PGC-1α-Mediated Branched-Chain Amino Acid Metabolism in the Skeletal Muscle

Yukino Hatazawa,Osamu Ezaki,Yasutomi Kamei,Miki Tadaishi,Shinji Miura,Yasuyuki Kitaura,Akihito Morita,Takako Takai-Igarashi,Yoshiharu Shimomura,Yuta Nagaike,Yoshihiro Ogawa,Laszlo Csernoch

doi:10.1371/journal.pone.0091006

Abstract

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 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-1α and cultured cells, we investigated whether PGC-1α stimulates BCAA metabolism by increasing the expression of enzymes involved in BCAA metabolism. Transgenic mice overexpressing PGC-1α specifically in the skeletal muscle had increased the expression of branched-chain aminotransferase (BCAT) 2, branched-chain α-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-1α. In C2C12 cells, the overexpression of PGC-1α significantly increased the expression of BCAT2 and BCKDH but not BCKDK. Thus, PGC-1α in the skeletal muscle is considered to significantly contribute to BCAA metabolism.

Highlights

Peroxisome proliferator-activated receptor (PPAR) c coactivator 1 a (PGC-1a) was identified as a nuclear receptor coactivator of PPARc in brown adipose tissue and found to be upregulated in brown adipose tissue and skeletal muscle in response to cold exposure [1]
We demonstrated that overexpression of PGC-1a-b in skeletal muscle but not in heart increases mitochondrial biogenesis and capillary density, contributing to improved exercise capacity [4]
We investigated whether PGC-1a stimulates Branched-chain amino acid (BCAA) metabolism with an increase in the expression of enzymes involved in BCAA metabolism, such as branched-chain aminotransferase (BCAT), branched-chain a-keto acid dehydrogenase (BCKDH) and BCKDH kinase (BCKDK), using cultured cells and murine skeletal muscle overexpressing PGC-1a

Summary

Introduction

Peroxisome proliferator-activated receptor (PPAR) c coactivator 1 a (PGC-1a) was identified as a nuclear receptor coactivator of PPARc in brown adipose tissue and found to be upregulated in brown adipose tissue and skeletal muscle in response to cold exposure [1]. Microarray analysis revealed that the BCAA catabolic pathway was coordinately activated in skeletal muscle of transgenic mice overexpressing PGC-1a. We investigated whether PGC-1a stimulates BCAA metabolism with an increase in the expression of enzymes involved in BCAA metabolism, such as BCAT, BCKDH and BCKDK, using cultured cells and murine skeletal muscle overexpressing PGC-1a.

Results

Conclusion