CCDC141 is a Connectin/Titin and Nesprin-1 binding protein that adapts cardiomyocytes to mechanical stress.

The heart adapts to mechanical stresses such as hypertension, yet the underlying mechanisms remain poorly understood. We identify CCDC141 as a mechanoadaptive factor in cardiomyocytes. CCDC141 interacts with the sarcomeric connectin/titin filament system and the nuclear envelope protein nesprin-1, and localizes to the costameres in adult cardiomyocytes. CCDC141-KO mouse cardiomyocytes exhibit hypertrophy. Their mitochondria display abnormal alignment and fusion, are burdened by elevated ATP production, and show reduced spare respiratory capacity. Increased SERCA2a expression enhances Ca²⁺ handling within the sarcoplasmic reticulum of CCDC141-KO cardiomyocytes. During pressure overload-induced heart failure in mice, CCDC141 relocalizes to the nuclear envelope, suggesting a stress-responsive role in maintaining nuclear integrity. CCDC141-KO hearts show low tolerance to mechanical stress, and despite only moderate pressure overload induced by transverse aortic constriction, they are more susceptible to fatal arrhythmias and progressive heart failure with disrupted nuclear morphology. These findings provide new insights into the molecular basis of cardiac mechanoadaptation and disease.