Deciphering the cardioprotective role of UFM1 modification in cardiac physiopathological remodeling

Ufmylation is a novel ubiquitin-like protein modification that plays a critical role in maintaining the homeostasis of different tissues but its role in the heart remains poorly understood. UFM1 (ubiquitin-fold modifier 1) resembles Ub-like proteins that covalently modifies protein substrates via a highly conserved E1 (UBA5)-E2 (UFC1)-E3 (UFL1) enzymatic cascade. We have previously reported that ufmylation is upregulated in compensated, hypertrophic mouse hearts but decreased in failing human hearts. However, its role in cardiac remodeling and if the ufmylation of cardiac proteins is required for heart function is unknown. To further address this question, cardiomyocyte-specific UFM1-knockout (UFM1 CKO ) mice were characterized during aging. The UFM1 CKO mice developed dilated cardiomyopathy at resting condition, as indicated by the left ventricle (LV) wall thinning, chamber dilatation, and impaired contractility at 4 months of age, further exacerbated by 6 months. When exposed to beta-adrenergic agonist Isoproterenol, UFM1-deficient hearts exhibited remarkably worsened cardiac contractility and exacerbated fibrosis compared with control counterparts. Mechanistically, UFM1 modification constrains physiopathological cardiac remodeling by maintaining ER homeostasis and regulating ER stress response. To further understand the significance of UFM1 modification in the heart, we replenished UFM1-deficient mice with cardiac-specific WT and conjugation-deficient mutant UFM1 via AAV9. Echocardiography revealed that, unlike wild-type (WT) UFM1, the overexpression of the conjugation-deficient mutant did not alleviate cardiac remodeling and dysfunction in the UFM1 CKO heart. This validates the hypothesis that UFM1 protects the heart by modifying cardiac proteins. Overall, these results demonstrate that ufmylation is essential for cardiac growth and pathological cardiac remodeling upon stress and that disruption of ufmylation predisposes the heart to heart failure. AHA24POST1196232 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.