Disruption of Lactate Metabolism in the Peripheral Nervous System Leads to Motor‐Selective Deficits

Schwann cells (SCs) myelinate and provide trophic support to axons in the peripheral nervous system (PNS). Disrupted SC metabolism can lead to demyelination and axon degeneration, cardinal deficits in peripheral neuropathy. The lactate shuttle hypothesis proposes that glycolytic support cells supply lactate to axons to sustain their high metabolic demands. This transfer requires lactate dehydrogenase (LDH) to interconvert lactate and pyruvate in both SCs and neurons. To test the importance of lactate metabolism in the PNS, we selectively knocked out both LDHA and LDHB in ChAT‐positive neurons, including motor neurons (MNs), Nav1.8‐lineage sensory neurons (SNs), or SCs. Interestingly, motor axons and their synapses progressively degenerate when LDH is deleted from either MNs or SCs, but defects in Nav1.8‐lineage sensory axons and their terminals are not observed when LDH is excised from either SNs or SCs. Deletion of LDH in SCs leads to decreased ATP in peripheral nerves despite marked accumulation of pyruvate and glycolytic intermediates, consistent with energetic deficits due to failed conversion of pyruvate to lactate. Cholinergic neuron‐specific gene expression using ribosome affinity profiling (RiboTag) identified a strong response to metabolic compromise by activating axon‐injury stress programs in LDH‐deficient neurons. Finally, blocking axon degeneration in LDH‐deficient mice by SARM1 deletion preserves axon morphology without ameliorating behavioral and electrophysiological defects, demonstrating functional decline of lactate‐deprived axons that remain physically intact. These results show a differential requirement for SC‐derived lactate by motor vs. sensory axons, suggesting that lactate availability could influence the course of motor neuron diseases.