Mechanical Acitivity and Myocyte Remodeling

University Of Illinois At Chicago, Chicago IL

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Abstract

Mechanical strain is a powerful stimulus for remodeling cardiac myocytes in normal and pathological situations. In order to study the myocyte response to mechanical stimuli, we have developed microtextured surfaces that allow cells to adhere and align in vitro and have shown that rat neonatal myocytes take one hour to add a new sarcomere in response to a single lengthening strain of 10%. We now extend our studies to determine how specific strain vectors and patterns of activation affect sarcomerogenesis as myocytes remodel. Our hypothesesare: (1) The sarcomere remodeling responses are regulated by the direction and strength of mechanical stimuli and the intervals between them. We test this by deforming myocytes with variables amplitudes, strain rates, stimulus intervals, and rest episodes and assess by phosphorylations of FAK, PKCe and paxillin, confocal microscopy, and subcellular proteomics for nuclear translocations of MLP, CapZ and paxillin. (2) Sarcomerogenesis in response to longitudinal and transverse strains occurs at the intercalated disks, costameres, and/or Z-disks, and depends on PKCe. We compare myocyte response to longitudinal and transverse strains to assess the effect directions have on the site of sarcomerogenesis. We use a phospho-proteomic approach to measure changes in paxillin and/or CapZ. The reincorporation of GFP-tagged CapZ and paxillin into their respective complexes is assessed after photo bleaching. We study processes of cellular elongation that occur in dilated cardiomyopathy and widening that occur in concentric cardiomyopathy that may precede heart failure. We address what, when, where and how the contractile cells of the heart respond to work in order to understand fundamental processes.