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Muscle RING Finger‐1 (MuRF1) inhibits insulin‐like growth factor‐1 (IGF‐1)‐dependent cardiomyocyte hypertrophy by reducing Akt nuclear activity
Author(s) -
Wadosky Kristine M.,
Hite Rebecca L.,
Willis Monte S.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.386.4
Subject(s) - protein kinase b , gene knockdown , muscle hypertrophy , nuclear localization sequence , medicine , phosphorylation , endocrinology , transcription factor , foxo1 , insulin like growth factor , signal transduction , microbiology and biotechnology , chemistry , cell growth , small interfering rna , nuclear transport , biology , growth factor , cell nucleus , nucleus , biochemistry , rna , apoptosis , receptor , gene
Previous studies in our laboratory have demonstrated that MuRF1 inhibits cardiomyocyte growth in pathological hypertrophy by inhibiting specific nuclear transcription factors. To further define MuRF1's role in regulating other types of hypertrophy, we investigated MuRF1's role in the development of exercise‐induced physiologic hypertrophy, acting through the IGF‐1 signaling pathway. The cardiomyocyte‐derived HL‐1 cell line was treated with 10nM of IGF‐1 after MuRF1 expression was increased or transiently knocked down using adenovirus constructs. MuRF1 knockdown elicited an exaggerated IGF‐1‐dependent increase in cell area (49.6%) compared to control adenovirus (30.1%), normalized to vehicle controls. Conversely, increased MuRF1 expression completely inhibited IGF‐1‐dependent growth. Since IGF‐1 signaling converges on the kinase Akt, we determined if IGF‐1‐stimulated cell growth with MuRF1 knockdown was accompanied by enhanced Akt signaling. Decreasing MuRF1 significantly increased active Akt localization in the nucleus, along with evidence of increased nuclear‐specific Akt activity‐increased nuclear phospho‐forkhead box protein O‐1 (FOXO1) and decreased prostaglandin D2 synthase (PDGS) expression. These findings suggest that MuRF1 inhibits IGF‐1‐dependent Akt nuclear localization and activity, identifying a novel mechanism of regulating physiologic cardiac hypertrophy.