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In Vivo Epinephrine-Mediated Regulation of Gene Expression in Human Skeletal Muscle

Unité de Recherches sur les Obésités, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 586 (N.V., P.B., D.Lar., D.Lan.), Institut Louis Bugnard, Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, 31403 Toulouse, France; INSERM Avenir and EA3502 Université Paris 6 (K.C., V.P., C.P.), Service de Médecine et Nutrition, Hôtel-Dieu, 75004 Paris, France; Laboratoire d’Informatique Médicale et de Bioinformatique (M.C., A.B., B.H., J.-D.Z.), Faculté de Médecine de Bobigny, Université Paris Nord, 93017 Bobigny, France; INSERM, Unité 449 (Y.K.), Faculté de Médecine R. Laennec, 69372 Lyon, France; Department of Pediatrics and Genetics (G.S.B.), Howard Hugues Medical Institute, Beckman Center, Stanford University School of Medicine, Stanford, California 94305; and Centre d’Investigation Clinique Inserm-Hôpitaux de Toulouse (C.T.), Hôpital Purpan, 31059 Toulouse, France

Address all correspondence and requests for reprints to: Dominique Langin, Unité de Recherche sur les Obésités, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 586, Institut Louis Bugnard, Bâtiment L3, Centre Hospitalier Universitaire Rangueil, 31403 Toulouse Cedex 4, France. E-mail: langin{at}toulouse.inserm.fr.

The stress hormone epinephrine produces major physiological effects on skeletal muscle. Here we determined skeletal muscle mRNA expression profiles before and during a 6-h epinephrine infusion performed in nine young men. Stringent statistical analysis of data obtained using 43,000 cDNA element microarrays showed that 1206 and 474 genes were up- and down-regulated, respectively. Microarray data were validated using reverse transcription quantitative PCR. Gene classification was performed through data mining of Gene Ontology annotations, cluster analysis of regulated genes among 14 human tissues, and correlation analysis of mRNA and clinical parameter variations. Evidence of an autoregulatory control was provided by the regulation of key genes of the cAMP-dependent transcription pathway. Genes with known functional cAMP response elements were regulated by the hormone. The impact on metabolism was illustrated by coordinated regulations of genes involved in carbohydrate and protein metabolisms. Epinephrine had a profound effect on genes involved in immunity and inflammatory response, a previously unappreciated aspect of catecholamine action. Information on 526 mRNAs corresponded to genes of unknown function. These data define the molecular signatures of epinephrine action in human skeletal muscle. They may contribute to the understanding of skeletal muscle alterations observed in pathological conditions characterized by sympathetic nervous system overdrive.

This work was supported by grants from INSERM (CIC-Merck Clinical Research Program) (to D.Lan. and P.B.), Action Thématique Concertée INSERM en Nutrition (to D.Lan. and K.C.), and Fondation Claude Bernard (to K.C.).

Abbreviations: apo, Apolipoprotein; aRNA, amplified RNA; CRE, cAMP response element; CREB, cAMP response element-binding protein; CREM, CRE modulator; FDR, false discovery rate; GO, Gene Ontology; ICER, inducible cAMP early repressor; NADH, nicotinamide adenine dinucleotide, reduced form; PDE, phosphodiesterase; PKA, protein kinase A; RT, reverse transcription; RT-qPCR, RT-quantitative real-time PCR; SAM, significance analysis of microarray; SSC, saline sodium citrate; UDP, uridine 5'-diphosphate; VO₂, oxygen consumption.

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