Muscle contraction is essential for the movement of joints (in the case of skeletal muscle) and propulsion of blood through the vasculature (in the case of cardiac muscle). Muscle cells are composed of densely packed myofibrils, which are, in turn, composed of sarcomeres arranged in series. Sarcomeres are a strikingly regular lattice of interdigitating actin “thin” filaments and myosin “thick” filaments that slide past one another and generate the forces of muscle contraction. Sarcomeres are linked to an elaborate network of accessory structures in muscle, including vesicular membrane compartments required for excitation-contraction coupling and calcium homeostasis, elastic elements for sensing and mechanotransduction of stress/strain, and cytoskeletal systems for lateral transmission of forces both intra- and extracellularly. Genetic defects in muscle proteins result in abnormalities in the assembly and/or maintenance of sarcomeres and the cytoskeleton in muscle cells, leading to various types of hereditary myopathies, such as the nemaline myopathies (generally arising from thin filament defects) and muscular dystrophies (generally arising from lateral force transmission defects).
Sarcomeres present an ideal system to study the assembly and length regulation of actin filaments. Thin filaments extend from either side of the Z-line, with their barbed ends anchored in the Z-line and pointed ends at the edge of the H-zone, traversing a distance of ~1.0 to 1.3 microns. While thin filament lengths are muscle-specific, they are extraordinarily uniform within a sarcomere. Muscle-specific thin filament lengths are the chief determinants of muscle-specific length-tension relationships, which quantitatively describe muscle force production as a function of sarcomere length. Thin filaments are stable, but they are still dynamic structures that are subject to actin turnover and exchange. Tropomodulin (Tmod) caps thin filament pointed ends, CapZ caps barbed ends, and tropomyosin (TM), copolymerizes with actin along the entire thin filament length and is critical for regulating actin/myosin crossbridge formation. Skeletal muscle thin filaments also contain nebulin, a large rod-like molecule associated with a ~1.0-micron-long core region of the thin filament. The uniform lengths of thin filaments contrast with the widely variable actin filament lengths that are found in the cytoskeletons of motile and proliferating cells. Major goals of our research include understanding how sarcomere assembly occurs during skeletal and cardiac muscle development, how thin filament lengths are regulated, and the unique roles of Tmod and TM in these processes. To address these goals, we are using both in vitro and in vivo perturbations of Tmod and TM in experimental muscle systems, including chicken cardiomyocytes and mouse skeletal muscle.
Key questions are:
• What is the sequence of events in thin filament and myofibril assembly – i.e. how does a collection of cytosolic proteins become organized into a semi-crystalline sarcomeric lattice?
• How do thin filament and myofibril assembly differ in cardiac vs. skeletal muscle?
• How do perturbations of Tmod, TM, and nebulin gene expression affect actin dynamics, actin turnover, and thin filament length in striated muscle?
• How do perturbations of Tmod, TM, and nebulin gene expression affect striated muscle function, including the ability to generate and transmit force?
• What is the relationship between aberrant thin filament length regulation and muscle pathology?
• What is the role of actin filament length regulation by Tmod and TM in the organization and force-transmitting properties of the cytoskeleton and/or membrane skeleton in striated muscle cells?
The Scripps Research Institute
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