The lncRNA H19 alleviates muscular dystrophy by stabilizing dystrophin

• Published in: Nature cell biology Vol. 22; no. 11; pp. 1332 - 1345
• Main Authors: Zhang, Yaohua, Li, Yajuan, Hu, Qingsong, Xi, Yutao, Xing, Zhen, Zhang, Zhao, Huang, Lisa, Wu, Jianbo, Liang, Ke, Nguyen, Tina K., Egranov, Sergey D., Sun, Chengcao, Zhao, Zilong, Hawke, David H., Li, Jin, Sun, Deqiang, Kim, Jean J., Zhang, Ping, Cheng, Jie, Farida, Abid, Hung, Mien-Chie, Han, Leng, Darabi, Radbod, Lin, Chunru, Yang, Liuqing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2020; Nature Publishing Group
• Subjects: 13; 13/100; 14; 14/28; 38; 42; 42/41; 59; 59/57; 631/337/384/2568; 631/45/474/2289; 631/80/304; 64/60; Agrin; Animals; Antipyrine - administration & dosage; Antipyrine - analogs & derivatives; Biodegradation; Biomedical and Life Sciences; Blood vessels; Cancer Research; Cardiac muscle; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathies - pathology; Cardiomyopathies - prevention & control; Cell Biology; Cell Line; Competition; Creatine; Creatine kinase; Degradation; Development and progression; Developmental Biology; Disease Models, Animal; Dystrophin; Dystrophin - genetics; Dystrophin - metabolism; Dystrophy; Enzyme Inhibitors - administration & dosage; Exon skipping; Female; Genetic aspects; Half-Life; Health aspects; Heart function; Histology; Humans; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; Kinases; Life Sciences; Male; Mice, Inbred C57BL; Mice, Inbred mdx; Mice, Mutant Strains; Muscle Proteins - antagonists & inhibitors; Muscle Proteins - metabolism; Muscle Strength; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscles; Muscular Dystrophies - genetics; Muscular Dystrophies - metabolism; Muscular Dystrophies - pathology; Muscular Dystrophies - prevention & control; Muscular dystrophy; Mutation; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Niacinamide - administration & dosage; Niacinamide - analogs & derivatives; Oligonucleotides; Oligonucleotides - administration & dosage; Oligonucleotides - genetics; Oligonucleotides - metabolism; Physiological aspects; Pluripotency; Protein Stability; Proteins; Proteolysis; Respiratory failure; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Skeletal muscle; Stem Cells; Tripartite Motif Proteins - antagonists & inhibitors; Tripartite Motif Proteins - metabolism; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - antagonists & inhibitors; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; United States
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-020-00595-5

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. Zhang et al. report that the lncRNA H19 stabilizes dystrophin by competing with the ubiquitin E3 ligase TRIM63 for association with dystrophin, thereby alleviating muscular dystrophies.