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Cited by 40Neurogenesis and neuroplasticity mechanismsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons

Open access
Späte, Erik, Zhou, Baoyu, Sun, Ting, Kusch, Kathrin, Asadollahi, Ebrahim, Siems, Sophie B., Depp, Constanze, Werner, Hauke B. +5 more·2024·Glia
DOI 10.1002/glia.24533
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Abstract

Oligodendrocytes and astrocytes are metabolically coupled to neuronal compartments. Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters. However, lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions. Here we show that mice with a cell type‐specific disruption of both Ldha and Ldhb genes in oligodendrocytes lack a pathological phenotype that would be indicative of oligodendroglial dysfunctions or lack of axonal metabolic support. Indeed, when combining immunohistochemical, electron microscopical, and in situ hybridization analyses in adult mice, we found that the vast majority of mature oligodendrocytes lack detectable expression of LDH. Even in neurodegenerative disease models and in mice under metabolic stress LDH was not increased. In contrast, at early development and in the remyelinating brain, LDHA was readily detectable in immature oligodendrocytes. Interestingly, by immunoelectron microscopy LDHA was particularly enriched at gap junctions formed between adjacent astrocytes and at junctions between astrocytes and oligodendrocytes. Our data suggest that oligodendrocytes metabolize lactate during development and remyelination. In contrast, for metabolic support of axons mature oligodendrocytes may export their own glycolysis products as pyruvate rather than lactate. Lacking LDH, these oligodendrocytes can also “funnel” lactate through their “myelinic” channels between gap junction‐coupled astrocytes and axons without metabolizing it. We suggest a working model, in which the unequal cellular distribution of LDH in white matter tracts facilitates a rapid and efficient transport of glycolysis products among glial and axonal compartments.

AI snapshot

Written from the paper’s full text.

TL;DR

Adult mature oligodendrocytes in mice largely lack detectable lactate dehydrogenase (LDHA/LDHB), and oligodendrocyte-specific double inactivation of *Ldha* and *Ldhb* causes no obvious pathological phenotype. The authors propose that mature oligodendrocytes export pyruvate rather than lactate to axons and can funnel astroglial lactate through myelinic channels without metabolizing it.

Key findings

  • Mature oligodendrocytes rarely express LDH: the highest percentage of LDH-positive oligodendrocytes was in brain stem, not surpassing 0.5% (mean LDHA 0.36% ± 0.47%; mean LDHB 0.32% ± 0.12%). Immunogold EM showed LDHA/LDHB preferentially in axons and astrocytes, not myelin or oligodendroglial somata; low oligodendrocyte/myelin signal was not further reduced in dKO and was interpreted as background.
  • Conditional double inactivation of *Ldha* and *Ldhb* in oligodendrocytes lacked detectable pathology: idKO mice were indistinguishable from controls up to 6 months; quantitative immunostainings showed no significant astrogliosis, microglial activation, T-cell infiltration, or axonal swellings (p GFAP+ = 0.101, p MAC3+ = 0.906, p CD3+ = 0.492, p APP+ = 0.347). In dKO optic nerves, g-ratio was not significantly different from controls (p = .1324).
  • LDHA is expressed in immature oligodendrocytes and during remyelination: in corpus callosum, LDHA-positive CC1+ oligodendrocytes declined from P10 92% ± 2.6%, P15 43% ± 9%, P25 16% ± 13%, to P75 0% ± 0% (slope = −30.4% ± 2.2%, p < .001). After cuprizone-induced demyelination, 85 ± 4% of CC1+ cells in remyelinating corpus callosum expressed LDHA at 6 weeks.
  • LDHA, but not LDHB, was enriched at astroglial gap junctions and at the astroglial side of astrocyte-oligodendrocyte junctions in optic nerve, supporting a model in which astrocytes produce lactate near gap junctions, oligodendrocytes/myelin funnel it to axons, and mature oligodendrocytes may supply pyruvate instead of lactate.

