title: Peroxisome Proliferator-activated Receptor γ Coactivator-1 α Isoforms Selectively Regulate Multiple Splicing Events on Target Genes.
abstract: Endurance and resistance exercise training induces specific and profound changes in the skeletal muscle transcriptome. Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) coactivators are not only among the genes differentially induced by distinct training methods, but they also participate in the ensuing signaling cascades that allow skeletal muscle to adapt to each type of exercise. Although endurance training preferentially induces PGC-1α1 expression, resistance exercise activates the expression of PGC-1α2, -α3, and -α4. These three alternative PGC-1α isoforms lack the arginine/serine-rich (RS) and RNA recognition motifs characteristic of PGC-1α1. Discrete functions for PGC-1α1 and -α4 have been described, but the biological role of PGC-1α2 and -α3 remains elusive. Here we show that different PGC-1α variants can affect target gene splicing through diverse mechanisms, including alternative promoter usage. By analyzing the exon structure of the target transcripts for each PGC-1α isoform, we were able to identify a large number of previously unknown PGC-1α2 and -α3 target genes and pathways in skeletal muscle. In particular, PGC-1α2 seems to mediate a decrease in the levels of cholesterol synthesis genes. Our results suggest that the conservation of the N-terminal activation and repression domains (and not the RS/RNA recognition motif) is what determines the gene programs and splicing options modulated by each PGC-1α isoform. By using skeletal muscle-specific transgenic mice for PGC-1α1 and -α4, we could validate, in vivo, splicing events observed in in vitro studies. These results show that alternative PGC-1α variants can affect target gene expression both quantitatively and qualitatively and identify novel biological pathways under the control of this system of coactivators.
authors.affiliation: From the Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology Unit and.
authors.forename: Vicente
authors.initials: V
authors.lastname: Martínez-Redondo
authors.affiliation: From the Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology Unit and School of Physical Education and Sport, University of São Paulo, 05508-030 São Paulo, Brazil, and.
authors.forename: Paulo R
authors.initials: PR
authors.lastname: Jannig
authors.affiliation: From the Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology Unit and.
authors.forename: Jorge C
authors.initials: JC
authors.lastname: Correia
authors.affiliation: From the Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology Unit and.
authors.forename: Duarte M S
authors.initials: DM
authors.lastname: Ferreira
authors.affiliation: From the Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology Unit and.
authors.forename: Igor
authors.initials: I
authors.lastname: Cervenka
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, SE-141 83 Huddinge, Sweden.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Lindvall
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, SE-141 83 Huddinge, Sweden.
authors.forename: Indranil
authors.initials: I
authors.lastname: Sinha
authors.affiliation: From the Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology Unit and.
authors.forename: Manizheh
authors.initials: M
authors.lastname: Izadi
authors.affiliation: From the Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology Unit and.
authors.forename: Amanda T
authors.initials: AT
authors.lastname: Pettersson-Klein
authors.affiliation: From the Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology Unit and.
authors.forename: Leandro Z
authors.initials: LZ
authors.lastname: Agudelo
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Gimenez-Cassina
authors.affiliation: School of Physical Education and Sport, University of São Paulo, 05508-030 São Paulo, Brazil, and.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Brum
authors.affiliation: Department of Biosciences and Nutrition, Novum, Karolinska Institutet, SE-141 83 Huddinge, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Dahlman-Wright
authors.affiliation: From the Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology Unit and Jorge.Ruas@ki.se.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Ruas
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D017124:Conserved Sequence; D005091:Exons; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D011987:Receptors, Steroid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000098825:Oxysterol Binding Proteins
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D020033:Protein Isoforms; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins
keywords: PGC-1α2; PGC-1α3; PGC-1α4; alternative splicing; exercise; exon array; gene regulation; peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) (PPARGC1A); skeletal muscle