Isoform-specific increases in murine skeletal muscle peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) mRNA in response to beta2-adrenergic receptor activation and exercise.
Adrenergic receptor (AR) activation increases expression of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1alpha (PGC-1alpha) mRNA, which may promote mitochondrial biogenesis in skeletal muscles. An AR-activated increase in PGC-1alpha mRNA was observed in exercise. PGC-1alpha mRNA is considered a single transcript (PGC-1alpha-a); however, a transcript search of PGC-1alpha in expressed sequence tag libraries revealed that two novel isoforms of PGC-1alpha mRNA, named PGC-1alpha-b and PGC-1alpha-c, were expressed in mice tissues. Compared with PGC-1alpha-a mRNA (a previously described isoform), PGC-1alpha-b or PGC-1alpha-c mRNA was transcribed by a different exon 1 of the PGC-1alpha gene and produced slightly smaller-sized proteins. PGC-1alpha-b or PGC-1alpha-c protein was functional; both isoforms possessed transcriptional activity and could coactivate PPARs, similar to those in PGC-1alpha-a in vitro. Transgenic mice overexpressing PGC-1alpha-b or PGC-1alpha-c in skeletal muscles showed increased gene expression related to mitochondrial biogenesis and fatty acid oxidation. In C57BL/6J mice, injection of the beta2-AR agonist clenbuterol increased PGC-1alpha-b and PGC-1alpha-c mRNA expression more than 350-fold, but not PGC-1alpha-a, in skeletal muscle. A single bout of exercise also increased PGC-1alpha-b and PGC-1alpha-c mRNAs, but not PGC-1alpha-a, in skeletal muscles. The increases in skeletal muscles in response to exercise were inhibited by pretreatment with the beta2-AR-specific inhibitor ICI 118,551. However, in liver, fasting increased PGC-1alpha-a mRNA, but not PGC-1alpha-b and PGC-1alpha-c mRNAs. These data indicate that AR activation is a major mechanism of an increase in PGC-1alpha expression in skeletal muscles, and the increase in PGC-1alpha mRNAs was isoform specific.
Miura
Shinji
S
National Institute of Health and Nutrition, Tokyo 162-8636, Japan. shinjim@nih.go.jp
Kai
Yuko
Y
Kamei
Yasutomi
Y
Ezaki
Osamu
O
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011412:Propanolamines / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011412:Propanolamines; D020033:Protein Isoforms; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D015534:Trans-Activators; D014157:Transcription Factors; C026777:ICI 118551