Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity
Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity
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DOI：
10.1016/j.cmet.2021.09.003
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发表时间：
2021-11-02
期刊：
影响因子：
29
通讯作者：
Ruas, Jorge L.
中科院分区：
文献类型：
--
作者：
Correia, Jorge C.;Kelahmetoglu, Yildiz;Ruas, Jorge L.
耐力运动促进骨骼肌血管化、氧化代谢、纤维类型转换和神经肌肉接头完整性。重要的是，肌纤维的代谢和收缩特性必须与支配运动神经元（MN）的特性相结合。在这里，我们展示了肌肉源性神经营养因子 (NRTN) 作用于肌肉纤维和 MN，以耦合它们的特性。使用肌肉特异性 NRTN 转基因小鼠 (HSA-NRTN) 和 MN 体细胞的 RNA 测序，我们观察到逆行 NRTN 信号传导促进了向缓慢 MN 身份的转变。在肌肉中，NRTN 增加毛细血管密度和氧化能力，并诱导转录重编程，有利于脂肪酸代谢而不是糖酵解。这种对肌肉和 MN 的作用组合使 HSA-NRTN 小鼠体型瘦削，并具有出色的运动表现和运动协调性。有趣的是，HSA-NRTN 小鼠在很大程度上重现了具有上游调节因子 PGC-1a1 肌肉特异性表达的小鼠的表型。这项工作确定了
Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics. Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) and RNA sequencing of MN somas, we observed that retrograde NRTN signaling promotes a shift toward a slow MN identity. In muscle, NRTN increased capillary density and oxidative capacity and induced a transcriptional reprograming favoring fatty acid metabolism over glycolysis. This combination of effects on muscle and MNs makes HSA-NRTN mice lean with remarkable exercise performance and motor coordination. Interestingly, HSA-NRTN mice largely recapitulate the phenotype of mice with muscle-specific expression of its upstream regulator PGC-1a1. This work identifies