| First Author | Luckey SW | Year | 2009 |
| Journal | J Mol Cell Cardiol | Volume | 46 |
| Issue | 5 | Pages | 739-47 |
| PubMed ID | 19233194 | Mgi Jnum | J:149164 |
| Mgi Id | MGI:3847840 | Doi | 10.1016/j.yjmcc.2009.02.010 |
| Citation | Luckey SW, et al. (2009) The role of Akt/GSK-3beta signaling in familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 46(5):739-47 |
| abstractText | 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. |
