Engineering Cardiac Troponin C: Potential Therapeutic for Heart Failure

Abstract

We have engineered cardiac TnCs with increased (L48Q) or decreased (D73N) Ca2+ sensitivity. To express these proteins in the in vivo heart we utilized an adeno-associated virus serotype 9 (AAV-9). The Ca2+ desensitized D73N TnC recapitulated a dilated cardiomyopathy phenotype and depressed function as observed by echocardiography and isolated cardiomyocytes. On the other hand, AAV-9 containing the Ca2+ sensitized L48Q TnC did not cause any disease phenotype or arrhythmias commonly associated with increased myofilament Ca2+ sensitivity. In healthy mice, L48Q TnC increased myocyte contraction and whole heart contractility with improved cardiovascular performance (increased V02max). Excitingly, L48Q TnC expressing mice were able to preserve higher contractility, ejection fraction, cardiac performance and decreased death rate even after undergoing trans-aortic constriction or myocardial infarction. Additionally, L48Q TnC was able to increase contractility, ejection fraction and cardiac performance in mice which expressed L48Q TnC after having a myocardial infarction. In summary, engineered TnCs show potential to be used as treatment strategies against different cardiomyopathies.