The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes
L. M. Dorsch, Diederik W.D. Kuster, Jan D.H. Jongbloed, Ludolf G. Boven, Karin Y. van Spaendonck‐Zwarts, Albert J.H. Suurmeijer, Aryan Vink, Gideon J. du Marchie Sarvaas, Maarten P. van den Berg, Jolanda van der Velden, Bianca J.J.M. Brundel, Paul A. van der Zwaag
Abstract
transients (CaT) in HL-1 cardiomyocytes were studied. To define toxic threshold levels, we performed dose-dependent transfection of TPM1 variants. In addition, cardiomyocyte structure was studied in human cardiac biopsies with TPM1 variants. Results - Overexpression of TPM1 variants led to time-dependent progressive deterioration of CaT, with the smallest effect seen for E62Q and larger and similar effects seen for the T201M and M281T variants. Overexpression of E62Q/M281T did not exacerbate the effects seen with overexpression of a single TPM1 variant. T201M (DCM) replaced endogenous tropomyosin dose-dependently, while M281T (HCM) did not. Human cardiac biopsies with TPM1 variants revealed loss of sarcomeric structures. Conclusion - All TPM1 variants result in reduced cardiomyocyte CaT amplitudes and loss of sarcomeric structures. These effects may underlie pathophysiology of different cardiomyopathy phenotypes.