Methods

  • Mouse genetics: floxed *Ldha* and *Ldhb* alleles were inactivated in oligodendrocytes using tamoxifen-inducible *PlpCreERT2* (idKO; tamoxifen at 8 weeks, analysis at 18 weeks) or *Cnp* Cre (dKO). Controls lacked Cre. Additional models included aged mice, 5xFAD, *App* NLGF, *Plp* null, conditional *Cox10* mutants, and cuprizone-induced demyelination/remyelination.
  • Expression and structural analyses: qRT-PCR, immunoblotting, immunohistochemistry, X-gal histochemistry, RNAscope in situ hybridization, primary oligodendrocyte cultures, transmission EM, immunogold EM, and g-ratio analysis. Public scRNA-seq/snRNA-seq datasets GSE129788 and GSE140511 were reanalyzed with Seurat.
  • Statistics: acquisition was blinded; graphs show means with SEM; Student’s t tests, ANOVAs, and linear/generalized linear mixed models were used, with p < .05 considered significant.

Limitations

  • Stated: *Cnp* Cre also recombines Schwann cells and off-target subsets of CNS neurons including motoneuronal precursors; because *Ldh* deletion in Schwann cells and motoneurons causes marked neuropathology, the authors refrained from histopathological analysis of brain and spinal cord in dKO mice and instead analyzed optic nerve, where all *Cnp* Cre recombined cells are oligodendroglial.
  • Stated: *PlpCreERT2* may have recombined floxed genes insufficiently, other cells may have upregulated LDHA/LDHB, or oligodendrocytes may contribute only marginally to adult corpus callosum *Ldh* mRNA/protein; the authors could not distinguish these possibilities from the initial idKO analysis.
  • Evident: the central model that mature oligodendrocytes export pyruvate rather than lactate, and that astroglial lactate is funneled through oligodendrocytes/myelin, remains a working hypothesis; the paper states there was previously no experimental approach to decide whether oligodendrocytes release lactate or pyruvate. Findings are from mouse models, with human relevance not established in the text.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/glia.24533

Cites

81 of 82 references verified0 citation errors · 1 not checkable

Statistics

Claims the paper makes

38 of 69 cited sources checked · 17 supported · 3 flagged · accuracy not yet measured

  • Premisecitation

    The model of glycolytic oligodendrocytes providing metabolic support is supported by ex vivo electrophysiological recordings of compound action potentials in optic nerves and by neuronally expressed ATP sensors.

    “The model is further supported by ex vivo electrophysiological recordings of compound action potentials in optic nerves under defined metabolic conditions and with the help of neuronally expressed ATP sensors (Saab et al., 2016;Trevisiol et al., 2017).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Saab et al., 2016 source

      The Results (‘Functional Analysis of Myelinated Axons’; page unavailable) report ex vivo compound action potential recordings from optic nerves under oxygen-glucose deprivation, supporting that part of the claim. The Experimental Procedures (‘Glucose Sensor Imaging’; page unavailable) describe a glucose sensor in cultured oligodendrocyte-lineage cells, not a neuronally expressed ATP sensor; our copy does not support attributing that method to Saab et al. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Trevisiol et al., 2017 source
  • Premisecitation

    Mature oligodendrocytes survive well in Cox10-deficient mice, in which oligodendrocytes lack an assembly factor of stable mitochondrial cytochrome c oxidase (COX, mitochondrial complex IV).

    “we found that mature oligodendrocytes survive well in Cox10 (protoheme IX farnesyltransferase)-deficient mice, in which oligodendrocytes lack an assembly factor of stable mitochondrial cytochrome c oxidase (COX, mitochondrial complex IV).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Fünfschilling et al., 2012 source
  • Premisecitation

    Lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions.

    “lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Miura, 1966a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Ross et al., 2010 source

      The Results passages describe LDH-mediated conversion between pyruvate and lactate and identify five isoenzymes made from different combinations of LDH-A and LDH-B subunits. They do not establish the broader claim that lactate can only be synthesized or used in metabolic reactions with LDH. Page numbers are not available in the supplied copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Goldberg et al., 2010 source

      In “Discovery of LDHC: The Beginning of a Journey” (page not provided), the paper says LDH catalyzes the interconversion of pyruvate and lactate and describes tetramers assembled from A and B subunits. But that section also identifies LDH-C4, a tetramer of C subunits, so the claim’s description of LDH as composed only of LDHA and LDHB is too narrow. The paper does not establish the claim’s absolute “can only” wording. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters.

