Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA; College of Biological Sciences, University of Minnesota, Minneapolis, MN, USA.
Redox Biol. 2020 Oct;37:101730. doi: 10.1016/j.redox.2020.101730. Epub 2020 Sep 18.
The highly ordered cortical microtubule lattice of skeletal muscle is disorganized in dystrophin-deficient mdx mice. Implicated mechanisms include loss of dystrophin binding, altered α-tubulin posttranslational modification, expression of a β-tubulin involved in regeneration, and reactive oxygen species (ROS). Here we show that the transverse microtubules in mdx muscle expressing miniaturized dystrophins are rapidly lost after eccentric contraction. Analysis of mdx lines expressing different dystrophin constructs demonstrate that spectrin-like repeats R4-15 and R20-23 were required for mechanically stable microtubules. Microtubule loss was prevented by the non-specific antioxidant N-acetylcysteine while inhibition of NADPH oxidase 2 had only a partial effect, suggesting that ROS from multiple sources mediate the rapid loss of transverse microtubules after eccentric contraction. Finally, ablation of α-dystrobrevin, β- or γ-cytoplasmic actin phenocopied the transverse microtubule instability of miniaturized dystrophins. Our data demonstrate that multiple dystrophin domains, α-dystrobrevin and cytoplasmic actins are necessary for mechanically stable microtubules.
骨骼肌中高度有序的皮质微管晶格在缺乏 dystrophin 的 mdx 小鼠中被打乱。涉及的机制包括 dystrophin 结合的丧失、α-微管蛋白翻译后修饰的改变、参与再生的β-微管蛋白的表达以及活性氧物种 (ROS)。在这里，我们表明在表达微型 dystrophin 的 mdx 肌肉中，横向微管在离心收缩后迅速丢失。对表达不同 dystrophin 构建体的 mdx 系的分析表明， spectrin 样重复 R4-15 和 R20-23 对于机械稳定的微管是必需的。非特异性抗氧化剂 N-乙酰半胱氨酸可防止微管丢失，而 NADPH 氧化酶 2 的抑制仅产生部分效果，表明来自多个来源的 ROS 介导了离心收缩后横向微管的快速丢失。最后，α-dystrobrevin、β-或 γ-细胞质肌动蛋白的消融模拟了微型 dystrophin 的横向微管不稳定性。我们的数据表明，多个 dystrophin 结构域、α-dystrobrevin 和细胞质肌动蛋白对于机械稳定的微管是必需的。
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