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Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins
Hui-Hua Li, … , David J. Glass, Cam Patterson
Hui-Hua Li, … , David J. Glass, Cam Patterson
Published October 25, 2007
Citation Information: J Clin Invest. 2007;117(11):3211-3223. https://doi.org/10.1172/JCI31757.
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Research Article Cardiology

Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins

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Abstract

Cardiac hypertrophy is a major cause of human morbidity and mortality. Although much is known about the pathways that promote hypertrophic responses, mechanisms that antagonize these pathways have not been as clearly defined. Atrogin-1, also known as muscle atrophy F-box, is an F-box protein that inhibits pathologic cardiac hypertrophy by participating in a ubiquitin ligase complex that triggers degradation of calcineurin, a factor involved in promotion of pathologic hypertrophy. Here we demonstrated that atrogin-1 also disrupted Akt-dependent pathways responsible for physiologic cardiac hypertrophy. Our results indicate that atrogin-1 does not affect the activity of Akt itself, but serves as a coactivator for members of the Forkhead family of transcription factors that function downstream of Akt. This coactivator function of atrogin-1 was dependent on its ubiquitin ligase activity and the deposition of polyubiquitin chains on lysine 63 of Foxo1 and Foxo3a. Transgenic mice expressing atrogin-1 in the heart displayed increased Foxo1 ubiquitylation and upregulation of known Forkhead target genes concomitant with suppression of cardiac hypertrophy, while mice lacking atrogin-1 displayed the opposite physiologic phenotype. These experiments define a role for lysine 63–linked ubiquitin chains in transcriptional coactivation and demonstrate that atrogin-1 uses this mechanism to disrupt physiologic cardiac hypertrophic signaling through its effects on Forkhead transcription factors.

Authors

Hui-Hua Li, Monte S. Willis, Pamela Lockyer, Nathaniel Miller, Holly McDonough, David J. Glass, Cam Patterson

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Figure 6

Enhanced Forkhead protein ubiquitylation and activity and suppressed IGF-1/GH-dependent cardiac hypertrophy in cardiac-specific atrogin-1 Tg mice.

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Enhanced Forkhead protein ubiquitylation and activity and suppressed IGF...
(A) Cardiac hypertrophy was induced in 8-wk-old mice with IGF-1/GH injections. Atrogin-1 Tg and WT mice were sacrificed 14 d later; their hearts were freshly isolated; and levels of the indicated total and phospho-proteins were determined by IB. Results were normalized to relative expression levels of phospho-Foxo1, Foxo3a, and Akt (n = 6). *P < 0.001 vs. WT. (B) Equal amounts of lysates from WT and Tg hearts were immunoprecipitated with Foxo3a antibody and analyzed by IB with antibodies against ubiquitin or Foxo3a to detect ubiquitylated forms of Foxo3a in vivo before and after IGF-1/GH treatment. (C) RT-PCR was performed to measure the expression of known Foxo1 and Foxo3a target genes in WT and Tg mouse hearts before and after IGF-1/GH treatment. Total RNA was isolated from mouse hearts, and expression of transcripts for Bim, p27Kip1, GADD45, SOD2, and GAPDH was determined and normalized to GAPDH (n = 6). *P < 0.001 vs. WT. A representative analysis is shown. (D) M-mode echocardiographic analysis of hearts from Tg and WT mice after 2 wk IGF-1/GH injection. (E) Representative macroscopic histologic analysis of H&E-stained hearts from indicated mice after 2 wk IGF-1/GH injection. Histologic sections were also stained with wheat germ agglutinin–TRITC conjugate to determine cell size. Scale bars: 1 mm (top); 50 μm (bottom). (F) Cardiomyocyte size from WT and Tg hearts after IGF-1/GH treatment.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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