Blocking cardiac growth in hypertrophic cardiomyopathy induces cardiac dysfunction and decreased survival only 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-3β (caGSK-3β). Active GSK-3β blocked cardiac hypertrophy in both male and female HCM mice. However, doubly transgenic males (HCM/GSK-3β) demonstrated depressed contractile function, reduced sarcoplasmic (endo) reticulum Ca²⁺-ATPase (SERCA) expression, elevated atrial natriuretic factor (ANF) expression, and premature death. In contrast, female HCM/GSK-3β 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-3β males. These findings indicate that activation of GSK-3β is sufficient to limit cardiac growth in this HCM model and the consequence of caGSK-3β was sexually dimorphic. Furthermore, these results show that blocking hypertrophy by active GSK-3β in this HCM model is not therapeutic.