Morrison Brett M, Tsingalia Akivaga, Vidensky Svetlana, Lee Youngjin, Jin Lin, Farah Mohamed H, Lengacher Sylvain, Magistretti Pierre J, Pellerin Luc, Rothstein Jeffrey D
Department of Neurology, School of Medicine, The Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA.
Department of Neurology, School of Medicine, The Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA; Brain Science Institute, School of Medicine, The Johns Hopkins University, 855 North Wolfe Street, Baltimore, MD 21205, USA.
Exp Neurol. 2015 Jan;263:325-38. doi: 10.1016/j.expneurol.2014.10.018. Epub 2014 Oct 29.
Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence in wild-type mice and tdTomato fluorescence in MCT1 BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves of MCT1 heterozygous null mice are crushed and peripheral nerve regeneration was quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21 days in wild-type mice to greater than 38 days in MCT1 heterozygote null mice. In fact, half of the MCT1 heterozygote null mice have no recovery of CMAP at 42 days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42 days post-crush in the MCT1 heterozygote null mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote null mice at 4 weeks and tibial mixed sensory and motor nerve at 3 weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly due to failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush.
损伤后周围神经会自发再生，但许多过程需要代谢能量。此前尚未确定轴突能量供应的机制。在中枢神经系统中，少突胶质细胞中表达的单羧酸转运蛋白1（MCT1）对于向轴突供应乳酸或其他能量代谢物至关重要。在当前研究中，通过野生型小鼠的MCT1免疫荧光和MCT1 BAC报告基因小鼠的tdTomato荧光显示，MCT1定位于周围神经系统的神经束膜细胞、背根神经节神经元和雪旺细胞。为了研究MCT1对于周围神经再生是否必要，对MCT1杂合缺失小鼠的坐骨神经进行挤压，并通过电生理和解剖学方法对周围神经再生进行量化。复合肌肉动作电位（CMAP）恢复时间从野生型小鼠的中位数21天延迟至MCT1杂合缺失小鼠的超过38天。事实上，一半的MCT1杂合缺失小鼠在42天时CMAP未恢复，而所有野生型小鼠均已恢复。此外，在挤压后42天时，MCT1杂合缺失小鼠的肌肉纤维萎缩程度比野生型小鼠高40%，神经肌肉接头失神经支配程度高40%。神经再生延迟不仅发生在运动轴突，与野生型小鼠相比，MCT1杂合缺失小鼠在4周时腓肠感觉神经和3周时胫神经混合感觉和运动神经中的再生轴突数量也显著减少。这种再生延迟可能部分归因于雪旺细胞功能障碍，因为髓磷脂碎片的早期吞噬和轴突节段的重新髓鞘化减少。这些数据首次证明，MCT1对于小鼠坐骨神经挤压后感觉和运动轴突的再生至关重要。
