Blocking cardiac hypertrophy via active GSK-3beta in a mouse model of hypertrophic cardiomyopathy induced depressed contractile function and premature death in males, but not in females.
Does blocking cardiac hypertrophy via active GSK-3beta improve outcomes in a mouse model of hypertrophic cardiomyopathy?
Blocking cardiac hypertrophy via GSK-3beta activation in an HCM mouse model is not therapeutic and causes sexually dimorphic maladaptive effects, including premature death in males.
Mutations in myosin heavy chain (MyHC) can cause hypertrophic cardiomyopathy (HCM) that is characterized by hypertrophy, histopathology, contractile dysfunction, and sudden death. The signaling pathways involved in the pathology of HCM have not been elucidated, and an unresolved question is whether blocking hypertrophic growth in HCM may be maladaptive or beneficial. To address these questions, a mouse model of HCM was crossed with an antihypertrophic mouse model of constitutive activated glycogen synthase kinase-3beta (caGSK-3beta). Active GSK-3beta blocked cardiac hypertrophy in both male and female HCM mice. However, doubly transgenic males (HCM/GSK-3beta) demonstrated depressed contractile function, reduced sarcoplasmic (endo) reticulum Ca(2+)-ATPase (SERCA) expression, elevated atrial natriuretic factor (ANF) expression, and premature death. In contrast, female HCM/GSK-3beta double transgenic mice exhibited similar cardiac histology, function, and survival to their female HCM littermates. Remarkably, dietary modification from a soy-based diet to a casein-based diet significantly improved survival in HCM/GSK-3beta males. These findings indicate that activation of GSK-3beta is sufficient to limit cardiac growth in this HCM model and the consequence of caGSK-3beta was sexually dimorphic. Furthermore, these results show that blocking hypertrophy by active GSK-3beta in this HCM model is not therapeutic.
Luckey et al. (Sat,) conducted a other in Hypertrophic cardiomyopathy. Constitutively active glycogen synthase kinase-3beta (caGSK-3beta) vs. HCM littermates without caGSK-3beta was evaluated on Cardiac hypertrophy, contractile function, and survival. Blocking cardiac hypertrophy via active GSK-3beta in a mouse model of hypertrophic cardiomyopathy induced depressed contractile function and premature death in males, but not in females.