Molecular mechanisms for length adaptation in smooth muscle cells

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Smooth muscle is found in hollow organs such as the stomach, intestine, urinary bladder, blood vessels, and airways. Contraction of the muscle allows the organs to perform functions like urination, moving the contents along the digestive tract, and the control of blood pressure and airway resistance. Because most of the hollow organs undergo large changes in volume while performing their functions, smooth muscle is required to maintain its ability to contract over a working length-range much larger than that in skeletal muscle. For a long time the theory explaining skeletal muscle contraction was also used to explain smooth muscle contraction, despite the fact that it cannot accommodate the large working length-range of smooth muscle. Increasingly it has been recognized that the subcellular structure of smooth muscle, call the cytoskeleton, is much more “fluid” than that in skeletal muscle; it is able to drastically alter its shape while maintaining its ability to contract. This is believed to be due to a transformation process called length adaptation during which plastic restructuring of the cytoskeleton takes place. It is also believed that the transformation allows the contractile filaments, called myosin and actin filaments, to maintain contact with each other and generate tension. The process is initiated when a large change in the muscle length occurs, and it involves sequential events with initial disassembly of existing cytoskeletal structures followed by reassembly of the structure to fit the new cell length. However, the molecular mechanism underlying this adaptation process is largely unknown. The goal of this research program is to unravel the molecular mechanism of length adaptation, a unique smooth muscle behavior essential for proper function of the cell. Our laboratory is a leader in this area of research (we coined the term “length adaptation” which has now appeared in physiology textbooks). There is evidence suggesting that the myosin and actin filaments depolymerize and repolymerize during length adaptation. We plan to investigate the temporal and spatial events associated with polymerization of myosin and actin filaments and how they are linked by adaptor (or connector) proteins to form different shapes of cytoskeleton tailored to different cell dimensions. Knowledge gained from the research will fill a void in our understanding of the molecular mechanisms of length adaptation in smooth muscle and other cell types that utilize deformation of the cytoskeleton and recruitment and redistribution of myosin molecules in cell functions like tension generation, movement, and cell division.