Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush

Morrison, Brett M.; Tsingalia, Akivaga; Vidensky, Svetlana; Lee, Youngjin; Jin, Lin; Farah, Mohamed H.; Lengacher, Sylvain; Magistretti, Pierre J.; Pellerin, Luc; Rothstein, Jeffrey D.

doi:10.1016/j.expneurol.2014.10.018

Cited by 77 publications

(79 citation statements)

References 47 publications

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“…We did not observe any change in lactate levels in the SN, but this does not preclude alterations in the flux of lactate between neurons and glia. Lactate transfer is mediated by the monocarboxylate transporters (MCTs), of which MCT-1 is the main isoform expressed in peripheral nerves (29). We identified/quantified MCT-1 in both the SN and the DRG but did not observe significantly altered expression in either tissue (Supplementary Table 2).…”

Section: Discussionmentioning

confidence: 87%

Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy

et al. 2015

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High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However, our understanding of the molecular mechanisms that cause the marked distal pathology is incomplete. We performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN. We integrated proteomics and metabolomics from the sciatic nerve (SN), the lumbar 4/5 dorsal root ganglia (DRG), and the trigeminal ganglia (TG) of streptozotocin-diabetic and healthy control rats. Even though all tissues showed a dramatic increase in glucose and polyol pathway intermediates in diabetes, a striking upregulation of mitochondrial oxidative phosphorylation and perturbation of lipid metabolism was found in the distal SN that was not present in the corresponding cell bodies of the DRG or the cranial TG. This finding suggests that the most severe molecular consequences of diabetes in the nervous system present in the SN, the region most affected by neuropathy. Such spatial metabolic dysfunction suggests a failure of energy homeostasis and/or oxidative stress, specifically in the distal axon/Schwann cell-rich SN. These data provide a detailed molecular description of the distinct compartmental effects of diabetes on the PNS that could underlie the distal-proximal distribution of pathology.Diabetic neuropathy (DN) will develop in ;30-50% of patients with diabetes. DN typically presents with sensory symptoms in a distal glove-and-stocking distribution (1,2). It is a poorly understood complication of diabetes, and currently, few treatments are available (3). Raised glucose has long been believed to instigate pathology in DN either through direct neurotoxicity or from the activation of secondary pathways (4,5). However, exactly how these pathways cause nerve conduction velocity deficits, neuropathic pain, distal axonopathy, and numbness in the extremities continues to elude us, and many clinical trials aimed at specific targets have failed due to lack of efficacy (3).Crossover exists between proposed pathogenic pathways in DN, but how these interact is unclear. This question can be approached by implementing extensive -omic technologies to measure many transcripts, proteins, or metabolites in parallel. Gene microarrays were among the first of these technologies to be used, and transcriptomic analyses have been performed on tissues such as the dorsal root ganglia (DRG) from streptozotocin (STZ)-diabetic rats compared with healthy controls (6), the sciatic nerve (SN) of db/db mice compared with those from db/+ mice (7), and sural nerve biopsy specimens from human patients whose neuropathy progressed over 1 year compared with those whose neuropathy did not (based on myelinated fiber density loss) (8). Common changes across these gene array studies highlight altered carbohydrate and lipid metabolism.Because gene transcript levels do not always correlate with protein expression due to varying transcriptional/translational

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Section: Discussionmentioning

confidence: 87%

Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy

et al. 2015

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“…Unlike the CNS, however, there are no published studies demonstrating the critical nature of lactate to peripheral nerve function in vivo under normal physiologic conditions. As discussed in greater detail below, we have shown that lactate transporters are important for the response of peripheral nerves to injury (Morrison et al, 2015). …”

Section: Fuels To Neural Cells: Glucose Its “By-product” Lactate Anmentioning

confidence: 99%

Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters

Jha

Morrison

2018

Experimental Neurology

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The brain is, by weight, only 2% the volume of the body and yet it consumes about 20% of the total glucose, suggesting that the energy requirements of the brain are high and that glucose is the primary energy source for the nervous system. Due to this dependence on glucose, brain physiology critically depends on the tight regulation of glucose transport and its metabolism. Glucose transporters ensure efficient glucose uptake by neural cells and contribute to the physiology and pathology of the nervous system. Despite this, a growing body of evidence demonstrates that for the maintenance of several neuronal functions, lactate, rather than glucose, is the preferred energy metabolite in the nervous system. Monocarboxylate transporters play a crucial role in providing metabolic support to axons by functioning as the principal transporters for lactate in the nervous system. Monocarboxylate transporters are also critical for axonal myelination and regeneration. Most importantly, recent studies have demonstrated the central role of glial cells in brain energy metabolism. A close and regulated metabolic conversation between neurons and both astrocytes and oligodendroglia in the central nervous system, or Schwann cells in the peripheral nervous system, has recently been shown to be an important determinant of the metabolism and function of the nervous system. This article reviews the current understanding of the long existing controversies regarding energy substrate and utilization in the nervous system and discusses the role of metabolic transporters in health and diseases of the nervous system.

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“…In addition to therapeutically addressing the plethora of inflammatory mediators present, remyelination of axons is considered as one of the most important endogenous axon‐protective mechanisms. Aside from restoring the conductive properties of the axon, remyelination provides insulation of the axon against a potentially hostile microenvironment and restores the close metabolic interaction with oligodendrocytes (Fünfschilling et al, 2012; Lee et al, 2012; Morrison et al, 2015). The correlation of early remyelination and axonal damage and whether damaged axons can be remyelinated, is unknown so far.…”

Section: Introductionmentioning

confidence: 99%

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination

Schultz

Meer

Wrzos

et al. 2017

Glia

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Remyelination is in the center of new therapies for the treatment of multiple sclerosis to resolve and improve disease symptoms and protect axons from further damage. Although remyelination is considered beneficial in the long term, it is not known, whether this is also the case early in lesion formation. Additionally, the precise timing of acute axonal damage and remyelination has not been assessed so far. To shed light onto the interrelation between axons and the myelin sheath during de‐ and remyelination, we employed cuprizone‐ and focal lysolecithin‐induced demyelination and performed time course experiments assessing the evolution of early and late stage remyelination and axonal damage. We observed damaged axons with signs of remyelination after cuprizone diet cessation and lysolecithin injection. Similar observations were made in early multiple sclerosis lesions. To assess the correlation of remyelination and axonal damage in multiple sclerosis lesions, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the number of APP‐ and SMI32‐ positive damaged axons and the density of SMI31‐positive and silver impregnated preserved axons. Early de‐ and remyelinating lesions did not differ with respect to axonal density and axonal damage, but we observed a lower axonal density in late stage demyelinated multiple sclerosis lesions than in remyelinated multiple sclerosis lesions. Our findings suggest that remyelination may not only be protective over a long period of time, but may play an important role in the immediate axonal recuperation after a demyelinating insult.

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Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush

Cited by 77 publications

References 47 publications

Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy

Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental Diabetic Neuropathy

Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination

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