The role of Akt/GSK-3β signaling in familial hypertrophic cardiomyopathy

Stephen W. Luckey, Lori A. Walker, Tyson Smyth, Jason Mansoori, Antke Messmer-Kratzsch, Anthony Rosenzweig, Eric N. Olson, Leslie A. Leinwand

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Mutations in cardiac troponin T (TnT) are a cause of familial hypertrophic cardiomyopathy (FHC). Transgenic mice expressing a missense mutation (R92Q) or a splice site donor mutation (Trunc) in the cardiac TnT gene have mutation-specific phenotypes but mice of both models have smaller hearts compared to wild type and exhibit hemodynamic dysfunction. Because growth-related signaling pathways in the hearts of mice expressing TnT mutations are not known, we evaluated the impact of increased Akt or glycogen synthase kinase-3β (GSK-3β) activity in both mutant TnT mice; molecules that increase heart size via physiologic pathways and block pathologic growth, respectively. Expression of activated Akt dramatically augments heart size in both R92Q and Trunc mice; however, this increase in heart size is not beneficial, since Akt also increases fibrosis in both TnT mutants and causes some pathologic gene expression shifts in the R92Q mice. Activated GSK-3β results in further decreases in left ventricular size in both R92Q and Trunc hearts, but this decrease is associated with significant mutation-specific phenotypes. Among many pathologic consequences, activating GSK-3β in R92Q hearts decreases phosphorylation of troponin I and results in early mortality. In contrast, increased GSK-3β activity in Trunc hearts does not significantly impact cardiac phenotypes. These findings demonstrate that increased Akt and its downstream target, GSK-3β can impact both cardiac size and phenotype in a mutation-specific manner. Moreover, increased activity of these molecules implicated in beneficial cardiac phenotypes exacerbates the progression of disease in the R92Q TnT mutant.

Original languageEnglish (US)
Pages (from-to)739-747
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume46
Issue number5
DOIs
StatePublished - May 1 2009

Keywords

  • Akt
  • Cardiomyopathy
  • Familial hypertrophic cardiomyopathy
  • Glycogen synthase kinase-3β (GSK-3β)
  • Troponin T

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    Luckey, S. W., Walker, L. A., Smyth, T., Mansoori, J., Messmer-Kratzsch, A., Rosenzweig, A., Olson, E. N., & Leinwand, L. A. (2009). The role of Akt/GSK-3β signaling in familial hypertrophic cardiomyopathy. Journal of Molecular and Cellular Cardiology, 46(5), 739-747. https://doi.org/10.1016/j.yjmcc.2009.02.010