Regulation of Cardiomyocyte Sarcolemmal Membrane Repair by TRIM72/MG53 Compensate for Pathology during Heart Failure

Regulation of cellular signaling responses through post‐translational modification of proteins is essential for many processes in cardiomyocytes. Ubiquitination of protein contributes both to proteasome‐mediated degradation of specific proteins as well as to modification of protein function as a component of cell signaling responses. The tripartite motif (TRIM) family of E3 ligases have been linked to regulation of many cellular function in cardiomyocytes. Previous studies show that TRIM72 (or MG53) is required for effective sarcolemmal membrane repair in cardiomyocytes. The membrane repair process is a highly conserved pathway were membrane disruptions trigger a robust exocytotic response that leads to formation of a membrane repair patch that can restore membrane integrity. Compromised membrane integrity can result in cardiomyopathy in multiple mouse models. While TRIM72 clearly contributes to sarcolemmal membrane repair the molecular mechanism of its function is not clear. In these studies, we resolve that acute activation of the PI3K‐Akt signaling axis is essential for membrane repair in cardiomyocytes and that TRIM72 function through interaction with the PI3K‐Akt pathway. Overexpression of TRIM72 results in an increased activation of PI3K and AKT and increases rates of exocytosis. This effect can be blocked either through pharmacological inhibition or dominant negative genetic approaches disrupting PI3K‐Akt signaling. These manipulations compromise basal sarcolemmal membrane repair and also block the elevated membrane repair following TRIM72 overexpression. Conversely, pharmaceutical activation of the PI3K‐Akt1 pathway can increase membrane repair in failing mouse hearts and myocardium from failing human hearts to compensate for reduced repair responses observed in failing cardiomyocytes. Mouse studies with trans‐aortic constriction surgery show that increasing membrane repair in failing hearts can minimize the pathology associated with heart failure in this model. These results show that TRIM72 mediated membrane repair acts through the PI3K/Akt pathway and that targeting membrane repair has therapeutic potential for the treatment of heart failure.