A Asai

A Crisp

A De Troyer

A Malerba

BJ Petrof

C Betts

C Kirchmann

CF Spurney

DJ Stuckey

DM Connuck

G Dickson

G Nigro

H Yin

J Alter

J Kuroda

J Morrison

JG Quinlan

JM Costas

JO Benditt

JW Carnwath

K Ito

K Ohlendieck

L Loufrani

M Ishizaki

M Mosqueira

M Palladino

MG Dunckley

N Jearawiriyapaisarn

P Melacini

QL Lu

S Fletcher

SD Wilton

Scientific Reports

English

AbstractDuchenne muscular dystrophy (DMD) is caused by absence of the integral structural protein, dystrophin, which renders muscle fibres susceptible to injury and degeneration. This ultimately results in cardiorespiratory dysfunction, which is the predominant cause of death in DMD patients and highlights the importance of therapeutic targeting of the cardiorespiratory system. While there is some evidence to suggest that restoring dystrophin in the diaphragm improves both respiratory and cardiac function, the role of the diaphragm is not well understood. Here using exon skipping oligonucleotides we predominantly restored dystrophin in the diaphragm and assessed cardiac function by MRI. This approach reduced diaphragmatic pathophysiology and markedly improved diaphragm function but did not improve cardiac function or pathophysiology, with or without exercise. Interestingly, exercise resulted in a reduction of dystrophin protein and exon skipping in the diaphragm. This suggests that treatment regimens may require modification in more active patients. In conclusion, whilst the diaphragm is an important respiratory muscle, it is likely that dystrophin needs to be restored in other tissues, including multiple accessory respiratory muscles and of course the heart itself for appropriate therapeutic outcomes. This supports the requirement of a body-wide therapy to treat DMD.</jats:p

Corinne A. Betts

Amer F. Saleh

Carolyn A. Carr

Sofia Muses

Kim E. Wells

Suzan M. Hammond

Caroline Godfrey

Graham McClorey

Caroline Woffindale

Kieran Clarke

Dominic J. Wells

Michael J. Gait

Matthew J. A. Wood

Crossref

Implications for Cardiac Function Following Rescue of the Dystrophic Diaphragm in a Mouse Model of Duchenne Muscular Dystrophy

Implications for Cardiac Function Following Rescue of the Dystrophic Diaphragm in a Mouse Model of Duchenne Muscular Dystrophy

Abstract

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