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Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha.

ABSTRACT: In mammals, maintenance of energy and nutrient homeostasis during food deprivation is accomplished through an increase in mitochondrial fatty acid oxidation in peripheral tissues. An important component that drives this cellular oxidative process is the transcriptional coactivator PGC-1alpha. Here, we show that fasting induced PGC-1alpha deacetylation in skeletal muscle and that SIRT1 deacetylation of PGC-1alpha is required for activation of mitochondrial fatty acid oxidation genes. Moreover, expression of the acetyltransferase, GCN5, or the SIRT1 inhibitor, nicotinamide, induces PGC-1alpha acetylation and decreases expression of PGC-1alpha target genes in myotubes. Consistent with a switch from glucose to fatty acid oxidation that occurs in nutrient deprivation states, SIRT1 is required for induction and maintenance of fatty acid oxidation in response to low glucose concentrations. Thus, we have identified SIRT1 as a functional regulator of PGC-1alpha that induces a metabolic gene transcription program of mitochondrial fatty acid oxidation. These results have implications for understanding selective nutrient adaptation and how it might impact lifespan or metabolic diseases such as obesity and diabetes.

SUBMITTER: Gerhart-Hines Z

PROVIDER: S-EPMC1847661 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha.

Gerhart-Hines Zachary Z Rodgers Joseph T JT Bare Olivia O Lerin Carles C Kim Seung-Hee SH Mostoslavsky Raul R Alt Frederick W FW Wu Zhidan Z Puigserver Pere P

The EMBO journal 20070308 7

In mammals, maintenance of energy and nutrient homeostasis during food deprivation is accomplished through an increase in mitochondrial fatty acid oxidation in peripheral tissues. An important component that drives this cellular oxidative process is the transcriptional coactivator PGC-1alpha. Here, we show that fasting induced PGC-1alpha deacetylation in skeletal muscle and that SIRT1 deacetylation of PGC-1alpha is required for activation of mitochondrial fatty acid oxidation genes. Moreover, ex ...[more]

PMID: 17347648

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Project description:Individual skeletal muscles in the animal body are heterogeneous, as each is comprised of different fiber types. Type I muscle fibers are rich with mitochondria, and have high oxidative metabolisms while type IIB fibers have few mitochondria and high glycolytic metabolic capacity. Peroxisome proliferator-activated receptor gamma coactivator 1? (PGC-1?), a transcriptional co-activator that regulates mitochondrial biogenesis and respiratory function, is implicated in muscle fiber-type switching. Over-expression of PGC-1? in transgenic mice increased the proportion of red/oxidative type I fiber. During pig muscle growth, an increased number of type I fibers can give meat more red color. To explore the roles of PGC-1? in regulation of muscle fiber type conversion, we generated skeletal muscle-specific PGC-1? transgenic mice and pig. Ectopic over-expression of PGC-1? was detected in both fast and slow muscle fibers. The transgenic animals displayed a remarkable amount of red/oxidative muscle fibers in major skeletal muscle tissues. Skeletal muscles from transgenic mice and pigs have increased expression levels of oxidative fiber markers such as MHC1, MHC2x, myoglobin and Tnni1, and decreased expressions of glycolytic fiber genes (MHC2a, MHC2b, CASQ-1 and Tnni2). The genes responsible for the TCA cycle and oxidative phosphorylation, cytochrome coxidase 2 and 4, and citrate synthase were also increased in the transgenic mice and pigs. These results suggested that transgenic over-expressed PGC-1? significantly increased muscle mitochondrial biogenesis, resulting in qualitative changes from glycolytic to oxidative energy generation. The transgenic animals also had elevated levels of PDK4 and PPAR? proteins in muscle tissue, which can lead to increased glycogen deposition and fatty acid oxidation. Therefore, the results support a significant role of PGC-1? in conversion of fast glycolytic fibers to slow and oxidative fiber through enhanced mitochondrial respiration and fatty acid oxidation, and transgenic over-expression of PGC-1? in skeletal muscle leads to more red meat production in pigs.

Dataset Information

Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha.

Publications

Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha.

Similar Datasets

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