Examining SERCA pump regulation in muscle

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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.