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Isoform-Specific Increases in Murine Skeletal Muscle Peroxisome Proliferator-Activated Receptor- Coactivator-1 (PGC-1) mRNA in Response to β2-Adrenergic Receptor Activation and Exercise

National Institute of Health and Nutrition (S.M., Y.K., O.E.), Shinjuku-ku, Tokyo 162-8636, Japan; and Tokyo Medical and Dental University (Y.K.), Bunkyo-ku, Tokyo 113-8510, Japan

Address all correspondence and requests for reprints to: Shinji Miura, Ph.D., or Osamu Ezaki, M.D., Ph.D., National Institute of Health and Nutrition, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8636, Japan. E-mail: shinjim{at}nih.go.jp or ezaki{at}nih.go.jp.

Adrenergic receptor (AR) activation increases expression of peroxisome proliferator-activated receptor (PPAR)- coactivator 1 (PGC-1) mRNA, which may promote mitochondrial biogenesis in skeletal muscles. An AR-activated increase in PGC-1 mRNA was observed in exercise. PGC-1 mRNA is considered a single transcript (PGC-1-a); however, a transcript search of PGC-1 in expressed sequence tag libraries revealed that two novel isoforms of PGC-1 mRNA, named PGC-1-b and PGC-1-c, were expressed in mice tissues. Compared with PGC-1-a mRNA (a previously described isoform), PGC-1-b or PGC-1-c mRNA was transcribed by a different exon 1 of the PGC-1 gene and produced slightly smaller-sized proteins. PGC-1-b or PGC-1-c protein was functional; both isoforms possessed transcriptional activity and could coactivate PPARs, similar to those in PGC-1-a in vitro. Transgenic mice overexpressing PGC-1-b or PGC-1-c in skeletal muscles showed increased gene expression related to mitochondrial biogenesis and fatty acid oxidation. In C57BL/6J mice, injection of the β2-AR agonist clenbuterol increased PGC-1-b and PGC-1-c mRNA expression more than 350-fold, but not PGC-1-a, in skeletal muscle. A single bout of exercise also increased PGC-1-b and PGC-1-c mRNAs, but not PGC-1-a, in skeletal muscles. The increases in skeletal muscles in response to exercise were inhibited by pretreatment with the β2-AR-specific inhibitor ICI 118,551. However, in liver, fasting increased PGC-1-a mRNA, but not PGC-1-b and PGC-1-c mRNAs. These data indicate that AR activation is a major mechanism of an increase in PGC-1 expression in skeletal muscles, and the increase in PGC-1 mRNAs was isoform specific.

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