    “Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Lee et al., 2012 source
    • cites Philips et al., 2021 source
  • Premisecitation

    The model is in agreement with axonal degeneration observed in mice lacking the monocarboxylate transporter MCT1 in oligodendrocyte lineage cells.

    “It is finally in agreement with axonal degeneration observed in mice lacking the monocarboxylate transporter MCT1 in oligodendrocytes lineage cells (Lee et al., 2012;Philips et al., 2021).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Lee et al., 2012 source

      The ‘Oligodendrocyte-specific MCT1 loss causes axonopathy’ section reports axonal degeneration in PLP-Cre mice after oligodendrocyte-specific MCT1 knockdown. It does not report mice completely lacking MCT1 specifically in oligodendrocyte-lineage cells; its other mouse model is a systemic heterozygote with partially reduced MCT1. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Philips et al., 2021 source
  • Classified as probably not a substantial claim. 21
  • May combine two claims. 26

  • Classified as probably not a substantial claim.

    Premisecitation

    There is so far no experimental approach to the question of whether oligodendrocytes release lactate or pyruvate for the support of axonal energy metabolism.

    “However, there is so far no experimental approach to the question of whether oligodendrocytes release lactate or pyruvate (Fünfschilling et al., 2012) for the support of axonal energy metabolism.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Fünfschilling et al., 2012 source

      The paper reports an experimental approach to this question: in vivo magnetic resonance spectroscopy measured increased lactate in Cox10 mutant brains, and the authors interpret the findings as compatible with oligodendroglial lactate release and use by other cells (passage [2], page unavailable). They also report an in vitro test showing that myelinated axons metabolize glial lactate. These experiments do not directly establish whether oligodendrocytes release lactate or pyruvate to support axons, but they contradict the claim that there was no experimental approach to the question. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    LDHA and LDHB are widely expressed including brain, while LDHC is restricted to testis and sperm.

    “While LDHA and LDHB are widely expressed including brain (Miura, 1966a;Miura, 1966b;Ross et al., 2010), LDHC is restricted to testis and sperm (Goldberg et al., 2010).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Miura, 1966a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Ross et al., 2010 source
    • cites Goldberg et al., 2010 source

      The Tissue localization section confirms LDHC in testis and sperm but says it is not restricted to them: LDHC protein was also detected in oocytes and fertilized eggs through the preimplantation blastocyst stage. The supplied passages do not give a page number. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationown data

    Astroglial lactate is preferentially produced at sites of transcellular transport, compatible with a model of astroglial lactate routed through oligodendrocytes to the axonal compartment.

    “This suggests that astroglial lactate is preferentially produced at sites of transcellular transport, compatible with a model of astroglial lactate routed through oligodendrocytes to the axonal compartment (Philippot et al., 2021).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Philippot et al., 2021 source

      The Discussion says thalamic oligodendrocytes mainly assist astrocytes in metabolite transport to postsynapses, “rather than by fueling axons or pre-synaptic structures.” That contradicts the proposed route to the axonal compartment. The Discussion also does not establish that astroglial lactate is preferentially produced at sites of transcellular transport; no page number is available in our copy. (LLM, conf=0.89)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • Rests on an assumption: LDH expression detected by immunohistochemistry, in situ hybridization, and immunogold EM accurately reflects functional LDH enzyme activity.
    • Rests on an assumption: The antibodies against LDHA and LDHB are specific.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In mammals, three Ldh genes give rise to subunits (LDHA, LDHB, LDHC) that form tetrameric LDH isoenzymes.

    “In mammals, three Ldh genes give rise to subunits (LDHA, LDHB, LDHC) that form tetrameric LDH isoenzymes.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Miura, 1966a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Goldberg et al., 2010 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Glycolytic oligodendrocytes provide direct metabolic support to axons via non-compacted cytoplasmic channels in myelin and monocarboxylate transporters, which preserves functional integrity and axon survival.

