Inherited neuropathies of the Charcot-Marie-Tooth (CMT) type 1 are still untreatable diseases of the peripheral nervous system. We have previously shown that macrophages substantially amplify neuropathic changes in various mouse models of CMT1 subforms and that targeting innate immune cells substantially ameliorates disease outcome. However, up to date, specific approaches targeting macrophages pharmacologically might entail side effects. Here, we investigate whether physical exercise dampens peripheral nerve inflammation in a model for an X-linked dominant form of CMT1 (CMT1X) and whether this improves neuropathological and clinical outcome subsequently. We found a moderate, but significant decline in the number of macrophages and an altered macrophage activation upon voluntary wheel running. These observations were accompanied by an improved clinical outcome and axonal preservation. Most interestingly, exercise restriction by ~40% accelerated amelioration of clinical outcome and further improved nerve structure by increasing myelin thickness compared to the unrestricted running group. This myelin-preserving effect of limited exercise was accompanied by an elevated expression of brain-derived neurotrophic factor (BDNF) in peripheral nerves, while the expression of other trophic factors like neuregulin-1, glial cell line-derived neurotrophic factor (GDNF) or insulin-like growth factor 1 (IGF-1) were not influenced by any mode of exercise. We demonstrate for the first time that exercise dampens inflammation and improves nerve structure in a mouse model for CMT1, likely leading to improved clinical outcome. Reducing the amount of exercise does not automatically decrease treatment efficacy, reflecting the need of optimally designed exercise studies to achieve safe and effective treatment options for CMT1 patients.

Charcot-Marie-Tooth (CMT) 1 型遗传性神经病仍然是无法治愈的周围神经系统疾病。我们之前已经表明，巨噬细胞在 CMT1 亚型的各种小鼠模型中显着放大了神经病理性变化，并且靶向先天免疫细胞显着改善了疾病结果。然而，迄今为止，在药理学上针对巨噬细胞的特定方法可能会产生副作用。在这里，我们研究体育锻炼是否会抑制 X 连锁显性 CMT1 (CMT1X) 模型中的周围神经炎症，以及这是否会随后改善神经病理学和临床结果。我们发现巨噬细胞的数量适度但显着下降，并且在自愿车轮运行时巨噬细胞活化改变。这些观察结果伴随着改善的临床结果和轴突保存。最有趣的是，与不受限制的跑步组相比，运动限制约 40% 加速了临床结果的改善，并通过增加髓鞘厚度进一步改善了神经结构。有限运动的这种髓鞘保护作用伴随着周围神经中脑源性神经营养因子 (BDNF) 的表达升高，而其他营养因子如神经调节蛋白-1、神经胶质细胞系源性神经营养因子 (GDNF) 或胰岛素样生长因子 1 (IGF-1) 不受任何运动方式的影响。我们首次证明运动可以抑制 CMT1 小鼠模型中的炎症并改善神经结构，这可能会改善临床结果。