Abstract
We previously identified that MuRF1 inhibits cardiomyocyte growth in pressure overload‐induced cardiac hypertrophy. To determine if MuRF1 more broadly regulates physiologic cardiac hypertrophy, we tested the hypothesis that MuRF1 regulates insulin‐like growth factor‐1 (IGF‐1)‐dependent cardiomyocyte growth that occurs in response to exercise. Transient MuRF1 knockdown in HL‐1 cardiomyocytes treated with IGF‐1 resulted in a 53.3% increase in cell size, compared to a 30.0% increase in cell size in scrambled siRNA control treated cells. This exaggerated IGF‐1‐dependent cell growth was abolished in cells with increased MuRF1 expression. Since IGF‐1signaling pathway converges on the serine/threonine kinase Akt‐1, we next determined MuRF1's role in IGF‐1 mediated Akt‐1 activation. Decreasing MuRF1 resulted in an increased IGF‐1‐dependent activation of Akt‐1. Since IGF‐1 signaling regulates physiologic cardiac growth, we next subjected MuRF1 −/− mice to voluntary wheel running. MuRF1−/− mice run significantly faster (4.47±0.28 vs. 3.31±0.14 mph) and for longer distances (17.2±1.5 vs. 12.1±0.7 km) compared to sibling‐matched wildtype mice, resulting in an increased left ventricular (LV) mass compared to sham (~40% greater vs. ~30% in MuRF1 +/+ mice). These studies suggest a role of MuRF1 in regulating exercise‐induced cardiac hypertrophy in vivo by its regulation of the IGF‐1 signaling pathway.
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