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

J Mol Cell Cardiol. 2009 May;46(5):739-47. doi: 10.1016/j.yjmcc.2009.02.010. Epub 2009 Feb 21.


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-3beta (GSK-3beta) 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-3beta 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-3beta in R92Q hearts decreases phosphorylation of troponin I and results in early mortality. In contrast, increased GSK-3beta activity in Trunc hearts does not significantly impact cardiac phenotypes. These findings demonstrate that increased Akt and its downstream target, GSK-3beta 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Body Weight
  • Cardiomyopathy, Hypertrophic, Familial / enzymology*
  • Cardiomyopathy, Hypertrophic, Familial / genetics
  • Enzyme Activation
  • Gene Expression Regulation
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Heart Ventricles / enzymology
  • Heart Ventricles / pathology
  • Hypertrophy / genetics
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mutation / genetics
  • Myocardium / pathology
  • Organ Size
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction*
  • Survival Analysis
  • Troponin T / metabolism


  • Troponin T
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3