title: Leptin impairs myogenesis in C2C12 cells through JAK/STAT and MEK signaling pathways.
abstract: Reduced lean body mass in genetically obese (ob/ob) or anorectic/cachectic subjects prompted us to verify the hypothesis whether leptin, white adipose tissue cytokine, might be a negative organizer of myogenesis. Recombinant leptin (100 ng/mL) stimulated mitogenesis together with the raise in T(202/)Y(204)P-ERK1/2 protein expression. Concomitantly, it impaired cell viability and muscle fiber formation from C2C12 mouse myoblasts. Detailed acute and chronic studies with the use of metabolic inhibitors revealed that both JAK/STAT3 and MEK/MAPK but not PI3-K/AKT/GSK-3β signaling pathways were activated by leptin, and that STAT3 (Y(705)P-STAT3) and MEK (T(202/)Y(204)P-ERK1/2) mediate these effects. In contrary, insulin evoked PI3-K-dependent phosphorylation of AKT (S(473)) and GSK-3β (S(9)) and insulin surpassed leptin-dependent inhibition of myogenic differentiation in PI3-K-dependent manner. GSK-3β seems to play dual role in muscle development. Insulin-dependent effect on GSK-3β (S(9)P-GSK-3β) led to accelerated myotube construction. In contrary, leptin through MEK-dependent manner caused GSK-3β phosphorylation (Y(216)P-GSK-3β) with resultant drop in myoblast fusion. Summing up, partially opposite effects of insulin and leptin on skeletal muscle growth emphasize the importance of interplay between these cytokines. They determine how muscle mass is gained or lost.
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences (SGGW), Nowoursynowska 159, 02-776 Warsaw, Poland.
authors.forename: Maja
authors.initials: M
authors.lastname: Pijet
authors.forename: Barbara
authors.initials: B
authors.lastname: Pijet
authors.forename: Anna
authors.initials: A
authors.lastname: Litwiniuk
authors.forename: Beata
authors.initials: B
authors.lastname: Pajak
authors.forename: Barbara
authors.initials: B
authors.lastname: Gajkowska
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Orzechowski
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology; D024510:Muscle Development / Q000187:drug effects*; D017570:MyoD Protein / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D018008:Myogenin / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D034421:Sus scrofa; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D005419:Flavonoids; D007328:Insulin; D020738:Leptin; D008934:Mitogens; D017570:MyoD Protein; D018008:Myogenin; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one