Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Video-Audio Media
MeSH terms
-
Animals
-
Antipyrine / administration & dosage
-
Antipyrine / analogs & derivatives
-
Cardiomyopathies / genetics
-
Cardiomyopathies / metabolism
-
Cardiomyopathies / pathology
-
Cardiomyopathies / prevention & control
-
Cell Line
-
Disease Models, Animal
-
Dystrophin / genetics
-
Dystrophin / metabolism
-
Enzyme Inhibitors / administration & dosage
-
Female
-
Half-Life
-
Humans
-
Induced Pluripotent Stem Cells / metabolism
-
Induced Pluripotent Stem Cells / pathology
-
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
-
Muscular Dystrophies / genetics
-
Muscular Dystrophies / metabolism
-
Muscular Dystrophies / pathology
-
Muscular Dystrophies / prevention & control*
-
Mutation
-
Myocytes, Cardiac / metabolism
-
Myocytes, Cardiac / pathology
-
Niacinamide / administration & dosage
-
Niacinamide / analogs & derivatives
-
Oligonucleotides / administration & dosage*
-
Oligonucleotides / genetics
-
Oligonucleotides / metabolism
-
Protein Stability
-
Proteolysis
-
RNA, Long Noncoding / genetics
-
RNA, Long Noncoding / metabolism*
-
Tripartite Motif Proteins / antagonists & inhibitors
-
Tripartite Motif Proteins / metabolism
-
Ubiquitin-Protein Ligases / antagonists & inhibitors
-
Ubiquitin-Protein Ligases / metabolism
-
Ubiquitination
Substances
-
Dmd protein, mouse
-
Dystrophin
-
Enzyme Inhibitors
-
H19 long non-coding RNA
-
Muscle Proteins
-
Oligonucleotides
-
RNA, Long Noncoding
-
Tripartite Motif Proteins
-
Niacinamide
-
nifenazone
-
Trim63 protein, mouse
-
Ubiquitin-Protein Ligases
-
Antipyrine