MYOM1 deficiency leads to dilated cardiomyopathy by disrupting the homeostasis of sarcoplasmic reticulum.

MYOM1, a major component of the vertebrate myofibrillar M band, binds myosin, titin, and light meromyosin, has been linked to cardiomyopathy and unexpected sudden death, yet the pathogenic mechanisms remain unclear. Leveraging the UK Biobank, we identified a significant association between dilated cardiomyopathy (DCM) and loss-of-function (LoF) MYOM1 variants. Functional studies showed that MYOM1 deficiency precipitates DCM with overt heart failure, accompanied by sarcomeric disorganization, pathological structural remodeling, and mitochondrial abnormalities. Optical mapping of cardiac electrophysiology revealed slowed ventricular conduction with increased heterogeneity, alongside marked prolongation of action potential duration and depolarization. At the molecular level, transcriptomic and immunoblot analyses demonstrated downregulation of key sarcoplasmic reticulum regulators, including RYR2 and SERCA2. Consistent with these findings, calcium imaging documented impaired calcium conduction velocity and blunted intracellular calcium transients, indicating sarcoplasmic reticulum dysfunction. Our study provided significant insights into the role of MYOM1 variants in DCM. LoF of MYOM1 contributes to DCM and heart failure by disrupting sarcomere integrity and destabilizing sarcoplasmic reticulum calcium homeostasis, with secondary mitochondrial abnormalities. These data establish MYOM1 as a disease-relevant determinant of myocardial remodeling and excitation-contraction coupling, and support MYOM1 as a potential target for risk stratification and therapy in DCM.