Prevention of exercised induced cardiomyopathy following Pip-PMO treatment in dystrophic mdx mice

Scientific Reports
Corinne BettsMatthew J A Wood

Abstract

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder caused by mutations in the Dmd gene. In addition to skeletal muscle wasting, DMD patients develop cardiomyopathy, which significantly contributes to mortality. Antisense oligonucleotides (AOs) are a promising DMD therapy, restoring functional dystrophin protein by exon skipping. However, a major limitation with current AOs is the absence of dystrophin correction in heart. Pip peptide-AOs demonstrate high activity in cardiac muscle. To determine their therapeutic value, dystrophic mdx mice were subject to forced exercise to model the DMD cardiac phenotype. Repeated peptide-AO treatments resulted in high levels of cardiac dystrophin protein, which prevented the exercised induced progression of cardiomyopathy, normalising heart size as well as stabilising other cardiac parameters. Treated mice also exhibited significantly reduced cardiac fibrosis and improved sarcolemmal integrity. This work demonstrates that high levels of cardiac dystrophin restored by Pip peptide-AOs prevents further deterioration of cardiomyopathy and pathology following exercise in dystrophic DMD mice.

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Citations

May 20, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tirsa L E van WesteringMatthew J A Wood
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Nov 20, 2021·Archives of Toxicology·Omar Sheikh, Toshifumi Yokota

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Methods Mentioned

BETA
pharmacotherapies
PCR

Software Mentioned

TREAT
ImageJ
Paravision
ImagePro
NMD
R
Pro
Image
Axiovision Rel
SPSS Statistics

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