    “This led to a working model of glycolytic oligodendrocytes providing direct metabolic support to axons via non-compacted cytoplasmic channels in myelin and monocarboxylate transporters, which preserves functional integrity and axon survival (Amaral et al., 2013;Fünfschilling et al., 2012;Lee et al., 2012).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Amaral et al., 2013

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Fünfschilling et al., 2012 source

      The paper proposes a model in which oligodendrocyte glycolysis supplies metabolites to axons, and it identifies MCT1 in myelin and MCT2 in myelinated axons (indexed section labelled Abstract; page unavailable). It also reports maintenance of myelin and axons in adult CNS mutants. Our copy does not describe transport via non-compacted cytoplasmic channels, so that specific route is not supported by this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Lee et al., 2012 source

      The Discussion (page unavailable) says oligodendroglia supply axons with lactate through MCT1 and that this support is critical for axon function and neuron survival. It does not describe transport through non-compacted cytoplasmic channels in myelin or establish the specific characterization of the supporting oligodendrocytes as glycolytic. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The original ANLS has been controversially discussed but has also gained considerable experimental support by in vitro and in vivo studies.

    “While the original ANLS has been controversially discussed (Albanese et al., 2016;Bosoi & Rose, 2014;Dienel, 2017;Liguori et al., 2015;Yellen, 2018), it has also gained considerable experimental support by in vitro (Bouzier-Sore et al., 2003;Karagiannis et al., 2021) and in vivo studies (Mächler et al., 2016;Suzuki et al., 2011;Wyss et al., 2011;Zuend et al., 2020).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Albanese et al., 2016 source

      Albanese et al. is cited for the claim that the original astrocyte–neuron lactate shuttle (ANLS) has been controversially discussed; the later experimental-support clause cites other studies. The Background describes conflicting measurements of cerebrospinal-fluid lactate in multiple sclerosis, while the Discussion describes the lactate-shuttle hypothesis without saying that the hypothesis itself is controversial. Searches for ANLS and lactate-shuttle controversy found no passage supporting that attributed point. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites Bouzier-Sore et al., 2003 source
    • cites Mächler et al., 2016 source

  • May combine two claims.

    Premisecitation

    Adult oligodendrocytes become predominantly glycolytic with a reduced rate of oxidative phosphorylation (OXPHOS).

    “This is compatible with the idea that adult oligodendrocytes become predominantly glycolytic with a reduced rate of oxidative phosphorylation (OXPHOS) (Fünfschilling et al., 2012).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Fünfschilling et al., 2012 source

      The passage labeled Abstract (page not provided) says that after myelination oligodendrocytes may tolerate a partly glycolytic metabolism and that mature wild-type cells have lower COX activity than precursor cells. This is compatible with a shift toward glycolysis, but it does not establish that adult oligodendrocytes are predominantly glycolytic or directly measure a reduced OXPHOS rate. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Because LDH tetramers with a surplus of LDHA subunits are biased toward lactate generation, findings argue that immature oligodendrocytes produce and release lactate during development and remyelination.

    “Since LDH tetramers with a surplus of LDHA subunits are biased toward the generation of lactate (Claps et al., 2022;Mishra & Banerjee, 2019) these findings rather argue in favor of the production and release of lactate from immature oligodendrocytes under these conditions.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Claps et al., 2022 source
    • cites Mishra & Banerjee, 2019 source

  • May combine two claims.

    Premisecitation

    The Cnp Cre driver line recombines floxed genes to virtually 100% in oligodendrocytes and up to 60% of OPCs.

    “that recombines floxed genes to virtually 100% in oligodendrocytes and up to 60% of OPCs (Madsen et al., 2016;Saab et al., 2016;Vajda et al., 2015).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Madsen et al., 2016 source
    • cites Saab et al., 2016 source

      In Results, under “Myelination In Vivo in the Absence of Oligodendroglial NMDA Receptors” (page unavailable), recombination reached 62% ± 8% of floxed alleles in adult optic nerve, approximately the expected proportion of oligodendrocytes. This is consistent with extensive recombination in mature oligodendrocytes, but the paper does not report recombination in up to 60% of OPCs. Its statement that virtually all recombined cells were oligodendroglial describes which cells recombined, not the percentage of either cell type that recombined. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Vajda et al., 2015

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    The data are compatible with a revised working model in which lactate is preferentially produced in astrocytes close to their gap junctions with neighboring cells, and myelinic channels funnel astroglial lactate and oligodendroglial pyruvate to the periaxonal space of myelinated internodes.

