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PLoS One ; 17(10): e0272097, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36194565

RESUMO

While lactate shuttle theory states that glial cells metabolize glucose into lactate to shuttle it to neurons, how glial cells support axonal metabolism and function remains unclear. Lactate production is a common occurrence following anaerobic glycolysis in muscles. However, several other cell types, including some stem cells, activated macrophages and tumor cells, can produce lactate in presence of oxygen and cellular respiration, using Pyruvate Kinase 2 (PKM2) to divert pyruvate to lactate dehydrogenase. We show here that PKM2 is also upregulated in myelinating Schwann cells (mSC) of mature mouse sciatic nerve versus postnatal immature nerve. Deletion of this isoform in PLP-expressing cells in mice leads to a deficit of lactate in mSC and in peripheral nerves. While the structure of myelin sheath was preserved, mutant mice developed a peripheral neuropathy. Peripheral nerve axons of mutant mice failed to maintain lactate homeostasis upon activity, resulting in an impaired production of mitochondrial ATP. Action potential propagation was not altered but axonal mitochondria transport was slowed down, muscle axon terminals retracted and motor neurons displayed cellular stress. Additional reduction of lactate availability through dichloroacetate treatment, which diverts pyruvate to mitochondrial oxidative phosphorylation, further aggravated motor dysfunction in mutant mice. Thus, lactate production through PKM2 enzyme and aerobic glycolysis is essential in mSC for the long-term maintenance of peripheral nerve axon physiology and function.


Assuntos
Axônios , Piruvato Quinase , Trifosfato de Adenosina/metabolismo , Animais , Axônios/metabolismo , Glucose/metabolismo , Glicólise , Lactato Desidrogenases , Lactatos/metabolismo , Camundongos , Bainha de Mielina/metabolismo , Oxigênio/metabolismo , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , Piruvatos/metabolismo , Células de Schwann/metabolismo , Nervo Isquiático/patologia
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