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.Endocrinology. 2008 Sep; 149(9):4527-33.E
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.