Disruption of lactate metabolism in the peripheral nervous system leads to motor-selective deficits
Open accessAbstract
Schwann cells (SCs) myelinate and provide trophic support to axons in the peripheral nervous system (PNS) and disruption of SC cellular metabolism leads to demyelination and axon degeneration, both symptoms of peripheral neuropathies. The lactate shuttle hypothesis proposes that glycolytic support cells supply lactate to adjacent axons to sustain their high metabolic demands, a process that requires the interconversion of lactate and pyruvate via lactate dehydrogenase (LDH) in both SCs and neurons. To test this hypothesis in the PNS, we selectively knocked out the genes for both LDH enzymes, LDHA and LDHB, in motor neurons (MNs), sensory neurons (SNs), or SCs. Interestingly, motor axons and their synapses progressively degenerate when LDH is deleted from either MNs or SCs; however, defects in sensory axons or their terminals were not observed when LDH was excised from either SNs or SCs. Deletion of LDH in SCs also leads to a decrease in total ATP levels in peripheral nerves despite a marked accumulation of pyruvate and glycolytic intermediates, consistent with the failure of pyruvate to lactate conversion in SCs leading to energetic deficits in axons. These results support a model in which motor axons are more dependent on SC-derived lactate than are sensory axons, a specific dependency that suggests LDH and lactate shuttling influence the course of motor-dominated neuropathies such as ALS.
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The deletion of Ldh genes in Schwann cells and motoneurons causes a marked neuropathology.
“The deletion of Ldh genes in Schwann cells and motoneurons causes a marked neuropathology (Bloom et al., 2022).”
From Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons (2024) · cites this paper as Bloom et al., 2022
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Späte, E., Zhou, B., Sun, T., Kusch, K., Asadollahi, E., Siems, S. B., Depp, C., Werner, H. B., Saher, G., Hirrlinger, J., et al. (2024) · Glia · doi:10.1002/glia.24533 · Cited by 40 · see citing works
- Authors
- Bloom, A. J., Hackett, A. R., Strickland, A., Yamada, Y., Ippolito, J., Schmidt, R. E., Sasaki, Y., DiAntonio, A., & Milbrandt, J.
- Affiliations
- Washington University in St. Louis (US)
- Niigata University (JP)
- Corresponding author
- Milbrandt, Jeffrey
- ORCID
- Venue
- Glia
- Publisher
- openRxiv
- Published
- 2022-06-30
- Volume
- 74
- Issue
- 12
- ISSN
- 0894-1491 (ISSN-L)
- PMC
- PMC13693490
- OpenAlex
- W7223353787
- Cited by
- 8
- References
- 4
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 1
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Glia (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- Funders
- Foundation for Barnes-Jewish Hospital (UL1TR002345, TR002345)
- Institute of Clinical and Translational Sciences (TR002345, UL1 TR002345)
- Alvin J. Siteman Cancer Center
- Georgia Clinical and Translational Science Alliance (#UL1 TR002345)
- National Institutes of Health (K99-R00, K99/R00 CA218869, UL1TR002345)
- Center for Cellular Imaging, Washington University
- National Institute on Aging (RF1AG013730)
- National Cancer Institute (R21CA242221, R00CA218869)
- National Institute of Neurological Disorders and Stroke (R37NS065053, R01NS119812, R01NS087632)
- National Center for Advancing Translational Sciences (TR002345, CTSA grant #UL1 TR002345)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- lactate dehydrogenase, lactate metabolism, Schwann cells, motor neurons, sensory neurons, axonal degeneration, demyelination, peripheral neuropathy, pyruvate metabolism, ATP depletion, SARM1, motor neuron disease, cholinergic neurons
- MeSH terms
- Animals, Axons, L-Lactate Dehydrogenase, Mice, Transgenic, Motor Neurons, Sensory Receptor Cells, Schwann Cells, Peripheral Nervous System, Mice, Knockout, Lactic Acid, Mice
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