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Peripheral nerves have the ability to regenerate following trauma, surgery, and exposure to medications and toxins; however, the rate of regeneration is often very slow. The molecular signals that encourage regeneration dissipate over time so that regeneration ends too soon to effectively heal long nerves. Authors of a new report elucidate the role of monocarboxylate transporters and macrophage metabolism is promoting nerve regeneration.

Macrophages (Greek for “large eaters”) are white blood cells that remove pathogens and cellular debris by engulfing and digesting them, making macrophages essential for cellular repair and immunity. Macrophages coordinate tissue regeneration efforts among multiple cell types by secreting a variety of cytokines to recruit additional support cells. In the case of nerve regeneration, macrophages promote the migration of Schwann cells, which produce myelin, to the site of damaged axons.

Monocarboxylate transporters (MCTs) facilitate the movement of small energy molecules such as lactate and pyruvate into cells. When oxygen levels are low or metabolic demand is high, monocarboxylate compounds can be used instead of glucose for cellular energy. Emerging research demonstrates the role of MCTs in the progression of central nervous system disorders and neurodegenerative diseases; however, the role of MCTs on peripheral nerve injury is unknown.

The authors utilized multiple mouse models for their study. First, they compared sciatic nerve regeneration following injury among mice that did not express the MCT-1 protein in one of four cell types: macrophages, perineurial cells, Schwann cells, or dorsal root ganglia neurons. Second, they observed sciatic nerve regeneration in mice that over-expressed the MCT-1 protein in macrophages. Finally, they tested the ability of macrophage adoptive cell transfer, in which macrophages that are isolated from bone marrow, cultured in vitro, and reinfused, to improve nerve regeneration in mice lacking the MCT-1 protein.

Removal of the MCT-1 protein from macrophages significantly reduced nerve regeneration as demonstrated by poor recovery of electrical activity over six weeks following nerve injury; however, removal of MCT-1 from perineurial cells, Schwann cells, or dorsal root ganglia neurons did not impair nerve regeneration. Removal of MCT-1 from macrophages also increased pro-inflammatory cytokines and decreased pro-regenerative cytokine concentrations in the damaged tissue. Not all of these altered cytokines are produced by macrophages, indicating that MCT-1 removal in macrophages modulates the activity of the broader immune system. MCT-1 removal from macrophages impaired mitochondrial function and reduced ATP production, worsening the ability of macrophages to adapt to stressful stimuli and/or high metabolic demands. These macrophages were also less able to clear cellular debris.

Mice that over-expressed the MCT-1 protein in macrophages had significantly faster never regeneration compared to normal mice. MCT-1 expression did not affect motor, sensory, or behavioral recovery following nerve injury. Finally, in mice that did not express MCT-1 protein in macrophages, adoptive transfer of cells led to a complete recovery from nerve injury.

The authors concluded that the MCT-1 protein in macrophages is essential for coordinating nerve regeneration and that adoptive macrophage transfer may be an important therapy in treating nerve injury. It is important to note that the MCT-1 protein transports ketones in addition to lactate and pyruvate. This invites speculation that certain forms of intense exercise, which promotes lactate uptake and utilization throughout the body, or nutritional ketosis may improve nerve regeneration; however, this theory has yet to be tested experimentally.

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