Investigating the role of dystrophin isoform deficiency in motor function in Duchenne muscular dystrophy.
Investigating the role of dystrophin isoform deficiency in motor function in Duchenne muscular dystrophy.
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DOI：
10.1002/jcsm.12914
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Muntoni F
中科院分区：
文献类型：
--
作者：
Chesshyre M;Ridout D;Hashimoto Y;Ookubo Y;Torelli S;Maresh K;Ricotti V;Abbott L;Gupta VA;Main M;Ferrari G;Kowala A;Lin YY;Tedesco FS;Scoto M;Baranello G;Manzur A;Aoki Y;Muntoni F
杜氏肌营养不良症（DMD）是由DMD突变导致肌营养不良蛋白丢失引起的。全长Dp427是主要的肌营养不良蛋白亚型，在肌肉中表达，也在中枢神经系统（CNS）中表达。两种较短的同工异构体Dp140和Dp71在中枢神经系统中高度表达。虽然Dp140和Dp71在DMD中枢神经系统共病中的作用是众所周知的，但预期破坏Dp140和Dp71的突变与运动结果之间的关系尚不清楚。387名4-15岁DMD男孩的功能结局数据被细分为DMD突变对肌营养不良蛋白异构体表达的预期影响；1组（Dp427缺失，Dp140/Dp71存在，n = 201）；2组（Dp427/Dp140缺失，Dp71存在，n = 152）；3组（Dp427/Dp140/Dp71缺失，n = 34）。采用回归分析探讨异构体组与North Star动态评估（NSAA）评分、10 m步行/跑步速度和上升时间速度之间的关系。采用Western blot分析研究了Dp427、Dp140和Dp71在肌源性细胞（对照和DMD人）、对照骨骼肌、来自三个亚型组的DMD骨骼肌和小鼠大脑皮层（野生型和DMD模型）中的产生。采用野生型小鼠和DMD小鼠模型进行握力和旋转棒跑动试验。DMD小鼠模型为mdx （Dp427缺失，Dp140/Dp71存在），mdx52 （Dp427/Dp140缺失，Dp71存在）和DMD‐null（缺失所有亚型）。DMD男孩5岁时NSAA平均评分3组比1组低6.1分（P < 0.01）， 3组比2组低4.9分（P = 0.05）。3组NSAA平均峰值评分比1组低4.0分（P < 0.01）， 2组比1组低1.6分（P = 0.04）。mdx52的平均四肢握力比mdx小鼠低1.5 g/g (P = 0.003)， DMD - null的平均四肢握力比mdx小鼠低1.5 g/g （P = 0.002）。Dp71在1组、2组和mdx小鼠的人的肌源性细胞（对照和DMD人）和骨骼肌中产生，但在人类对照的骨骼肌、3组的人的肌源性细胞和骨骼肌或野生型、mdx52或DMD - null小鼠的骨骼肌中不产生。我们的研究结果强调了在考虑DMD运动损伤的模式以及临床实践和临床试验的意义时，考虑DMD突变对肌营养不良蛋白异构体产生的预期影响的重要性。我们的研究结果表明，大脑中表达的肌营养不良蛋白亚型与DMD运动功能之间存在复杂的关系。
Duchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full‐length Dp427 is the primary dystrophin isoform expressed in muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS comorbidities is well known, relationships between mutations expected to disrupt Dp140 and Dp71 and motor outcomes are not. Functional outcome data from 387 DMD boys aged 4–15 years were subdivided by DMD mutation expected effects on dystrophin isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n = 201); Group 2 (Dp427/Dp140 absent, Dp71 present, n = 152); and Group 3 (Dp427/Dp140/Dp71 absent, n = 34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10 m walk/run velocities and rise time velocities were explored using regression analysis. Western blot analysis was used to study Dp427, Dp140 and Dp71 production in myogenic cells (control and DMD human), control skeletal muscle, DMD skeletal muscle from the three isoform groups and cerebral cortex from mice (wild‐type and DMD models). Grip strength and rotarod running test were studied in wild‐type mice and DMD mouse models. DMD mouse models were mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD‐null (lacking all isoforms). In DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in Group 3 than Group 1 (P < 0.01) and 4.9 points lower in Group 3 than Group 2 (P = 0.05). Mean peak NSAA scores were 4.0 points lower in Group 3 than Group 1 (P < 0.01) and 1.6 points lower in Group 2 than Group 1 (P = 0.04). Mean four‐limb grip strength was 1.5 g/g lower in mdx52 than mdx mice (P = 0.003) and 1.5 g/g lower in DMD‐null than mdx mice (P = 0.002). Dp71 was produced in myogenic cells (control and DMD human) and skeletal muscle from humans in Groups 1 and 2 and mdx mice, but not skeletal muscle from human controls, myogenic cells and skeletal muscle from humans in Group 3 or skeletal muscle from wild‐type, mdx52 or DMD‐null mice. Our results highlight the importance of considering expected effects of DMD mutations on dystrophin isoform production when considering patterns of DMD motor impairment and the implications for clinical practice and clinical trials. Our results suggest a complex relationship between dystrophin isoforms expressed in the brain and DMD motor function.
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