Wnt/β-catenin pathway induces cardiac dysfunction via AKAP6-mediated RyR2 phosphorylation and sarcoplasmic reticulum calcium leakage.

The Wnt signaling pathway plays important roles in cardiomyocyte proliferation and cardiac regeneration after heart injury. Abnormal activation of the Wnt pathway causes a reduction in cardiomyocyte function, leading to hypertrophy, fibrosis, and heart failure. However, the mechanism through which Wnt signaling affects cardiomyocyte function during cardiac diseases is still unclear. In this study, we observed that activation of the Wnt/β-catenin pathway, but not the Wnt/Ca2+ pathway, leads to significant cytosol calcium enrichment. Such an effect can be inhibited by cycloheximide that blocks the downstream gene expression. By analyzing the transcriptome data, we found that activation of the Wnt/β-catenin pathway significantly upregulates the expression level of muscle-selective A kinase anchoring protein (mAKAP, also called AKAP6), a scaffold protein that can improve the interaction between protein kinase A (PKA) and its substrate ryanodine receptor 2 (RyR2) in cardiomyocytes. We further identified that AKAP6 is a target gene of the canonical Wnt pathway and increasing AKAP6 expression can enhance RyR2 phosphorylation by PKA, causing the sarcoplasmic reticulum calcium leakage and finally heart dysfunction. Our finding that the Wnt/β-catenin pathway affects cardiac calcium regulation via AKAP6 and RyR2 provides profound insights into heart diseases and sheds light on potential therapeutic strategies.