FUNCTION OF GIANT SARCOMERE MATRIX PROTEINS IN MUSCLE

最近发现了两种巨大的肌肉蛋白质， 肌联蛋白和星云蛋白，约占肌原纤维蛋白的10- 15 马萨诸塞州 这项提案的广泛的长期目标是研究 了解这些蛋白质在肌肉疾病中的作用。 最近的研究表明，在脊椎动物肌肉和minititin， 在昆虫飞行肌（IFM）中发现的类似蛋白质， 力 被动力是一个重要的因素，但没有得到很好的研究， 肌肉. 这种重要性在心肌中尤其突出， 被动力是舒张期室壁张力的一部分， 心脏充盈程度及其随后的每搏输出量。 引人注目 最近还发现昆虫IFM中的被动力呈线性变化 与主动力，表明被动力调节跨桥 相互作用（Granzier和Wang，1993）。 因此，对肌联蛋白和 minititin提供了一个基础，了解分子机制， 是被动力的基础，以及这种力如何与肌动球蛋白相互作用 系统 主要实验： 目的1）研究以下因素之间相互作用的机制： 被动张力和肌动球蛋白相互作用。 的影响 被动张力将研究的速率常数为 从力生成状态到非力生成状态的跨桥转换 力=生成状态（gapp）和返回到 Force-generating-status（fapp）; 目的2）被动张力和肌动球蛋白相互作用之间是否存在相互作用 发生在心肌和骨骼肌中 这将由以下人员进行调查 研究被动张力对弱桥和强桥的影响， 心肌细胞和骨骼肌纤维（参见，Granzier & Wang，1993）; 目的3）研究肌联蛋白与肌纤维中其他纤维的相互作用。 肌节 (a)肌联蛋白和蛋白质之间相互作用的性质是什么？ 粗丝 (b)肌联蛋白与细丝相互作用吗？ 对肌联蛋白功能的研究， 星云蛋白将有助于我们更好地理解 心脏和骨骼肌。这将改善 以了解骨骼肌和心肌的各种肌病。

Two giant muscle proteins Mr about 10 6) have been discovered recently, titin and nebulin, that constitute about 10-15% of the myofibrillar protein mass. The broad long-term goal of this proposal is to study the function of these proteins and understand their role in muscle disease. Recent studies indicate that titin in vertebrate muscle and minititin, the analogous protein found in insect flight muscle (IFM), may develop passive force. Passive force is an important, but not well investigated factor in muscle. This importance is especially striking in cardiac muscle where passive force is part of the diastolic wall tension that determines the extent of filling of th heart and its subsequent stroke volume. Striking also is the recent finding that passive force in insect IFM varies linearly with active force, indicating that passive force regulates cross-bridge interaction (Granzier and Wang, 1993). Thus, the study of titin and minititin provides a basis for understanding the molecular mechanism that underlies passive force, and how this force interacts with the actomyosin system. Main experiments: Aim 1) Investigate the mechanism that underlies the interplay between passive tension and actomyosin interaction in insect IFM. The effect of passive tension will be investigated on the rate constant for the transition of cross-bridges from force-generating-states to non- force=generating states (gapp) and on the rate constant for the return to force-generating-status (fapp); Aim 2) Does interplay between passive tension and actomyosin interaction occur in cardiac and skeletal muscle? This will be investigated by studying the effect of passive tension on weak and strong cross-bridges in cardiac myocytes and skeletal muscle fibers (cf. Granzier & Wang, 1993); Aim 3) Study the interaction between titin and the other filaments in the sarcomere. (a) What is the nature of interaction between titin and the thick filaments? (b) Does the titin interact with thin filaments? It is expected that the proposed studies into the function of titin and nebulin will lead to a better fundamental understanding of the physiology of cardiac and skeletal muscles. and that this will improve the foundation for understanding various myopathies of skeletal and cardiac muscle.