Molecular and Functional Characterization of a Novel Cardiac-Specific Human Tropomyosin Isoform

Background-Tropomyosin (TM), an essential actin-binding protein, is central to the control of calcium-regulated striated muscle contraction. Although TPM1 alpha (also called alpha-TM) is the predominant TM isoform in human hearts, the precise TM isoform composition remains unclear. Methods and Results-In this study, we quantified for the first time the levels of striated muscle TM isoforms in human heart, including a novel isoform called TPM1 kappa. By developing a TPM1 kappa-specific antibody, we found that the TPM1 kappa protein is expressed and incorporated into organized myofibrils in hearts and that its level is increased in human dilated cardiomyopathy and heart failure. To investigate the role of TPM1 kappa in sarcomeric function, we generated transgenic mice overexpressing cardiac-specific TPM1 kappa. Incorporation of increased levels of TPM1 kappa protein in myofilaments leads to dilated cardiomyopathy. Physiological alterations include decreased fractional shortening, systolic and diastolic dysfunction, and decreased myofilament calcium sensitivity with no change in maximum developed tension. Additional biophysical studies demonstrate less structural stability and weaker actin-binding affinity of TPM1 kappa compared with TPM1 alpha. Conclusions-This functional analysis of TPM1 kappa provides a possible mechanism for the consequences of the TM isoform switch observed in dilated cardiomyopathy and heart failure patients. (Circulation. 2010;121:410-418.)