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-1 (IGF-1)-mediated physiologic cardiomyocyte growth. We identified two lines of evidence to support this hypothesis: 1) IGF-1 stimulation of cardiac-derived cells with MuRF1 knockdown exhibited an exaggerated hypertrophy; 2) Conversely, increased MuRF1 expression abolished IGF-1-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 MuRF1 inhibits total protein levels of Akt, GSK3β (downstream of Akt) and mTOR, while limiting c-Jun protein expression, a mechanism recently shown to govern Akt, GSK3β, and mTOR activities and expression. These findings establish that MuRF1 inhibits IGF-1 signaling by restricting c-Jun activity, a novel mechanism recently identified in the context of ischemia reperfusion injury. Since IGF-1 regulates exercise-mediated physiological cardiac growth, we challenged MuRF1 -/- and MuRF1Tg+ mice and their wildtype sibling controls to 5 weeks of voluntary wheel running. MuRF1 -/- cardiac growth was significantly increased over wildtype control; converse the enhanced exercise-induced cardiac growth was lost in MuRF1Tg+ animals. These studies demonstrate that MuRF1-dependent attenuation of IGF-1 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-1 signaling.