Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy.
Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy.
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DOI：
10.1016/j.ebiom.2016.12.011
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发表时间：
2017-02
期刊：
影响因子：
11.1
通讯作者：
Nishino I
中科院分区：
文献类型：
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作者：
Noguchi S;Ogawa M;Malicdan MC;Nonaka I;Nishino I
先天性肌营养不良伴胶原VI缺乏症是一种具有广泛临床表现的遗传性肌肉疾病，由COL6A1-3基因突变引起。肌肉病理的特点是纤维大小变化，间质纤维化和脂肪生成增加。在这项研究中，我们定义了导致胶原VI缺乏小鼠模型肌肉无力和纤维化的关键事件。Col6a1GT/GT小鼠从年轻时开始出现非进行性虚弱，并伴有由于IGF-1信号活性降低而导致的肌肉生长迟缓。此外，Col6a1GT/GT小鼠具有大量间质骨骼肌间充质祖细胞，随着肌纤维的反复坏死/再生，其数量急剧增加。我们的研究结果表明，新生儿肌肉生长受损和骨骼肌间充质细胞的激活有助于胶原VI缺乏症肌营养不良的病理，更重要的是，为胶原VI缺乏症的治疗策略提供了见解。VI型胶原肌营养不良小鼠肌肉萎缩，肌内膜纤维化。Col6a1GT/GT中IGF-1信号传导不足是围产期肌肉生长过程中肌纤维数量减少的原因。Col6a1GT/GT中MPCs的过度激活在很大程度上导致了纤维化，可能解释了人类患者的表型。先天性肌营养不良伴VI型胶原缺乏表现出以纤维大小变化、间质纤维化和脂肪生成增加为特征的特殊肌肉病理。我们在模型小鼠中发现了两个机制事件，一个是由于IGF-1信号不足导致围产期肌肉生长受损，另一个是由于肌肉间充质祖细胞过度激活导致肌内膜纤维化。这种过度激活诱导失调的肌肉生态位，导致特定病理的胶原VI缺乏肌营养不良。
Congenital muscular dystrophies with collagen VI deficiency are inherited muscle disorders with a broad spectrum of clinical presentation and are caused by mutations in one of COL6A1–3 genes. Muscle pathology is characterized by fiber size variation and increased interstitial fibrosis and adipogenesis. In this study, we define critical events that contribute to muscle weakness and fibrosis in a mouse model with collagen VI deficiency. The Col6a1GT/GT mice develop non-progressive weakness from younger age, accompanied by stunted muscle growth due to reduced IGF-1 signaling activity. In addition, the Col6a1GT/GT mice have high numbers of interstitial skeletal muscle mesenchymal progenitor cells, which dramatically increase with repeated myofiber necrosis/regeneration. Our results suggest that impaired neonatal muscle growth and the activation of the mesenchymal cells in skeletal muscles contribute to the pathology of collagen VI deficient muscular dystrophy, and more importantly, provide the insights on the therapeutic strategies for collagen VI deficiency. Collagen VI muscular dystrophy mouse shows small muscle size and endomysial fibrosis. Insufficient IGF-1 signaling in Col6a1GT/GT is responsible for decreased myofiber numbers during perinatal muscle growth. Overactivation of MPCs in Col6a1GT/GT largely contributes to fibrosis, possibly explaining the phenotype of human patients. Congenital muscular dystrophy with collagen VI deficiency shows specific muscle pathology characterized by fiber size variation and increased interstitial fibrosis and adipogenesis. We show two mechanistic events in the model mouse, an impaired muscle growth during perinatal due to insufficient IGF-1 signaling, and an endomysial fibrosis by overactivation of muscle-residential mesenchymal progenitor cells. This overactivation induces the dysregulated muscle niche, which results in specific pathology in collagen VI deficient muscular dystrophy.