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 towards a slow MN identity. In muscle, NRTN increased capillary density, 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-1?1. This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity. Overall design: We used laser capture microdissection to isolate discrete motor neurons from the lumbar spinal cord of HSA-NRTN mice and wild-type littermates. We performed RNA-sequencing analysis in pools of approximately 50 motor neurons per mouse (5 HSA-NRTN and 5 wild-type controls).