    “Our data are thus compatible with a revised working model of Fünfschilling et al. (2012), in which lactate is preferentially produced in astrocytes close to their gap junctions with neighboring cells, and in which myelinic channels funnel astroglial lactate and oligodendroglial pyruvate to the periaxonal space of myelinated internodes.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Fünfschilling et al., 2012 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Ldhb mRNA was prominent in neurons of the basal forebrain, including several thalamic nuclei and in the midbrain.

    “The more widely expressed Ldhb mRNA was also prominent in neurons of the basal forebrain, including several thalamic nuclei and in the midbrain as described (Laughton et al., 2000;Ross et al., 2010) (Figure 2g).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Laughton et al., 2000 source
    • cites Ross et al., 2010 source

      The Results section says LDH-B mRNA was highly expressed throughout the brain and more widely expressed than LDH-A. It does not specifically identify neurons of the basal forebrain, thalamic nuclei, or midbrain as sites of prominent expression. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • Rests on an assumption: LDH expression detected by immunohistochemistry, in situ hybridization, and immunogold EM accurately reflects functional LDH enzyme activity.
    • Rests on an assumption: The antibodies against LDHA and LDHB are specific.

  • May combine two claims.

    Premisecitation

    Cnp Cre mice also recombine Schwann cells and off-target in subsets of CNS neurons including motoneuronal precursors.

    “However, Cnp Cre mice also recombine Schwann cells and off-target in subsets of CNS neurons including motoneuronal precursors (Genoud et al., 2002;Jo et al., 2021;Tognatta et al., 2017) (Figure S1a-e).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Genoud et al., 2002 source

      The Results (Fig. 1) report Cnp-Cre recombination in the developing spinal cord’s ventral horns, presumably in motoneurons, and the Discussion describes Cre expression in early oligodendrocyte progenitors and motoneurons. Our copy does not report recombination in Schwann cells; the Fig. 1 caption identifies nearby nerve roots and dorsal root ganglia as PNS structures but does not establish Schwann-cell recombination. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Jo et al., 2021

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Tognatta et al., 2017

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Ldha gene expression was strongest in the cerebral cortex and hippocampus.

    “Ldha gene expression was strongest in the cerebral cortex and hippocampus as previously reported (Laughton et al., 2000;Ross et al., 2010) (Figure 2g).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Laughton et al., 2000 source
    • cites Ross et al., 2010 source
    • Rests on an assumption: LDH expression detected by immunohistochemistry, in situ hybridization, and immunogold EM accurately reflects functional LDH enzyme activity.
    • Rests on an assumption: The antibodies against LDHA and LDHB are specific.

  • May combine two claims.

    Premisecitation

    During developmental myelination, oligodendrocytes import and utilize lactate for ATP generation and the synthesis of myelin lipids, which requires functional expression of LDH.

    “During developmental myelination, oligodendrocytes are thought to import and utilize lactate for ATP generation and the synthesis of myelin lipids (Amaral et al., 2016;Rinholm et al., 2011;Sánchez-Abarca et al., 2001), which requires functional expression of LDH.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Amaral et al., 2016

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Rinholm et al., 2011 source

      The Introduction says oligodendrocytes need ATP and lipids for myelination and reports that cultured oligodendrocytes use lactate to fuel mitochondria and synthesize lipids. The Discussion confirms lactate uptake and shows that added lactate supports myelination under low-glucose conditions. The cited paper does not establish the added claim that this requires functional LDH expression. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Sánchez-Abarca et al., 2001 source

  • May combine two claims.

    Findingown data

    In adult control mice, both LDHA and LDHB are found foremost in neurons and region-dependently in subsets of astrocytes, but only rarely in oligodendrocytes.

    “By immunohistochemistry of different brain regions from adult control mice (age 6 months) we found both LDHA and LDHB foremost in neurons and also region-dependently in subsets of astrocytes (Figures 2, S2), but only rarely in oligodendrocytes throughout the”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LDHB was only marginally expressed in CC1+ oligodendrocytes at P10, too low to be reliably quantified.

