A role for OPG/Rank/Rank1 pathway in muscle fiber phenotype and growth

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The OPG/Rank/Rankl pathway is a member of the tumour necrosis factor (TNF) superfamily that is well characterized in bone tissue. Rankl is expressed on osteoblast cells and its receptor Rank, on pre-osteoclastic cells. The Rankl/Rank interaction induces the differentiation and formation of multinucleated mature osteoclasts, hence bone resorption. The third protagonist, OPG is also produced by osteoblasts and exerts an inhibitory effect on the pre-osteoclastic differentiation process. While bone and muscle share many biological characteristics, it is not known whether the OPG/Rank/Rankl pathway plays a role in skeletal muscle. We will pursue 3 specific objectives over the next 5 years. The first objective will be to verify the efficacy of osteoprotegerin (OPG) in preventing muscle atrophy and promoting regrowth. Hindlimb unloading and myotubes deprived of serum will be used to induce muscle cell atrophy in vivo and in vitro. Mice and myotubes in vitro will then be treated with different concentrations of OPG. The second objective will be to determine the role of Rank/Rankl in the reconversion from fast-to-slow muscle fibres. Our preliminary functional and histological data show that fast-to-slow twitch muscle fibre reconversion is abrogated in Rank knockout mice upon reloading. The third objective will be to test whether mechanical loading in vitro modulates the myotube phenotype via the OPG/Rank/Rankl pathway.