Muscle RING finger-1 attenuates IGF-I-dependent cardiomyocyte hypertrophy by inhibiting JNK signaling

作者：Wadosky Kristine M; Rodriguez Jessica E; Hite Rebecca L; Min Jin Na; Walton Bethany L; Willis Monte S^*

来源：American Journal of Physiology - Endocrinology And Metabolism, 2014, 306(7): E723-E739.

DOI：10.1152/ajpendo.00326.2013

• insulin-like growth factor I
• c-Jun NH2-terminal kinase
• cardiac hypertrophy
• muscle RING finger-1
• Akt

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 cardiacderived 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-3 beta (downstream of Akt), and mTOR while limiting c-Jun protein expression, a mechanism recently shown to govern Akt, GSK-3 beta, 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.

• 出版日期2014-4