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

OPG/Rank/Rankl通路是骨组织中肿瘤坏死因子（TNF）超家族的一员。Rankl在成骨细胞及其受体Rank上表达，表达于破骨前细胞。Rankl/Rank相互作用诱导多核成熟破骨细胞的分化和形成，从而促进骨吸收。第三个主角OPG也由成骨细胞产生，对破骨前分化过程有抑制作用。虽然骨骼和肌肉有许多共同的生物学特征，但目前尚不清楚OPG/Rank/Rankl通路是否在骨骼肌中起作用。我们将在未来5年实现3个具体目标。第一个目标将是验证骨保护素（OPG）在预防肌肉萎缩和促进再生方面的功效。在体内和体外实验中，将后肢脱药和肌管脱血清用于诱导肌肉细胞萎缩。然后用不同浓度的OPG处理小鼠和体外肌管。第二个目标是确定Rank/Rankl在从快肌纤维到慢肌纤维的再转化中的作用。我们的初步功能和组织学数据表明，在Rank敲除小鼠中，快速到缓慢的抽搐肌纤维再转化在重新加载后被取消。第三个目的是测试体外机械负荷是否通过OPG/Rank/Rankl途径调节肌管表型。

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. In conclusion, the signalling pathways involved in myofibre conversion and muscle growth are of particular interest for several human disorders, including muscle dystrophy, metabolic disorders, disuse induced muscle atrophy, and aging. Most importantly, the present proposal may elucidate a new pathway that regulates muscle fibre phenotype and muscle growth, thus linking bone and muscle atrophy to a single signalling pathway, the OPG/Rank/Rankl pathway.