Phosphoinositide 3-kinase (P110alpha) directly regulates key components of the Z-disc and cardiac structure.

Maintenance of cardiac structure and Z-disc signaling are key factors responsible for protecting the heart in a setting of stress, but how these processes are regulated are not well defined. We recently demonstrated that phosphoinositide 3-kinase [PI3K(p110α)] protects the heart against myocardial infarction (MI). The aim of this study was to determine whether PI3K(p110α) directly regulates components of the Z-disc and cardiac structure. To address this question a unique 3D Virtual Muscle model (VMus3D) was applied to gene expression data from transgenic mice with increased or decreased PI3K(p110α) activity under basal conditions (sham) and in a setting of MI to display the location of structural proteins. Key findings from this analysis were then validated experimentally. VMus3D visually highlighted reciprocally regulated transcripts associated with PI3K activation that encoded key components of the Z-disc and costamere including melusin. Studies were performed to assess whether PI3K and melusin interact in the heart. Here, we identify a novel melusin-PI3K interaction that generates lipid kinase activity. The direct impact of PI3K(p110α) on myocyte structure was assessed by treating neonatal rat ventricular myocytes with PI3K(p110α) inhibitors, and examining myofiber morphology of hearts from PI3K transgenic mice. Results demonstrate that PI3K is critical for myofiber maturation and Z-disc alignment. In summary, PI3K regulates the expression of genes essential for cardiac structure and Z-disc signaling, interacts with melusin, and is critical for Z-disc alignment.