BPS2026 – The D73N troponin C mouse: A translational model of dilated cardiomyopathy with mitochondrial ROS and novel atrial myxomas

Dilated cardiomyopathy (DCM) is a major cause of heart failure, defined by ventricular dilation and reduced systolic performance. To dissect the molecular underpinnings of DCM, we employed a knock-in mouse model expressing the D73N mutation in cardiac troponin C (cTnC). This targeted mutation, introduced into the Ca 2+ -binding regulatory N domain of cTnC, accelerates Ca 2+ dissociation, thereby desensitizing myofilaments to Ca 2+ . These mice recapitulate hallmarks of human DCM, including reduced ejection fraction, ventricular dilation, and early mortality. Notably, these mice also exhibit elevated mitochondrial reactive oxygen species (ROS) levels, consistent with redox dysregulation in failing myocardium. Furthermore, a subset of D73N mice develop left atrial cardiac myxomas, a rare but pathologically relevant finding that may reflect altered biomechanical or paracrine signaling within the stressed cardiac microenvironment. Despite these severe cardiac abnormalities, no functional deficits were observed in peripheral tissues. Cage-side observations, diaphragm contractility, carotid artery responsiveness, and skeletal muscle force output were all preserved compared to wild-type controls. Further, whole-body metabolic parameters, insulin, and glucose tolerances also remained unchanged, confirming that the D73N model is cardiac-specific and not confounded by systemic dysfunction. Together, these findings establish the D73N knock-in mouse as a highly specific and translationally relevant model of DCM, distinguished by cardiac-restricted dysfunction, oxidative stress, and the emergence of atrial myxoma. This model is ideal for testing therapies aimed at restoring Ca 2+ sensitivity, redox balance, or preventing maladaptive cardiac remodeling.