In an average, healthy, adult human, the heart beats 72 times a minute. Each heartbeat is the synchronized contraction of specialized cells, the cardiac sarcomeres. In each sarcomere is a well-regulated, energy-dependent mechanism involving the proteins actin, myosin, troponin, and tropomyosin. In the resting state, the heads of the myosin motors are detached from actin filaments that run through the sarcomere. A muscle contraction is initiated by the influx of calcium ions into the cardiomyocytes, where it binds a specialized complex of three proteins: the troponin complex. The resulting conformational change in the troponin complex changes the position of tropomyosin wound along the length of the actin filament. This change allows the binding of the myosin head to the actin filament, ATP hydrolysis and the release of chemical energy to pull the filaments closer and contract the sarcomere.

Primary cardiomyopathies are heart muscle disorders occurring in the absence of other cardiac conditions, which eventually lead to heart failure. Due to the increased availability of genetic testing, we are learning that most primary cardiomyopathies are inherited. In most instances, a change in a single amino acid of a sarcomeric protein is the cause of the disease. Hundreds of different mutations, primarily single amino-acid substitutions, resulting in cardiomyopathies have been identified in the 8 primary sarcomeric proteins. Cardiomyopathies can be grouped into the following three types: hypertrophic (HCM), dilated (DCM), and restrictive (RCM).

Our group at inStem is trying to understand inherited cardiomyopathies at multiple scales of organization. This work is part of an international collaboration, initiated by Jim Spudich (Stanford University, NCBS & inStem) and also involving Norio Nakatsuji (iCeMS, Kyoto), Kouichi Hasegawa (iCeMS and inStem), R. Sowdhamini (NCBS), Maneesha Inamdar (JNCASR and inStem) and K. VijayRaghavan (NCBS & inStem). We are interested in understanding how single amino acid changes in sarcomeric proteins, cause cardiomyopathies. Cardiomyopathy-causing mutations in myosin, actin, tropomyosin or the troponins affect the behaviour of this system at multiple levels. Our initial efforts have focused on alpha-tropomyosin and troponin T, employing multiple methods to detect alterations, including ATPase assays, in vitro motility assays, laser trapping, and single-cell contractility assays.

Since a single amino-acid change is sufficient to cause disease and human and mouse sarcomeric proteins tend to have multiple differences between them, we are humanising the mouse cardiac sarcomere to develop better animal models. Our goal is to group the mutants mechanistically in as an initial step in developing small molecule treatments.

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