Dystrophin proteomic regulation in Muscular Dystrophies (MD) remains unclear. We report that a long noncoding RNA (lncRNA),
H19
, associates with dystrophin and inhibits E3 ligase-dependent poly-ubiquitination at Lys3584 (referred to as Ub-DMD) and its subsequent protein degradation. In-frame deletions in BMD and a DMD non-silent mutation (C3340Y) result in defects in the protein’s ability to interact with
H19
, causing elevated Ub-DMD levels and dystrophin degradation.
Dmd
C3333Y mice exhibited progressive muscular dystrophy, elevated serum CK, 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/inhibited TRIM63.
Dmd
C3333Y animals, iPSC-derived skeletal muscle cells from BMD patients, or mdx mice subjected to exon-skipping exhibited inhibited dystrophin degradation, preserved skeletal/cardiac muscle histology, and improved strength/heart function following AGR-
H19
or Nifenazone treatment. Our study paves the way to meaningful targeted therapeutics for BMD and certain DMD patients.
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