Disruption of Lactate Metabolism in the Peripheral Nervous System Leads to Motor-Selective Deficits.
6 affiliations
- 1Department of Genetics Washington University School of Medicine St. Louis Missouri USA
- 2Needleman Center for Neurometabolism and Axonal Therapeutics St. Louis Missouri USA
- 3Department of Developmental Biology Washington University School of Medicine St. Louis Missouri USA
- 4Center for Advanced Oral Science Niigata University Niigata Japan
- 5Mallinckrodt Institute of Radiology Washington University School of Medicine St. Louis Missouri USA
- 6Department of Pathology and Immunology, Division of Neuropathology Washington University School of Medicine St. Louis Missouri USA
Abstract
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.
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BibTeX
@article{bloom2026disruption,
title = {{Disruption of Lactate Metabolism in the Peripheral Nervous System Leads to Motor-Selective Deficits.}},
author = {A. Joseph Bloom and Shweta Tendulkar and Amber R. Hackett and Amy M. Strickland and Yurie Yamada and Liya Yuan and Wendy Dong and Joseph E. Ippolito and Robert E. Schmidt and Yo Sasaki and Aaron DiAntonio and Jeffrey Milbrandt},
journal = {Glia},
year = {2026},
month = oct,
doi = {10.1002/glia.70245},
url = {https://europepmc.org/article/MED/42925132},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Disruption of Lactate Metabolism in the Peripheral Nervous System Leads to Motor-Selective Deficits.
AU - A. Joseph Bloom
AU - Shweta Tendulkar
AU - Amber R. Hackett
AU - Amy M. Strickland
AU - Yurie Yamada
AU - Liya Yuan
AU - Wendy Dong
AU - Joseph E. Ippolito
AU - Robert E. Schmidt
AU - Yo Sasaki
AU - Aaron DiAntonio
AU - Jeffrey Milbrandt
PY - 2026
DA - 2026/10/23
JO - Glia
DO - 10.1002/glia.70245
UR - https://europepmc.org/article/MED/42925132
AB - 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.
SN - 0894-1491
SN - 1098-1136
ER -