title: Muscle RING finger-1 attenuates IGF-I-dependent cardiomyocyte hypertrophy by inhibiting JNK signaling.
abstract: Recent studies implicate the muscle-specific ubiquitin ligase muscle RING finger-1 (MuRF1) in inhibiting pathological cardiomyocyte growth in vivo by inhibiting the transcription factor SRF. These studies led us to hypothesize that MuRF1 similarly inhibits insulin-like growth factor-I (IGF-I)-mediated physiological cardiomyocyte growth. We identified two lines of evidence to support this hypothesis: IGF-I stimulation of cardiac-derived cells with MuRF1 knockdown 1) exhibited an exaggerated hypertrophy and, 2) conversely, increased MuRF1 expression-abolished IGF-I-dependent cardiomyocyte growth. Enhanced hypertrophy with MuRF1 knockdown was accompanied by increases in Akt-regulated gene expression. Unexpectedly, MuRF1 inhibition of this gene expression profile was not a result of differences in p-Akt. Instead, we found that MuRF1 inhibits total protein levels of Akt, GSK-3β (downstream of Akt), and mTOR while limiting c-Jun protein expression, a mechanism recently shown to govern Akt, GSK-3β, and mTOR activities and expression. These findings establish that MuRF1 inhibits IGF-I signaling by restricting c-Jun activity, a novel mechanism recently identified in the context of ischemia-reperfusion injury. Since IGF-I regulates exercise-mediated physiological cardiac growth, we challenged MuRF1(-/-) and MuRF1-Tg+ mice and their wild-type sibling controls to 5 wk of voluntary wheel running. MuRF1(-/-) cardiac growth was increased significantly over wild-type control; conversely, the enhanced exercise-induced cardiac growth was lost in MuRF1-Tg+ animals. These studies demonstrate that MuRF1-dependent attenuation of IGF-I signaling via c-Jun is applicable in vivo and establish that further understanding of this novel mechanism may be crucial in the development of therapies targeting IGF-I signaling.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Wadosky
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Rodríguez
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hite
authors.forename: Jin-na
authors.initials: JN
authors.lastname: Min
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Walton
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D007334:Insulin-Like Growth Factor I; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Akt; c-Jun NH2-terminal kinase; cardiac hypertrophy; insulin-like growth factor I; muscle RING finger-1