The role of Akt/GSK-3β 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-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.

A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy

“…Indeed, stimulation-frequency dependent translocation of NFAT to the nucleus was observed with both a gain and loss in myofilament activation. While not tested here, there are several regulators of NFAT translocation and cardiac hypertrophy including glycogen synthase kinase 3β (GSK3β) that may help account for this feature, even in an HCM background (Luckey et al, 2009). Our observations that loss of the Ppp3cb gene reduces growth in the I61Q background, but not ventricular remodeling, is consistent with an array of past data in the literature implicating calcineurin-NFAT signaling as a primary determinant of generalized cardiac hypertrophy (Houser and Molkentin, 2008).…”

Abnormal heart rate regulation in murine hearts with familial hypertrophic cardiomyopathy-related cardiac troponin T mutations

“…However, it is important to note that the clinical profiles and genetic backgrounds for HCM patients in these studies vary considerably, potentially obscuring the benefits of autonomic function assessment. We were able to address these potential obstacles in our highly backcrossed TG mouse models of FHC by comparing two independent cTnT mutations that have been extensively studied in previous studies (3,4,10,14,18,19,21,31,33). In doing so, we can now determine that the R92Q cTnT mutation leads to altered HR regulation, and, thus, we can identify a genotype-specific phenotype using a noninvasive technique in mice.…”

Supplementation of Creatine and Ribose Prevents Apoptosis and Right Ventricle Hypertrophy in Hypoxic Hearts

“…Whereas p-Akt mediates cardiac protection against hypoxia and reoxygenation injury [35] and delays the onset of apoptosis by inducing ERK and inhibiting JNK and p38 [36], it is also recognized as a pivotal participant in hypertrophic signaling [37]. Indeed, Akt regulates cardiac hypertrophy mainly by increasing cardiomyocyte size rather than cardiomyocyte proliferation [38,39]. By preventing the activation of AMPK and Akt, administration of CrRib should lead to the reduction of hypertrophy and, at the same time, the increase of apoptosis.…”