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

• DOI: 10.1161/circulationaha.109.889725
• Publication Date: 2010-01-12T03:21:10Z
• Authors: Sudarsan Rajan; Ganapathy Jagathe...; Chehade N. Karam; Marco L. Alves; Ilona Bodi; Arnold Schwartz; Christian F. Bulcao; Karen M. D'Souza; Shahab A. Akhter; Greg P. Boivin; Dipak K. Dube; Natalia Petrashev...; Andrew B. Herr; Roger Hullin; Stephen B. Liggett; Beata M. Wolska; R. John Solaro; David F. Wieczorek
• Keywords: Myofilament; Tropomyosin; Myofibril; Dilated Cardiomyopathy; Cardiac muscle

Background— Tropomyosin (TM), an essential actin-binding protein, is central to the control of calcium-regulated striated muscle contraction. Although TPM1α (also called α-TM) predominant TM isoform in human hearts, precise composition remains unclear. Methods and Results— In this study, we quantified for first time levels isoforms heart, including a novel TPM1κ. By developing TPM1κ-specific antibody, found that TPM1κ protein expressed incorporated into organized myofibrils hearts its level increased dilated cardiomyopathy heart failure. To investigate role sarcomeric function, generated transgenic mice overexpressing cardiac-specific Incorporation myofilaments leads cardiomyopathy. Physiological alterations include decreased fractional shortening, systolic diastolic dysfunction, myofilament calcium sensitivity with no change maximum developed tension. Additional biophysical studies demonstrate less structural stability weaker affinity compared TPM1α. Conclusions— This functional analysis provides possible mechanism consequences switch observed failure patients.