Investigations into tropomyosin function using mouse models

G Jagatheesan, S Rajan, DF Wieczorek - Journal of molecular and cellular …, 2010 - Elsevier
G Jagatheesan, S Rajan, DF Wieczorek
Journal of molecular and cellular cardiology, 2010Elsevier
Tropomyosin plays a key role in controlling calcium regulated sarcomeric contraction
through its interactions with actin and the troponin complex. The focus of this review is on
striated muscle tropomyosin isoforms and the in vivo approach we have taken to define the
functional differences among these isoforms in regulating cardiac physiology. In addition, we
address specific regions within tropomyosin that differ among the isoforms to impart
differences in the physiological performance of muscle and the sarcomere itself. There is a …
Tropomyosin plays a key role in controlling calcium regulated sarcomeric contraction through its interactions with actin and the troponin complex. The focus of this review is on striated muscle tropomyosin isoforms and the in vivo approach we have taken to define the functional differences among these isoforms in regulating cardiac physiology. In addition, we address specific regions within tropomyosin that differ among the isoforms to impart differences in the physiological performance of muscle and the sarcomere itself. There is a high degree of amino acid identity among the three striated muscle α-, β-, and γ-tropomyosin isoforms; this identity ranges from 86% to 91%. We employ transgenic mouse model systems that express the different tropomyosin isoforms or chimeric tropomyosin molecules specifically in the myocardium. Results show that the three isoforms differentially regulate the rates of cardiac contraction and relaxation, along with conferring differences in myofilament calcium sensitivity and sarcomere tension development. We also found the putative troponin T binding regions of tropomyosin (amino acids 175–190 and 258–284) appear to a play significant role in imparting these physiological differences that are observed during cardiac and sarcomeric contraction/relaxation. In addition, we have successfully used chimeric tropomyosin molecules to rescue cardiomyopathic diseased mice by normalizing sarcomeric performance. These studies illustrate not only the importance of tropomyosin structure and function for understanding muscle physiology, but also demonstrate how this information can potentially be used for gene therapy.
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