Grantee Spotlight Interview

What inspired you to pursue aging research?

My postgraduate training was focused on exercise physiology, and many of my subjects were athletes, i.e. sprinters, cyclists. I was amazed by their sports performance and their muscle powers. However, some of my subjects were aged athletes who also used to possess those powerful muscles only decades ago, and now they are suffering from muscle atrophy and weakness. I was shocked by the rapid drop of their muscle function, and also, I believed that there must be something deleterious from aging that impairs muscle function. Then in my postdoctoral research, I decided to find out the underlying mechanism of aging induced muscle weakness and atrophy, and also I will try to target those newly defined mechanisms and delay or alleviate the effect of aging on muscle function.

In your view, what does AFAR mean to the field, and what does it mean, for you, to receive an AFAR grant now?

Aging is a broad field in research, it involves in many diseases and syndromes. In the past, studies in different areas solely focused on their own disease and pathways, and the aging impact on these diseases was not paid enough attention. AFAR provides a new platform bringing researchers from all different areas together to a common focus on studying aging itself and its effects on the onset and development of these diseases. With this goal, AFAR will provide resources in aging research and contribute novel insights in disease treatment and clinical care for elderly population.

For me, receiving this AFAR grant will provide me additional training opportunities in developing the essential skills that are required for an independent researcher, such as designing and conducting experiments independently, budgeting skills, laboratory and animal colony management, etc. Overall, this AFAR grant will propel me towards my career goal of becoming an independent researcher in the field of aging and skeletal muscle research.

What is exciting about your research’s potential impact?

It is well known that Ca²⁺ is the critical mediator for regulating muscle force generation, and our previous studies also indicated that Ca²⁺ homeostasis is impaired in aging muscles. However, it is not quite clear that how the Ca²⁺ regulation is disturbed during aging, and what potential pathway is involved in this Ca²⁺ dysregulation. With this current project, I will interrogate the aging induced muscle Ca²⁺ dysregulation from a completely new angel, the impeding of Ca²⁺ circulation in muscle cells by oxidized lipid. The information we gain in this study will for the first define the relationship of oxidized lipid and Ca²⁺ regulation in aging skeletal muscle, and provide the basis for a more in-depth study into calcium regulating pathways and muscle weakness in aging and other conditions.

How would you describe your research to a non-scientist?

As we age, our muscles become weaker and smaller, a phenomenon known as sarcopenia. The process of sarcopenia starts in the 4th decade of life and is a major cause of disability in old age. Calcium ions (Ca²⁺) are key signaling molecules in regulating muscle force, and the dysregulation of Ca²⁺ in muscle is a significant contributor to sarcopenia. Yet the role of calcium in the loss of the ability of aged muscle to produce force is not completely understood. Harnessing calcium regulation provides a key opportunity for the identification of new potential therapies to maintain muscle force generating capacity during aging. Muscle contraction is a complex process that begins with the release of Ca²⁺ ions from an intracellular store (called the sarcoplasmic reticulum or SR). Ca²⁺ ions then bind contractile filaments to generate force. After contraction, they need to be returned to the SR for storage. However, there is a net loss of Ca²⁺ each time because some of Ca²⁺ will be released out of the cell to prevent potential harmful accumulation of high concentrations of Ca²⁺ in the cytosol. If this process was allowed to continue uncorrected, SR Ca²⁺ storage would eventually be too low to support muscle twitches after several cycles of Ca²⁺ release. Hence, there is a mechanism to protect and supplement the SR Ca²⁺ storage that is called store-operated Ca²⁺ entry (SOCE). When SR Ca²⁺ storage is low, a sensor protein called STIM1 is activated to interact with Ca²⁺ influx channel Orai1 to facilitate uptake of Ca²⁺ from outside of the cell. In addition, this process is facilitated by an enzyme, iPLA2, a Ca²⁺-independent phospholipase A2 (PLA2) that provides the fatty acid substrates (e.g., arachidonic acid) for generation of oxylipin signaling molecules and lysophospholipids (LPL). iPLA2 is thought to regulate SOCE by activating the Orai1 channel through its product LPL, thus “shortcutting” the need for STIM1. Our preliminary data shows that the deletion of iPLA2 results in improved Ca²⁺ regulation through enhanced STIM1-Orai1 interaction, along with increased muscle force in a model of muscle denervation which is a characteristic of sarcopenia and aging muscle. We also measured a decrease in SOCE activity in aged muscles which is reactivated by inhibiting iPLA2. Based on these preliminary data, we propose that iPLA2 and generation of LPL act to inhibit SOCE during aging. Therefore, in this study, we will establish an animal model with muscle specific deletion of iPLA2 to reduce the amount of iPLA2 and its product LPL, and determine its effect on STIM1-Orai1 interaction and SOCE activity in young and old muscles. The overall goal of this study is to increase our understanding of the role of iPLA2 on SOCE in young and old muscles, and to determine whether SOCE and muscle force generation are protected by loss of iPLA2. This study will be the first to fully define the role of both STIM1 and iPLA2 in mediating SOCE activity in skeletal muscle, as well as the impact of aging on these processes, which is important for developing interventions for targeting muscle force generation in elderly in the future.