Reduced Expression of MTSS1 Increases Sarcomere Number and Improves Contractility in Select Forms of Monogenic DCM

The I-bar protein MTSS1 has been implicated in heart failure and contractility by multiple genome-wide association studies. Human genetic analyses suggested that a variant lowering cardiac MTSS1 expression was associated with significantly improved survival in individuals with TTN dilated cardiomyopathy (DCM). Experimental knockdown of MTSS1 via small interfering RNA (siRNA) in induced pluripotent stem cell-derived cardiomyocytes deficient in TTN, CSRP3, or RBM20 led to improved increased sarcomere number and enhanced contractility. Engineered heart tissue models confirmed increased twitch force following MTSS1 siRNA knockdown across these genetic forms of DCM. Unbiased mass-spectrometry suggests that MTSS1 was found to interact with MYO18A, a protein critical for sarcomere assembly, and siRNA knockdown of MTSS1 up-regulated MYH7 and other sarcomere-related genes. These findings may suggest that MTSS1 impacts contractility as a negative regulator of sarcomere formation or turnover, and that reduction of MTSS1 may be a therapeutic target in select forms of genetic DCM.