OXIDATION AND AGING IN CARDIAC AND SKELETAL MUSCLE

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Our long-term goal is to understand the role of protein (and lipid) oxidation in age-related modifications of calcium regulation in cardiac and skeletal muscle. Our focus involves two proteins central to calcium regulation in muscle: (a) the intrinsic membrane protein, the Ca-ATPase of sarcoplasmic reticulum (SR), and (b) the soluble protein, calmodulin. Specifically, we aim to: (1) initiate model studies to identify the structural and functional consequences of in vitro protein modification by physiologically relevant free radical species, whose chemistry allows their quantification. These free radicals will be targeted either to the lipid bilayer or to the aqueous medium, in order to specifically oxidize membrane-spanning or soluble peptides, respectively. In this way, we seek to gain mechanistic information regarding the relative roles specific reactive oxygen species to the oxidative damage of cellular proteins. The relationship between reactive oxygen species and function is not available from biologically aged systems where the large number of reactions, coupled with the presence of cellular repair mechanisms, complicate our understanding of processes leading to protein damage. In order to understand the physiological relevance of the information obtained from model systems, (2) we will identify age-related oxidative modifications of protein and SR lipids, as well as associated structural and functional alterations. (3) Finally, we will initiate similar studies to identify age-related molecular defects of the more highly regulated Ca-ATPase of cardiac SR. Work with both model and biologically aged systems will emphasize quantitative identification of the products of free radical-mediated modifications of proteins and lipids. The combined use of fluorescence and spin-label electron paramagnetic conformation and bilayer structure. An increased understanding of age- related molecular defects of calcium regulation in both cardiac and skeletal muscle is relevant to human health, since oxidation of biomolecules is though to play a major role in aging. This understanding in turn, is a necessary requirement for the design of effective therapies for delaying the onset and progress of decreased muscle function.