Dynamic limits on contraction of gastrointestinal smooth muscle

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A hallmark of smooth muscle behavior is its ability to adapt to changes in functional demand by remodeling, as in diabetes and in obstructive disorders of the gastrointestinal tract such as megacolon of Hirschsprung's disease, which are a major focus of this project. Remodeling may include smooth muscle growth (hypertrophy, hyperplasia) together with or without concomitant changes in extracellular matrix. Smooth muscle shortening depends on (a) external applied loads and (b) internal resistances provided by the extracellular connective tissue matrix which links smooth muscle cells together and to neighboring cells that are exerting force. Both factors also govern the length-force relationships and shortening range, which may be differentially changed as a result of remodeling. Complicating this further is the recent finding that stimulation initiates a length- dependent polymerization of actin filaments in the cellular cortex, ostensibly strengthening the cytoskeleton and enhancing force, which would be expected to provide an internal load and impede shortening. A rigorous analysis of the effects of the cytoskeletal remodeling on the mechanical properties of intact muscle is warranted. Our structural studies on g.i. smooth muscles prompted our central hypothesis that in intact muscles, overall force output and shortening are limited due to the failure of transmission of events occurring at the crossbridge, resulting from floppiness of the extracellular matrix, contractile filament misalignment and possibly also formation of a stiff cytoskeleton. There is a critical need for an integrated view on how structure limits function in smooth muscle. We will study (1) remodeling in the colon of (a) the lethal spotted murine model of Hirschsprung's megacolon which shows enhanced force production at short muscle lengths and increased compliance, favoring extensive shortening, (b) a rat model of diabetes (streptozotocin), which shows stiffening at rest, enhanced force production at short muscle lengths, and a limited capacity to shorten, and (2) two normal gastrointestinal smooth muscles representing the extremes in their relationships between length and force production and ability to shorten: the rabbit taenia coli and rat anococcygeus m. Our long term goal is to define the mechanisms, physiological and structural, limiting force output and shortening in smooth muscles and, thereby, identify likely candidates for therapeutic intervention following remodeling in disease. Specific Aim 1 is to determine how the extent of actin-myosin interaction and transmission of mechanical events through intra- and extracellular matrices, concomitantly with changes in structural orientation, govern force output of smooth muscle as a function of muscle length. Specific Aim 2 is to determine the mechanical factors that control the polymerization and depolymerization of cytoskeletal actin, and how these dynamic transitions limit force production, shortening and work production in intact muscles. Specific Aim 3 is to define and quantify the composition of the extracellular matrix that account for the drastic and disparate changes in resting compliance that occur following remodeling in the diabetic colon and in the Hirschsprung's megacolon.
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