC-1? enhanced mitochondrial oxidation of palmitate and lactate to CO(2), but not glucose oxidation. The other most significantly associated GOs for the upregulated genes were chemotaxis and cytokine activity, and several cytokines, including IL-8/CXCL8, CXCL6, CCL5 and CCL8, were within the most highly induced genes. Indeed, PGC-1? highly increased IL-8 cell protein content. The most upregulated gene was PVALB, which is related to calcium signaling. Potential metabolic regulators of fatty acid and glucose storage were among mainly regulated genes. The mRNA and protein level of FITM1/FIT1, which enhances the formation of lipid droplets, was raised by PGC-1?, while in oleate-incubated cells PGC-1? increased the number of smaller lipid droplets and modestly triglyceride levels, compared to controls. CALM1, the calcium-modulated ? subunit of phosphorylase kinase, was downregulated by PGC-1?, while glycogen phosphorylase was inactivated and glycogen storage was increased by PGC-1?. In conclusion, of the metabolic transcriptome deficiencies of cultured skm cells, PGC-1? rescued the expression of genes encoding mitochondrial proteins and FITM1. Several myokine genes, including IL-8 and CCL5, which are known to be constitutively expressed in human skm cells, were induced by PGC-1?.

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The transcriptional coregulator PGC-1? controls mitochondrial function and anti-oxidant defence in skeletal muscles.

Publications

The transcriptional coregulator PGC-1β controls mitochondrial function and anti-oxidant defence in skeletal muscles.

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