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PGC-1 and PGC-1 have both similar and distinct effects on myofiber switching toward an oxidative phenotype

¹Department of Medical Biochemistry and Genetics, University of Copenhagen, and ³Department of Molecular Muscle Biology, Copenhagen Muscle Research Centre and Rigshospitalet, Copenhagen; and ²Department of Diabetes Biology, Novo Nordisk, Måløv, Denmark

Submitted 29 November 2005 ; accepted in final form 2 May 2006

Peroxisome proliferator-activated receptor- coactivator-1 and -1 (PGC-1 and PGC-1) were overexpressed by adenovirus-mediated gene transfer in cultures of primary rat skeletal muscle cells derived from neonatal myoblasts. Effects on muscle fiber type transition and metabolism were studied from days 5 to 22 of culture. PGC-1 and PGC-1 overexpression caused a three- to fourfold increase in mRNA level, a doubling of enzymatic activity of citrate synthase, a slight increase in short-chain acyl-CoA dehydrogenase mRNA, a doubling of the mRNA level, and a 30–50% increase in enzymatic activity of glyceraldehyde-3-phosphate dehydrogenase. Lactate dehydrogenase or creatine kinase activity was unchanged. PGC-1 enhanced glycogen buildup twofold at 5 or 25 mM glucose, whereas PGC-1 caused a decrease. Both PGC-1 and PGC-1 overexpression caused a faster maturation of myotubes, as seen by mRNA downregulation of the immature embryonal and perinatal myosin heavy-chain (MHC) isoforms. PGC-1 or PGC-1 overexpression enhanced mRNA of the slow oxidative-associated MHC isoform MHCIb and downregulated mRNA levels of the fast glycolytic-associated MHC isoforms MHCIIX and MHCIIB. Only PGC-1 overexpression caused an increase in mRNA of the intermediary fast oxidative-associated MHC isoform MHCIIA. PGC-1 or PGC-1 overexpression upregulated GLUT4 mRNA and downregulated myocyte enhancer factor 2C transcription factor mRNA; only PGC-1 overexpression caused an increase in the mRNA expression of TRB3, a negative regulator of insulin signaling. These results show that both PGC-1 and PGC-1 are involved in the regulation of skeletal muscle fiber transition and metabolism and that they have both overlapping and differing effects.

skeletal muscle cell culture; peroxisome proliferator-activated receptor coactivator-1; myosin heavy chain; enzyme activities; glycogen

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