title: The role of Akt/GSK-3beta signaling in familial hypertrophic cardiomyopathy.
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-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.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Campus Box 347, Boulder, Colorado 80309-0347, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Luckey
authors.forename: Lori A
authors.initials: LA
authors.lastname: Walker
authors.forename: Tyson
authors.initials: T
authors.lastname: Smyth
authors.forename: Jason
authors.initials: J
authors.lastname: Mansoori
authors.forename: Antke
authors.initials: A
authors.lastname: Messmer-Kratzsch
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Leinwand
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001835:Body Weight; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000201:enzymology* / Q000235:genetics; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006352:Heart Ventricles / Q000201:enzymology / Q000473:pathology; D006984:Hypertrophy / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D020107:Troponin T / Q000378:metabolism
chemical_list: D020107:Troponin T; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3