ACTIVITY INDUCED GROWTH OF SKELETAL MUSCLE

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The goal of this research is to understand the mechanisms by which muscle activity and hence structural and contractile demands affect muscle size and function. Experiments are designed to explore the coordinate nature and molecular basis of the adaptive changes in extracellular architectural components and functional or contractile elements of fast- and slow-twitch skeletal muscles in response to overload-induced hypertrophy and denerva- tion-induced atrophy in vivo and mechanical stress of isolated muscles in vitro. The proposed research will use new techniques of improved sen- sitivity and quantitative accuracy to measure the content and rates of synthesis of the two major collagen types in the tissues, collagens type I and type III. This information will be correlated with the contents and rates of synthesis of myosin heavy chain in myocytes and vimentin in mesenchymal cells of the tissue (fibroblasts and blood vessel endothelial cells). We will determine how these parameters are altered temporally in different longitudinal segments of the muscles in the in vivo models of altered stress and innervation as well as determine the level of the control of rates of synthesis of procollagens and myosin of the tissue by correlations with measured changes in the messenger RNAs specific for the proteins. We will test the hypotheses that discoordinate changes in extracellular matrix and myocyte protein content in denervated muscles are due to differential responses in the turnover rates of the proteins and that beta-2 adrenergic agonists differentially effect the turnover rates of collagens versus myosin in the tissue. The mechanism(s) whereby passive stress of skeletal muscles increases the synthesis of myosin and collagen will be examined in an in vitro system with an initial focus on the participation of cyclic AMP as an element in the transducing pathway. The new information sought in this project is basic to understanding the molecular basis of changes in the extracellular matrix during growth and atrophy of skeletal muscle and prerequisite for defining target responses relevant to understanding the nature and mechanism of action of candidate stimuli for growth and remodeling of the tissue.