Deletion of the transcriptional coactivator PGC1α in skeletal muscles is associated with reduced expression of genes related to oxidative muscle function.
The expression of the transcriptional coactivator PGC1α is increased in skeletal muscles during exercise. Previously, we showed that increased PGC1α leads to prolonged exercise performance (the duration for which running can be continued) and, at the same time, increases the expression of branched-chain amino acid (BCAA) metabolism-related enzymes and genes that are involved in supplying substrates for the TCA cycle. We recently created mice with PGC1α knockout specifically in the skeletal muscles (PGC1α KO mice), which show decreased mitochondrial content. In this study, global gene expression (microarray) analysis was performed in the skeletal muscles of PGC1α KO mice compared with that of wild-type control mice. As a result, decreased expression of genes involved in the TCA cycle, oxidative phosphorylation, and BCAA metabolism were observed. Compared with previously obtained microarray data on PGC1α-overexpressing transgenic mice, each gene showed the completely opposite direction of expression change. Bioinformatic analysis of the promoter region of genes with decreased expression in PGC1α KO mice predicted the involvement of several transcription factors, including a nuclear receptor, ERR, in their regulation. As PGC1α KO microarray data in this study show opposing findings to the PGC1α transgenic data, a loss-of-function experiment, as well as a gain-of-function experiment, revealed PGC1α's function in the oxidative energy metabolism of skeletal muscles.
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan; Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan.
Yukino
Y
Hatazawa
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan.
Kimiko
K
Minami
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan.
Ryoji
R
Yoshimura
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan.
Takumi
T
Onishi
Graduate School of Agriculture, Division of Food Science and Biotechnology, Laboratory of Nutrition Chemistry, Kyoto University, Kyoto, Japan.
Mark Christian
MC
Manio
Graduate School of Agriculture, Division of Food Science and Biotechnology, Laboratory of Nutrition Chemistry, Kyoto University, Kyoto, Japan.
Kazuo
K
Inoue
Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, 60637, USA; Global COE Program, Tokyo Medical and Dental University, Tokyo, Japan.
Naoki
N
Sawada
Laboratory of Animal Models for Human Diseases, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
Osamu
O
Suzuki
Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, Shizuoka, Japan.
Shinji
S
Miura
Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan. Electronic address: kamei@kpu.ac.jp.
Yasutomi
Y
Kamei
D000818:Animals; D019295:Computational Biology; D015536:Down-Regulation / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators
Energy metabolism; Exercise; PGC1α; Skeletal muscle; Transcription coactivator