Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity

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

Automated summary

Endurance exercise has various effects on skeletal muscle, including promoting vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. The characteristics of muscle fibers must be linked to the identity of the innervating motor neuron, which is influenced by muscle-derived neurturin (NRTN). The NRTN signaling pathway can induce shifts in motor neuron identity towards slower types, while also increasing capillary density and oxidative capacity in muscle fibers.