Altered muscle niche contributes to myogenic deficit in the D2- mdx model of severe DMD.
Altered muscle niche contributes to myogenic deficit in the D2- mdx model of severe DMD.
复制标题
肌肉生态位的改变导致严重 DMD 的 D2-mdx 模型中的肌源性缺陷。
DOI：
10.1101/2023.03.27.534413
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Jaiswal,JyotiK
中科院分区：
文献类型：
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作者：
Mázala,DaviAG;Hindupur,Ravi;Moon,YoungJae;Shaikh,Fatima;Gamu,IteoluwakishiH;Alladi,Dhruv;Panci,Georgiana;Weiss-Gayet,Michèle;Chazaud,Bénédicte;Partridge,TerenceA;Novak,JamesS;Jaiswal,JyotiK
肌营养不良蛋白表达的缺乏是杜氏肌营养不良症（DMD）的潜在遗传基础。然而，疾病的严重程度因患者而异，基于特定的遗传修饰剂。D2-mdx是严重DMD的模型，其表现出加剧的肌肉变性和即使在疾病的幼年阶段也不能再生。我们发现，青少年D2-mdx肌肉的不良再生与肌肉损伤的炎症反应增强有关，肌肉损伤不能有效解决，并支持成纤维脂肪祖细胞（FAP）的过度积累，导致纤维化增加。出乎意料的是，幼年D2-mdx肌肉的损伤和变性程度在成年人中显著降低，并且与对肌肉损伤的炎症和FAP反应的恢复相关。这些改善增强了成人D2-mdx肌肉的再生肌生成，达到了与轻度DMD的B10-mdx模型相当的水平。健康卫星细胞（SC）与幼年D2-mdxFAP的离体共培养降低了它们的融合功效。野生型幼年D2小鼠也表现出再生性肌源性缺陷，糖皮质激素治疗改善了它们的肌肉再生。我们的研究结果表明，异常的基质细胞反应有助于不良的再生肌发生和更大的肌肉变性在青少年D2-mdx肌肉和逆转这减少病理在成人D2-mdx肌肉，确定这些反应作为一个潜在的治疗靶点治疗DMD。
Lack of dystrophin expression is the underlying genetic basis for Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2-mdxis a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even in the juvenile stage of the disease. We show that poor regeneration of juvenile D2-mdxmuscles is associated with an enhanced inflammatory response to muscle damage that fails to resolve efficiently and supports the excessive accumulation of fibroadipogenic progenitors (FAPs), leading to increased fibrosis. Unexpectedly, the extent of damage and degeneration in juvenile D2-mdxmuscle is significantly reduced in adults, and is associated with the restoration of the inflammatory and FAP responses to muscle injury. These improvements enhance regenerative myogenesis in the adult D2-mdxmuscle, reaching levels comparable to the milder B10-mdxmodel of DMD. Ex vivo co-culture of healthy satellite cells (SCs) with juvenile D2-mdxFAPs reduces their fusion efficacy. Wild-type juvenile D2 mice also manifest regenerative myogenic deficit and glucocorticoid treatment improves their muscle regeneration. Our findings indicate that aberrant stromal cell responses contribute to poor regenerative myogenesis and greater muscle degeneration in juvenile D2-mdxmuscles and reversal of this reduces pathology in adult D2-mdxmuscle, identifying these responses as a potential therapeutic target for the treatment of DMD.