Neuromuscular junction pathology is correlated with differential motor unit vulnerability in spinal and bulbar muscular atrophy.
Neuromuscular junction pathology is correlated with differential motor unit vulnerability in spinal and bulbar muscular atrophy.
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DOI：
10.1186/s40478-022-01402-y
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发表时间：
2022-07-05
影响因子：
7.1
通讯作者：
中科院分区：
文献类型：
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脊髓和延髓肌萎缩症(SBMA)是一种X连锁的神经肌肉退行性疾病，目前还没有治愈的方法。该病的特点是快速肌肉力量(如舌压、握力)选择性降低，并伴有快速抽动肌肉纤维的选择性丧失。然而，神经肌肉接头(NMJ)病理与快速抽动运动单位易损性之间的关系仍有待探讨。在这项研究中，我们使用两种SBMA小鼠模型的交叉模型比较来评估神经肌肉连接的病理，糖酵解到氧化纤维类型的转换，以及胫前肌(TA)、腓肠肌和比目鱼肌后肢肌肉突触前和突触后末端的细胞骨架变化。我们观察到比目鱼肌的快抽动、TA和腓肠肌的糖酵解运动单位与慢抽动、氧化运动单位相比，NMJ和肌纤维病理显著增加，表现为突触前和突触后膜面积减少，突触前和突触后膜共存减少，乙酰胆碱受体致密性增加，终板面积和复杂性减少，神经丝重链缺陷。我们的数据还显示代谢紊乱和肌纤维萎缩与NMJ病理的严重程度相关。我们提出了一个模型，在这个模型中，运动神经元和肌肉之间的动态交流关系以及肌肉的发育亚型促进了运动单位亚型特异性易损性、代谢改变和NMJ病理。网上版载有补充材料，可在10.1186/s40478-022-01402-y查阅。
Spinal and bulbar muscular atrophy (SBMA) is an X-linked, neuromuscular neurodegenerative disease for which there is no cure. The disease is characterized by a selective decrease in fast-muscle power (e.g., tongue pressure, grip strength) accompanied by a selective loss of fast-twitch muscle fibers. However, the relationship between neuromuscular junction (NMJ) pathology and fast-twitch motor unit vulnerability has yet to be explored. In this study, we used a cross-model comparison of two mouse models of SBMA to evaluate neuromuscular junction pathology, glycolytic-to-oxidative fiber-type switching, and cytoskeletal alterations in pre- and postsynaptic termini of tibialis anterior (TA), gastrocnemius, and soleus hindlimb muscles. We observed significantly increased NMJ and myofiber pathology in fast-twitch, glycolytic motor units of the TA and gastrocnemius compared to slow-twitch, oxidative motor units of the soleus, as seen by decreased pre- and post-synaptic membrane area, decreased pre- and post-synaptic membrane colocalization, increased acetylcholine receptor compactness, a decrease in endplate area and complexity, and deficits in neurofilament heavy chain. Our data also show evidence for metabolic dysregulation and myofiber atrophy that correlate with severity of NMJ pathology. We propose a model in which the dynamic communicative relationship between the motor neuron and muscle, along with the developmental subtype of the muscle, promotes motor unit subtype specific vulnerability, metabolic alterations, and NMJ pathology. The online version contains supplementary material available at 10.1186/s40478-022-01402-y.
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DOI：
10.1073/pnas.1900544116
发表时间：
2019-08-06
影响因子：
11.1
作者：
Delezie, Julien;Weihrauch, Martin;Handschin, Christoph
通讯作者：
Handschin, Christoph
影响因子：
5.5
作者：
Hernandez-Torres F;Rodríguez-Outeiriño L;Franco D;Aranega AE
通讯作者：
Aranega AE
DOI：
10.1523/jneurosci.2635-09.2009
发表时间：
2009-09-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chen PC;Qin LN;Li XM;Walters BJ;Wilson JA;Mei L;Wilson SM
通讯作者：
Wilson SM
影响因子：
16.2
作者：
Katsuno, M;Adachi, H;Sobue, G
通讯作者：
Sobue, G
DOI：
10.1073/pnas.85.12.4530
发表时间：
1988-06-01
影响因子：
11.1
作者：
HOFFMAN, PN;CLEVELAND, DW
通讯作者：
CLEVELAND, DW