Reduced Sarcolemmal Membrane Repair Exacerbates Striated Muscle Pathology in a Mouse Model of Duchenne Muscular Dystrophy.
Reduced Sarcolemmal Membrane Repair Exacerbates Striated Muscle Pathology in a Mouse Model of Duchenne Muscular Dystrophy.
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肌膜修复减少加重Duchenne肌营养不良症小鼠模型的横纹肌病理。
DOI：
10.3390/cells11091417
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发表时间：
2022-04-22
期刊：
影响因子：
6
通讯作者：
Weisleder, Noah
中科院分区：
文献类型：
--
作者：
Paleo, Brian J.;McElhanon, Kevin E.;Bulgart, Hannah R.;Banford, Kassidy K.;Beck, Eric X.;Sattler, Kristina M.;Goines, Briana N.;Ratcliff, Shelby L.;Crowe, Kelly E.;Weisleder, Noah
杜氏肌营养不良症 (DMD) 是一种常见的 X 连锁退行性肌肉疾病，涉及 DMD 基因突变，这种突变经常会降低肌营养不良蛋白的表达，损害肌膜的结构完整性，使其在肌肉收缩和松弛周期中容易受到损伤。这导致肌膜破坏的频率增加，从而损害膜的屏障功能并导致肌细胞死亡。肌膜修复过程可以潜在地补偿 DMD 肌细胞中增加的膜破坏。先前的研究表明，TRIM72 是一种富含肌肉的三联基序 (TRIM) 家族蛋白，也称为 mitsugumin 53 (MG53)，是横纹肌细胞膜修复机制的一个组成部分。为了测试横纹肌膜修复在补偿 DMD 膜脆性方面的重要性，我们将 TRIM72/MG53 敲除小鼠与 DMD mdx 小鼠模型杂交。通过免疫球蛋白 G 染色和离体肌肉激光显微镜损伤测定来测量，与 mdx 小鼠相比，这些双敲除 (DKO) 小鼠的肌膜完整性受损。我们还发现，与 6 周龄和 1.5 岁时的 mdx 小鼠相比，其肌肉离体收缩功能显着下降。随着 DKO 小鼠年龄的增长，与 mdx 小鼠相比，它们的骨骼肌出现更广泛的纤维化。我们的研究结果表明，TRIM72/MG53 介导的膜修复可以部分补偿与 DMD 相关的肌膜脆弱性，并且膜修复的丧失会导致 DKO 小鼠的病理增加。
Duchenne muscular dystrophy (DMD) is a common X-linked degenerative muscle disorder that involves mutations in the DMD gene that frequently reduce the expression of the dystrophin protein, compromising the structural integrity of the sarcolemmal membrane and leaving it vulnerable to injury during cycles of muscle contraction and relaxation. This results in an increased frequency of sarcolemma disruptions that can compromise the barrier function of the membrane and lead to death of the myocyte. Sarcolemmal membrane repair processes can potentially compensate for increased membrane disruptions in DMD myocytes. Previous studies demonstrated that TRIM72, a muscle-enriched tripartite motif (TRIM) family protein also known as mitsugumin 53 (MG53), is a component of the cell membrane repair machinery in striated muscle. To test the importance of membrane repair in striated muscle in compensating for the membrane fragility in DMD, we crossed TRIM72/MG53 knockout mice into the mdx mouse model of DMD. These double knockout (DKO) mice showed compromised sarcolemmal membrane integrity compared to mdx mice, as measured by immunoglobulin G staining and ex vivo muscle laser microscopy wounding assays. We also found a significant decrease in muscle ex vivo contractile function as compared to mdx mice at both 6 weeks and 1.5 years of age. As the DKO mice aged, they developed more extensive fibrosis in skeletal muscles compared to mdx. Our findings indicate that TRIM72/MG53-mediated membrane repair can partially compensate for the sarcolemmal fragility associated with DMD and that the loss of membrane repair results in increased pathology in the DKO mice.
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DOI：
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发表时间：
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