Dystrophin proteomic regulation in muscular dystrophies (MDs) remains unclear. We report that a long noncoding RNA (lncRNA), H19, associates with dystrophin and inhibits E3-ligase-dependent polyubiquitination at Lys 3584 (referred to as Ub-DMD) and its subsequent protein degradation. In-frame deletions in BMD and a DMD non-silent mutation (C3340Y) resulted in defects in the ability of the protein to interact with H19, which caused elevated Ub-DMD levels and dystrophin degradation. Dmd C3333Y mice exhibited progressive MD, elevated serum creatine kinase, heart dilation, blood vessel irregularity and respiratory failure with concurrently reduced dystrophin and increased Ub-DMD status. H19 RNA oligonucleotides conjugated with agrin (AGR–H19) and nifenazone competed with or inhibited TRIM63. Dmd C3333Y animals, induced-pluripotent-stem-cell-derived skeletal muscle cells from patients with Becker MD and mdx mice subjected to exon skipping exhibited inhibited dystrophin degradation, preserved skeletal and cardiac muscle histology, and improved strength and heart function following AGR–H19 or nifenazone treatment. Our study paves the way for meaningful targeted therapeutics for Becker MD and for certain patients with Duchenne MD.

肌营养不良症 (MDs) 中肌营养不良蛋白的蛋白质组学调控仍不清楚。我们报告了一个长的非编码 RNA (lncRNA) H19，与肌营养不良蛋白相关，并抑制 Lys 3584 处的 E3 连接酶依赖性多泛素化（称为 Ub-DMD）及其随后的蛋白质降解。BMD 中的框内缺失和 DMD 非沉默突变 (C3340Y) 导致蛋白质与 H19 相互作用的能力缺陷，从而导致 Ub-DMD 水平升高和肌营养不良蛋白降解。Dmd C3333Y 小鼠表现出进行性 MD、血清肌酸激酶升高、心脏扩张、血管不规则和呼吸衰竭，同时肌营养不良蛋白减少和 Ub-DMD 状态增加。与集聚蛋白 (AGR-H19) 结合的 H19 RNA 寡核苷酸和硝苯酮竞争或抑制 TRIM63。dmdC3333Y 动物、来自 Becker MD 患者和mdx小鼠的诱导多能干细胞衍生的骨骼肌细胞受到外显子跳跃的抑制，表现出抗肌萎缩蛋白降解受到抑制，骨骼肌和心肌组织学保持不变，并且在 AGR-H19 或硝苯酮治疗。我们的研究为 Becker MD 和某些 Duchenne MD 患者进行有意义的靶向治疗铺平了道路。