title: c-Flip overexpression affects satellite cell proliferation and promotes skeletal muscle aging.
abstract: This study shows that forcing c-Flip overexpression in undifferentiated skeletal myogenic cells in vivo results in early aging muscle phenotype. In the transgenic mice, adult muscle histology, histochemistry and biochemistry show strong alterations: reduction of fibers size and muscle mass, mitochondrial abnormalities, increase in protein oxidation and apoptosis markers and reduced AKT/GSK3β phosphorylation. In the infant, higher levels of Pax-7, PCNA, P-ERK and active-caspase-3 were observed, indicating enhanced proliferation and concomitant apoptosis of myogenic precursors. Increased proliferation correlated with NF-κB activation, detected as p65 phosphorylation, and with high levels of embryonic myosin heavy chain. Reduced regenerative potential after muscle damage in the adult and impaired fiber growth associated with reduced NFATc2 activation in the infant were also observed, indicating that the satellite cell pool is prematurely compromised. Altogether, these data show a role for c-Flip in modulating skeletal muscle phenotype by affecting the proliferative potential of undifferentiated cells. This finding indicates a novel additional mechanism through which c-Flip might possibly control tissue remodeling.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Giampietri
authors.forename: S
authors.initials: S
authors.lastname: Petrungaro
authors.forename: P
authors.initials: P
authors.lastname: Coluccia
authors.forename: F
authors.initials: F
authors.lastname: Antonangeli
authors.forename: K
authors.initials: K
authors.lastname: Giannakakis
authors.forename: T
authors.initials: T
authors.lastname: Faraggiana
authors.forename: A
authors.initials: A
authors.lastname: Filippini
authors.forename: G
authors.initials: G
authors.lastname: Cossu
authors.forename: E
authors.initials: E
authors.lastname: Ziparo
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D005615:Freezing; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D019076:Transgenes / Q000235:genetics
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3