从梭内肌钙稳态改变引发的肌梭收缩特性的改变探讨失重性肌萎缩的发生机制

One of the most important and urgent issues, which should be solved in the field of space medicine, is to reveal the potential mechanism of the muscle atrophy of disused skeletal muscle during the weightlessness or microgravity environment. These may help researchers to find out effective method for the prevention and treatment of muscle atrophy during a long-term space flight.Extensive experiment data have shown that the muscle spindle discharges decrease significantly following the hindlimb unloading, which may play a vital role in the progress of muscle atrophy. Since the intrafusal fibres control the pattern of muscle spindle discharge via its contraction or relaxation, the contraction property of intrafusal fibres play a very important role in retaining discharge activities during simulated and real weightlessness. Calcium is a key factor of excitation-contraction coupling. Thus, the purpose of this subject was to probe into the mechanism of weightlessness-induced muscle atrophy from the changes of calcium homeostasis in intrafusal fibres.Using laser confocal investigate the potential variations of the intracellular resting calcium level in intrafusal fibres, and to discuss the underlying mechanisms of such changes from the impact of involved in calcium cycle.The calcium level , contractile tention will be measured and the activities of muscle spindle afferents recorded simulatedly in order to investigate the causal relationships among the intracellular resting calcium level variations in intrafusal fibres,contractive property variations in isolated muscle spindle, the activities of muscle spindle afferents and variations in extrafusal fibres. The role of Ca2+-dependent proteases activation was introduced to probe the mechanisms of calcium destructive effect in intrafusal fibres under gravitational unloading.This study will improve our understanding of muscle spindle activities during microgravity environment, which can lead to the establishment of a theoretic basis for effective prevention and treatment muscle atrophy induced by weightlessness.

探明失重性肌萎缩的机理，寻找出预防和治疗肌萎缩的有效措施，是航天医学亟待解决的重要课题之一。研究资料表明，模拟失重状态下肌梭功能活动的改变可能是失重性肌萎缩发生的始动因素之一；梭内肌纤维收缩功能是失重条件下肌梭传入活动能否维持的关键。钙离子是兴奋收缩偶联的关键因子。因此，本项目拟从梭内肌钙稳态的改变引发的肌梭收缩功能的改变探讨失重性肌萎缩的发生机制。利用共聚焦技术观察模拟失重对梭内肌纤维静息[Ca2+]i的影响，从影响钙离子循环的多个环节探讨[Ca2+]i发生改变的机制；用电生理技术观察模拟失重对肌梭收缩特性、传入放电活动的影响，从梭内肌纤维[Ca2+]i的改变激活蛋白酶分解通路揭示肌梭功能发生改变的机制。分析[Ca2+]i的改变与肌梭收缩特性、传入放电、梭外肌形态结构改变之间的因果对应关系；揭示肌梭在失重性肌萎缩发生中的作用，为探明失重性肌萎缩的发生机制和制定有效的防治措施提供研究资料。

本研究应用失重性肌萎缩模型，采用传统电生理学方法、膜片钳技术、激光共聚焦扫描等技术，从模拟失重条件下梭内肌纤维[Ca2+]i 的改变揭示了模拟失重条件下肌梭收缩功能改变的可能机制。研究结果表明，模拟失重后肌梭的电生理活性明显减少;后肢脱负荷7天，梭内肌纤维对琥珀胆碱的反应性降低，14天后肌梭对牵拉的反应开始出现明显降低，提示肌梭电生理活性的降低，可能是梭内肌纤维收缩功能降低引起的。吊尾7天后，肌梭钙超载，梭内肌纤维对咖啡因的反应性明显降低；咖啡因诱导肌梭的传入放电频率的降低，进一步提示模拟失重后肌梭放电活动的改变可能和梭内肌纤维内钙离子的代谢异常有关。上述研究结果进一步揭示肌梭在失重性肌萎缩发生中的作用，为探明失重性肌萎缩的发生机制和制定有效的防治措施提供研究资料。