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

OPG/Rank/Rank1 通路在肌纤维表型和生长中的作用

• 批准号: 227114-2011
• 负责人: Frenette, Jérôme
• 金额: $ 1.75万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=570243
• 关键词: role; OPG; Rank; Rank1; pathway

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.

OPG/Rank/Rankl途径是肿瘤坏死因子（TNF）超家族的成员，在骨组织中得到充分表征。Rankl在成骨细胞上表达，其受体Rank在前骨细胞上表达。Rankl/Rank相互作用诱导多核成熟破骨细胞的分化和形成，因此诱导骨吸收。第三个主角，OPG也是由成骨细胞产生的，并对前骨细胞分化过程产生抑制作用。虽然骨骼和肌肉共享许多生物学特性，但尚不清楚OPG/Rank/Rankl通路是否在骨骼肌中起作用。我们将在未来五年内实现三个具体目标。第一个目标是验证骨保护素（OPG）在预防肌肉萎缩和促进再生方面的疗效。后肢卸载和去除血清的肌管将用于在体内和体外诱导肌细胞萎缩。然后用不同浓度的OPG处理体外小鼠和肌管。第二个目标是确定Rank/Rankl在从快肌纤维到慢肌纤维的再转换中的作用。我们的初步功能和组织学数据表明，快到慢的抽搐肌纤维再转换废除Rank敲除小鼠后重新加载。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。 总之，参与肌纤维转化和肌肉生长的信号传导途径对几种人类疾病特别感兴趣，包括肌肉营养不良、代谢紊乱、废用诱导的肌肉萎缩和衰老。最重要的是，本提案可能阐明一种调节肌纤维表型和肌肉生长的新途径，从而将骨和肌肉萎缩与单一信号传导途径OPG/Rank/Rankl途径联系起来。