    “LDHB was only marginally expressed in CC1 + oligodendrocytes at P10 (Figure 3c), too low to be reliably quantified.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: LDH expression detected by immunohistochemistry, in situ hybridization, and immunogold EM accurately reflects functional LDH enzyme activity.
    • Rests on an assumption: The antibodies against LDHA and LDHB are specific.

  • May combine two claims.

    Findingown data

    Immunohistological analysis of GFAP revealed a normal astroglial scaffold and no signs of astrogliosis in adult mutants.

    “Immunohistological analysis of glial fibrillary acidic protein (GFAP) revealed a normal astroglial scaffold and no signs of astrogliosis (Figure 1b,c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Stainings for MAC3, CD3, and APP indicated the absence of inflammation and axonal swellings in adult mutants.

    “Stainings for MAC3 as a marker for activated microglia, CD3 as a marker for infiltrating T-cells, and amyloid precursor protein (APP) as a surrogate marker for axonal transport defects indicated the absence of inflammation and axonal swellings (Figure 1b,c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the optic nerve, LDHA is enriched at astrocyte-astrocyte gap junctions and on the astroglial side of astrocyte-oligodendrocyte junctions.

    “Moreover, in the optic nerve we found LDHA enriched at astrocyte-astrocyte gap junctions and on the astroglial side of astrocyte-oligodendrocyte junctions.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: LDH expression detected by immunohistochemistry, in situ hybridization, and immunogold EM accurately reflects functional LDH enzyme activity.
    • Rests on an assumption: The antibodies against LDHA and LDHB are specific.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    A priori, pyruvate could serve the same metabolic functions as lactate in myelinated tracts, as long as oligodendrocytes can oxidize NADH and regenerate the NAD+ that is spent in glycolysis.

    “A priori, pyruvate could serve the same metabolic functions as lactate in myelinated tracts, as long as oligodendrocytes can oxidize NADH and regenerate the NAD + that is spent in glycolysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    LDH catalyzes the bidirectional conversion of pyruvate and lactate, with LDHA having a higher affinity for pyruvate and LDHB a higher affinity for lactate.

    “LDH catalyzes the bidirectional conversion of pyruvate and lactate, with LDHA reportedly having a higher affinity for pyruvate (Claps et al., 2022;Mishra & Banerjee, 2019) and LDHB a higher affinity for lactate (Kopperschläger & Kirchberger, 1996;Read et al., 2001).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Claps et al., 2022 source
    • cites Kopperschläger & Kirchberger, 1996 source
    • cites Read et al., 2001

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Elevated brain lactate measured in Cox10 fl/fl;Cnp Cre/wt mice may have secondarily built up within LDH-positive axonal compartments in response to the influx of oligodendrocyte-derived pyruvate.

    “This would implicate that elevated brain lactate measured in Cox10 fl/fl ;Cnp Cre/wt mice had secondarily built up within the LDH-positive axonal compartments in response to the influx of oligodendrocyte-derived pyruvate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cnp Cre-mediated neuronal off-target recombination can be detected in subsets of forebrain neurons and may have contributed to the observed axonal lactate peaks in Cox10 fl/fl;Cnp Cre mice.

    “We must, however, also consider that Cnp Cre mediated neuronal off-target recombination can be detected in subsets of forebrain neurons (Jo et al., 2021;Tognatta et al., 2017) (Figure S1) and may thus have contributed to the observed axonal lactate peaks in Cox10 fl/fl ; Cnp Cre mice.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Jo et al., 2021

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Tognatta et al., 2017

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All data acquisition was performed blinded.

    “All data acquisition was performed blinded.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    Given low LDH in oligodendrocytes, the model is refined to hypothesize that predominantly oligodendrocyte-derived pyruvate enters the axonal compartment.

    “Given the low levels of LDH in oligodendrocytes, we can refine our model and hypothesize that it is predominantly oligodendrocyte-derived pyruvate, which enters the axonal compartment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The virtual lack of LDH from mature oligodendrocytes and myelin separates astroglial and axonal lactate metabolism, enabling efficient lactate funneling without loss in oligodendroglial metabolism.

