Deciphering the role of RANK/RANKL/OPG in skeletal muscle

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The discovery of RANK/RANKL/OPG the receptor-activator of nuclear factor κB (RANK), the receptor-activator of nuclear factor κB ligand (RANKL), and the osteoprotegerin (OPG) pathway has been among the most important advances in bone biology and disease. RANK/RANKL/OPG form a key cytokine system for regulating osteoclast differentiation and function. RANKL is expressed by osteoblasts while RANK, its receptor, is expressed on pre-osteoclastic cells. The RANK/RANKL interaction induces the formation of multinucleated mature osteoclasts, ultimately causing bone resorption. However, the third protagonist, OPG, is also produced by osteoblasts and exerts an inhibitory effect on pre-osteoclastic differentiation. OPG, by binding to RANKL, inhibits the RANKL/RANK interaction and the subsequent osteoclastogenesis. The fact that OPG-null mice are osteoporotic is testimony to the physiological importance of OPG. OPG also serves as a decoy receptor for the tumour necrosis factor-related apoptosis-inducing ligand and increases cell survival by blocking the pro-apoptotic effects of the RANK/RANKL interaction. OPG is thus a very efficient anti-resorptive and anti-apoptotic agent. However, our recent publication in Am. J. Pathol. (2015) convincingly showed that OPG-Fc completely restores the function of fast-twitch extensor digitorum longus muscles and significantly improves the function of slow-twitch soleus and diaphragm muscles in mdx mice, indicating that OPG is not only a protector of bone but also skeletal muscles.***In this proposal, we will use genetic and pharmacological approaches to determine how RANK/RANKL/OPG triad, known for its role in bone regulation, regulates skeletal muscle phenotype, muscle function and SERCA-2a content and SERCA activity. We have also accumulated substantial evidence to support the observation that RANKL binds to muscle RANK but RANKL/OPG would also have its own muscle receptor acting directly on skeletal muscle. We thus intend to pursue three specific aims over the next 5 years.******(1) To understand the interplay between OPG, RANKL, mechanical loading and extracellular Ca2+ in muscle cells in culture.***(2) To determine how extracellular Ca2+ influences muscle performance in dystrophic muscle RANK deficient mice.***(3) To demonstrate that RANKL influences SERCA-2a content in C2C12 myotubes through a RANKL/RANK interaction-independent mechanism.******Together, this basic research proposal highlights the mutual cooperative interactions between skeletal muscle and bone and should open new physiological mechanisms for RANK/RANKL/OPG pathway.**