Examining SERCA pump regulation in muscle

肌浆网(SERCA)和肌浆网钙泵(SERCA)以及其他重要的肌浆网蛋白组成了调节人体细胞内钙离子的膜系统。如果没有钙调节系统，就不会有运动、没有心跳、没有记忆，这可能会使SER和SERCA分别泵出我们体内最重要的膜系统和膜蛋白。我的研究计划的一个主要目标是提高对SERCA泵调节的基本了解，SERCA泵是负责诱导肌肉松弛和维持细胞钙稳态的蛋白质。通过对最典型的SERCA调节蛋白--磷蛋白(PLN)和肌磷脂(SLN)的研究，我们发现这两种蛋白不仅是肌肉收缩和松弛的关键调节因子，而且还具有其他重要的生物学功能。PLN和SLN在细胞应激过程中稳定SERCA的结构和功能，从而防止SERCA功能的损伤和丧失。SLN而不是PLN增加了SERCA泵所需的能量，使SLN成为骨骼肌能量代谢的关键调节器，并对饮食诱导的肥胖具有保护作用。最后，SLN在激活钙信号通路中发挥关键作用，钙信号通路控制肌肉萎缩和疾病条件下肌肉块的适应。总体而言，我们的研究支持SLN可能在肌肉衰老中发挥重要作用的假设，这与氧化应激增加、钙调节和能量代谢中断、肌肉质量减少和脂肪质量增加有关。然而，到目前为止，还没有研究检查SLN在肌肉老化中的作用。当前建议的一个主要目的是确定SLN是否随着年龄的增长而改变，以及SLN的丢失是否会导致更严重的钙处理障碍、肌肉萎缩和虚弱、代谢率降低和脂肪质量随着年龄的增加而增加。如果我们的假设是正确的，增加肌肉中SLN蛋白质含量的新策略可能有助于减少加拿大老年人口的肥胖和骨骼减少。在过去的几年里，人们发现了一些新的SERCA调节蛋白，包括肌肉调节蛋白(myoRegin，MLN)和矮小开放阅读框架(Dwarf Open Reader Frame，DWORF)，它们被证明是肌肉收缩和放松的关键调节蛋白。然而，MLN和DWORF是否也像SLN和PLN一样具有不同的生物学作用尚不清楚。因此，本研究的另一个主要目的是确定MLN和DWORF是否能够像SLN和PLN一样在细胞应激时保护SERCA的结构和功能，或者像SLN一样调节SERCA泵和钙信号的利用。了解控制细胞内钙稳态的蛋白质之间的动态和复杂的相互作用对于促进我们对骨骼肌在健康和疾病中的发育、维持和功能的了解至关重要。

The sarco(endo)plasmic reticulum (SER) with the SER calcium (SERCA) pump and other important SER proteins make up the membrane system that regulates calcium inside the cells of our bodies. Without the calcium regulatory system, there would be no movement, no heartbeat and no memory, perhaps making the SER and SERCA pump the most important membrane system and membrane protein, respectively, in our bodies. A major objective of my research program is to improve fundamental understanding of the regulation of SERCA pumps, the proteins responsible for inducing muscle relaxation and for maintaining cellular calcium homeostasis. Through our examination of the most well characterized SERCA regulatory proteins, phospholamban (PLN) and sarcolipin (SLN), we have established that both proteins are not only key regulators of muscle contraction and relaxation but they also have other important biological functions. Both PLN and SLN stabilize SERCA structure and function during cellular stress and thus prevent damage and loss of SERCA function. SLN but not PLN increases the amount of energy required by SERCA pumps, making SLN a key modulator of skeletal muscle energy metabolism, and it is protective against diet-induced obesity. Finally, SLN plays a critical role in activating calcium signalling pathways that control adaptations in muscle mass under conditions of muscle atrophy and disease. Overall, our research supports the hypothesis that SLN could play an important role in aging muscle, which is associated with increased oxidative stress, disrupted calcium regulation and energy metabolism, decreased muscle mass and increased fat mass. However, no study has examined the role of SLN in aging muscle to date. A major aim of the current proposal is to determine if SLN is altered in muscle with age and if loss of SLN results in greater calcium handling impairments, muscle atrophy and weakness, reduced metabolic rate and increased fat mass with aging. If our hypotheses are correct, novel strategies to increase SLN protein content in muscle may aid in reducing obesity and sarcopenia in Canada's older adult population. The past several years have seen the discovery of a handful of new SERCA regulatory proteins, including myoregulin (MLN) and dwarf open reading frame (DWORF), which have been shown to be key regulators of muscle contraction and relaxation. However, whether MLN and DWORF also have diverse biological roles like SLN and PLN is unknown. Therefore, another major aim of this proposal is to determine whether MLN and DWORF are capable of protecting SERCA structure and function during cellular stress like SLN and PLN or regulating energy utilization of SERCA pumps and calcium signalling like SLN. Understanding the dynamic and complex interactions between the proteins that govern intracellular calcium homeostasis will be critical in advancing our knowledge of skeletal muscle development, maintenance and function in health and disease, across the lifespan.