    “The virtual lack of LDH from mature oligodendrocytes and myelin separates astroglial and axonal lactate metabolism, enabling efficient lactate funneling without loss in oligodendroglial metabolism.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: LDH expression detected by immunohistochemistry, in situ hybridization, and immunogold EM accurately reflects functional LDH enzyme activity.
    • Rests on an assumption: The antibodies against LDHA and LDHB are specific.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Quantifications were performed with ImageJ/Fiji and the experimenter was blinded to the genotype.

    “Quantifications were performed with ImageJ/Fiji and the experimenter blinded to the genotype.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Cytosolic GPD1 in oligodendrocytes may provide an additional way to make NAD+ regeneration partly independent of mitochondrial NADH shuttles and may substitute for the lack of LDH reaction to a certain extent.

    “Cytosolic GPD1 in oligodendrocytes may thus provide an additional way to make NAD+ regeneration partly independent from the action of mitochondrial NADH shuttles and may thus substitute for the lack of LDH reaction in oligodendrocytes to a certain extent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The negligible LDH expression in mature oligodendrocytes may be explained by sufficient OXPHOS activity in wildtype oligodendrocytes to regenerate NAD+ and residual activity in the absence of Cox10.

    “This may be best explained by sufficient OXPHOS activity in wildtype oligodendrocytes to regenerate NAD + and even residual activity in the absence of Cox10.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Statistical power of the LMMs was estimated using a simulation-based power analysis (n = 1000).

    “Statistical power of the LMMs was estimated using a simulation-based power analysis (n = 1000).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    Oligodendrocytes and myelin provide the space and architecture for astroglial lactate to diffuse towards the axon, essentially as a funnel for glycolysis products.

    “Thus, we hypothesize that oligodendrocytes and myelin also provide the space and architecture for astroglial lactate to diffuse towards the axon, essentially as a”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The enrichment of LDHA at astroglial gap junctions and MCT1 at the inner tongue of myelin is compatible with a model in which astrocytes funnel lactate through oligodendrocytes and the cytosolic myelin compartment to axons, while oligodendrocytes deliver self-generated pyruvate to the axonal compartment.

    “This enrichment of LDHA at GJ in combination with the localization of MCT1 at the inner tongue of myelin (Figure 5e) is compatible with a model that astrocytes”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    The enrichment of LDH at astroglial gap junctions is compatible with the hypothesis that astrocyte glycolysis products, generated from glycogen upon acute energetic demands, are shuttled as lactate via oligodendrocytes/myelin into the axonal compartment.

    “The enrichment of LDH at gap junctions of adjacent astrocytes and at the astroglial aspect of astrocyteto-oligodendrocyte junctions in the optic nerve is compatible with the hypothesis that glycolysis products of astrocytes, generated quickly from glycogen stores upon acute energetic demands, are shuttled as lactate via oligodendrocytes/myelin into the axonal compartment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All primers were intron-spanning.

    “All primers were intronspanning.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All analyses were performed blind to the conditions of the mice.

    “All analyses were performed blind to the conditions of the mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Lactate synthesized by adult oligodendrocytes is unlikely a supporting metabolite for axons, suggesting pyruvate as a possible alternative.

    “Therefore, our findings indicate that lactate synthesized by adult oligodendrocytes is unlikely a supporting metabolite for axons, suggesting pyruvate as a possible alternative.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: LDH expression detected by immunohistochemistry, in situ hybridization, and immunogold EM accurately reflects functional LDH enzyme activity.
    • Rests on an assumption: The antibodies against LDHA and LDHB are specific.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All primers were designed with Universal Probe Library from Roche Applied Systems and validated with NIH PrimerBlast.

    “All primers (Table 1) were designed with Universal Probe Library from Roche Applied Systems (https://www.roche-applied-science. com) and validated with NIH PrimerBlast.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Oligodendrocytes may be distinguished from astrocytes, which express LDH and reportedly use a lactate shuttle to directly support synaptic energy metabolism in cortical gray matter.

