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PGC-1?-mediated branched-chain amino acid metabolism in the skeletal muscle.

ABSTRACT: Peroxisome proliferator-activated receptor (PPAR) ? coactivator 1? (PGC-1?) is a coactivator of various nuclear receptors and other transcription factors, which is involved in the regulation of energy metabolism, thermogenesis, and other biological processes that control phenotypic characteristics of various organ systems including skeletal muscle. PGC-1? in skeletal muscle is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Branched-chain amino acid (BCAA) metabolism mainly occurs in skeletal muscle mitochondria, and enzymes related to BCAA metabolism are increased by exercise. Using murine skeletal muscle overexpressing PGC-1? and cultured cells, we investigated whether PGC-1? stimulates BCAA metabolism by increasing the expression of enzymes involved in BCAA metabolism. Transgenic mice overexpressing PGC-1? specifically in the skeletal muscle had increased the expression of branched-chain aminotransferase (BCAT) 2, branched-chain ?-keto acid dehydrogenase (BCKDH), which catabolize BCAA. The expression of BCKDH kinase (BCKDK), which phosphorylates BCKDH and suppresses its enzymatic activity, was unchanged. The amount of BCAA in the skeletal muscle was significantly decreased in the transgenic mice compared with that in the wild-type mice. The amount of glutamic acid, a metabolite of BCAA catabolism, was increased in the transgenic mice, suggesting the activation of muscle BCAA metabolism by PGC-1?. In C2C12 cells, the overexpression of PGC-1? significantly increased the expression of BCAT2 and BCKDH but not BCKDK. Thus, PGC-1? in the skeletal muscle is considered to significantly contribute to BCAA metabolism.

SUBMITTER: Hatazawa Y

PROVIDER: S-EPMC3956461 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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PGC-1α-mediated branched-chain amino acid metabolism in the skeletal muscle.

Hatazawa Yukino Y Tadaishi Miki M Nagaike Yuta Y Morita Akihito A Ogawa Yoshihiro Y Ezaki Osamu O Takai-Igarashi Takako T Kitaura Yasuyuki Y Shimomura Yoshiharu Y Kamei Yasutomi Y Miura Shinji S

PloS one 20140317 3

Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) is a coactivator of various nuclear receptors and other transcription factors, which is involved in the regulation of energy metabolism, thermogenesis, and other biological processes that control phenotypic characteristics of various organ systems including skeletal muscle. PGC-1α in skeletal muscle is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular s ...[more]

PMID: 24638054

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Project description:Skeletal muscle loss (sarcopenia) is a major clinical complication in alcoholic cirrhosis with no effective therapy. Skeletal muscle autophagic proteolysis and myostatin expression (inhibitor of protein synthesis) are increased in cirrhosis and believed to contribute to anabolic resistance. A prospective study was performed to determine the mechanisms of sarcopenia in alcoholic cirrhosis and potential reversal by leucine. In six well-compensated, stable, alcoholic patients with cirrhosis and eight controls, serial vastus lateralis muscle biopsies were obtained before and 7 hours after a single oral branched chain amino acid mixture enriched with leucine (BCAA/LEU). Primed-constant infusion of l-[ring-(2) H5 ]-phenylalanine was used to quantify whole-body protein breakdown and muscle protein fractional synthesis rate using liquid chromatography/mass spectrometry. Muscle expression of myostatin, mammalian target of rapamycin (mTOR) targets, autophagy markers, protein ubiquitination, and the intracellular amino acid deficiency sensor general control of nutrition 2 were quantified by immunoblots and the leucine exchanger (SLC7A5) and glutamine transporter (SLC38A2), by real-time polymerase chain reaction. Following oral administration, plasma BCAA concentrations showed a similar increase in patients with cirrhosis and controls. Skeletal muscle fractional synthesis rate was 9.63?±?0.36%/hour in controls and 9.05?±?0.68%/hour in patients with cirrhosis (P?=?0.54). Elevated whole-body protein breakdown in patients with cirrhosis was reduced with BCAA/LEU (P?=?0.01). Fasting skeletal muscle molecular markers showed increased myostatin expression, impaired mTOR signaling, and increased autophagy in patients with cirrhosis compared to controls (P?<?0.01). The BCAA/LEU supplement did not alter myostatin expression, but mTOR signaling, autophagy measures, and general control of nutrition 2 activation were consistently reversed in cirrhotic muscle (P?<?0.01). Expression of SLC7A5 was higher in the basal state in patients with cirrhosis than controls (P?<?0.05) but increased with BCAA/LEU only in controls (P?<?0.001).Impaired mTOR1 signaling and increased autophagy in skeletal muscle of patients with alcoholic cirrhosis is acutely reversed by BCAA/LEU.

Dataset Information

PGC-1?-mediated branched-chain amino acid metabolism in the skeletal muscle.

Publications

PGC-1α-mediated branched-chain amino acid metabolism in the skeletal muscle.

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