Neuroscience Program, Michigan State University, 108 Giltner Hall, East Lansing, MI, 48824-1115, USA.
Program in Neurosciences and Mental Health, The Hospital for Sick Children, 686 Bay St, Toronto, ON, M5G 0A4, Canada.
J Physiol. 2020 Jul;598(13):2719-2739. doi: 10.1113/JP279208. Epub 2020 May 29.
Muscle-derived neurotrophic factors may offer therapeutic promise for treating neuromuscular diseases. We report that a muscle-derived neurotrophic factor, BDNF, rescues synaptic and muscle function in a muscle-type specific manner in mice modelling Kennedy's disease (KD). We also find that BDNF rescues select molecular mechanisms in slow and fast muscle that may underlie the improved cellular function. We also report for the first time that expression of BDNF, but not other members of the neurotrophin family, is perturbed in muscle from patients with KD. Given that muscle BDNF had divergent therapeutic effects that depended on muscle type, a combination of neurotrophic factors may optimally rescue neuromuscular function via effects on both pre- and postsynaptic function, in the face of disease.
Deficits in muscle brain-derived neurotrophic factor (BDNF) correlate with neuromuscular deficits in mouse models of Kennedy's disease (KD), suggesting that restoring muscle BDNF might restore function. To test this possibility, transgenic mice expressing human BDNF in skeletal muscle were crossed with '97Q' KD mice. We found that muscle BDNF slowed disease, doubling the time between symptom onset and endstage. BDNF also improved expression of genes in muscle known to play key roles in neuromuscular function, including counteracting the expression of neonatal isoforms induced by disease. Intriguingly, BDNF's ameliorative effects differed between muscle types: synaptic strength was rescued only in slow-twitch muscle, while contractile strength was improved only in fast-twitch muscle. In sum, muscle BDNF slows disease progression, rescuing select cellular and molecular mechanisms that depend on fibre type. Muscle BDNF expression was also affected in KD patients, reinforcing its translational and therapeutic potential for treating this disorder.
肌肉源性神经营养因子可能为治疗神经肌肉疾病提供治疗前景。我们报告说，一种肌肉源性神经营养因子 BDNF 以肌肉类型特异性的方式挽救了模拟肯尼迪病 (KD) 的小鼠的突触和肌肉功能。我们还发现 BDNF 挽救了慢肌和快肌中可能是改善细胞功能的特定分子机制。我们还首次报道，BDNF 的表达，而不是神经营养因子家族的其他成员，在 KD 患者的肌肉中受到干扰。鉴于肌肉 BDNF 的治疗效果因肌肉类型而异，因此通过对突触前和突触后功能的影响，神经营养因子的组合可能是优化治疗神经肌肉功能的最佳方法，以应对疾病。
肌肉脑源性神经营养因子 (BDNF) 的缺乏与肯尼迪病 (KD) 小鼠模型中的神经肌肉缺陷相关，这表明恢复肌肉 BDNF 可能恢复功能。为了验证这一可能性，我们将表达人类 BDNF 的转基因小鼠与 '97Q' KD 小鼠杂交。我们发现肌肉 BDNF 减缓了疾病的发展，使症状出现和终末期之间的时间延长了一倍。BDNF 还改善了肌肉中已知在神经肌肉功能中起关键作用的基因的表达，包括抵消疾病诱导的新生型同工型的表达。有趣的是，BDNF 的改善作用因肌肉类型而异：只有在慢肌中才会挽救突触强度，而只有在快肌中才会改善收缩强度。总之，肌肉 BDNF 减缓疾病进展，挽救依赖纤维类型的特定细胞和分子机制。KD 患者的肌肉 BDNF 表达也受到影响，这增强了其治疗这种疾病的转化和治疗潜力。