    “This may distinguish oligodendrocytes from astrocytes that express LDH and reportedly use a”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Magistretti & Allaman, 2018 source
    • cites Pellerin & Magistretti, 1994 source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Analysis procedure and parameters for reanalysis of single-cell RNA sequencing data were identical to the original publications, with cell type annotations cross-checked using calculated cluster marker genes.

    “Analysis procedure and parameters were identical to the original publications, with cell type annotations cross-checked using calculated cluster marker genes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All models were intensively checked using the DHARMA and performance R packages to verify assumptions and fit.

    “All models were intensively checked using the DHARMA (0.4.6) and performance (0.10.4) R packages to verify assumptions and fit.”
    Quote in the paperNot a substantial claim
40 of 40

  • The paper relies on this without support.

    LDH expression detected by immunohistochemistry, in situ hybridization, and immunogold EM accurately reflects functional LDH enzyme activity.

    “we found that the vast majority of mature oligodendrocytes lack detectable expression of LDH.”
    “by immunoelectron microscopy LDHA was particularly enriched at gap junctions formed between adjacent astrocytes and at junctions between astrocytes and oligodendrocytes.”

  • The paper relies on this without support.

    The antibodies against LDHA and LDHB are specific.

    “using specific antibodies against LDHA and LDHB, respectively.”

  • The paper relies on this without support.

    In vivo evidence for the use of lactate during developmental myelination is lacking.

    “Nevertheless, in vivo evidence for the use of lactate during developmental myelination is lacking.”

  • The paper relies on this without support.

    LDH expression levels reflect lactate metabolism capacity.

    “We conclude that mature oligodendrocytes in adult mice show no obvious adaptation of LDH expression and thus lactate metabolism when facing neurodegeneration and metabolic stress.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • OLs funnel energy substrates directly to the axonal space through myelinic channels.

    “OLs funnel energy substrates directly to the axonal space through myelinic channels [279].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [279]

    The Discussion describes a working model in which myelinic channels funnel astroglial lactate and oligodendroglial pyruvate to the periaxonal space. The citing sentence presents that proposed transport as an established fact, whereas the paper says its data are compatible with the model. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(3, 8.93) = 19.74reported p < .001 · recomputed p < .001

    “F(3, 8.93) = 19.74,p < .001”

  • ConsistentF(3, 9.26) = 41.66reported p < .001 · recomputed p < .001

    “F(3,9.26)= 41.66,p < .001”

2 of 2

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. 10.3389/fendo.2013.00054/bibtex · DOI
  2. 10.1152/physrev.00043.2018/asset/images/large/z9j0042029570010.jpeg · DOI
  3. 10.1002/1097-0134 · DOI

Cited by

Sorted by citations

Related

Authors
Späte, E., Zhou, B., Sun, T., Kusch, K., Asadollahi, E., Siems, S. B., Depp, C., Werner, H. B., Saher, G., Hirrlinger, J., Möbius, W., Nave, K., & Goebbels, S.
Affiliations
Max Planck Society (DE)
Corresponding author
  • Nave, Klaus‐Armin
  • Goebbels, Sandra
ORCID
Venue
Glia
Publisher
Wiley
Published
2024-04-08
Volume
72
Issue
8
Pages
1374-1391
ISSN
  • 0894-1491 (ISSN-L)
  • 1098-1136
DOI
10.1002/glia.24533
OpenAlex
W4394577280
Cited by
40
References
79
Citations by year
2026: 16 · 2025: 17 · 2024: 7
FWCI
6.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Glia (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by-nc-nd)
Funders
  • European Research Council
  • Deutsche Forschungsgemeinschaft (SPP1757)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
lactate dehydrogenase, oligodendrocytes, LDHA, LDHB, glycolysis, lactate transport, pyruvate, astrocytes, gap junctions, remyelination, oligodendrocyte development, monocarboxylate transporters, white matter, neurodegeneration
MeSH terms
Lactate Dehydrogenase 5, Animals, Astrocytes, Axons, Glycolysis, Isoenzymes, L-Lactate Dehydrogenase, Mice, Inbred C57BL, Mice, Transgenic, Oligodendroglia, Down-Regulation, Gap Junctions, Mice, Knockout, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-02.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-02.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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