title: Implications for Cardiac Function Following Rescue of the Dystrophic Diaphragm in a Mouse Model of Duchenne Muscular Dystrophy.
abstract: Duchenne 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.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Corinne A
authors.initials: CA
authors.lastname: Betts
authors.affiliation: 1] Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK [2] AstraZeneca R&D, Discovery Safety, Drug safety and Metabolism, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: Amer F
authors.initials: AF
authors.lastname: Saleh
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Carr
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK.
authors.forename: Sofia
authors.initials: S
authors.lastname: Muses
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Wells
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Suzan M
authors.initials: SM
authors.lastname: Hammond
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Caroline
authors.initials: C
authors.lastname: Godfrey
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Graham
authors.initials: G
authors.lastname: McClorey
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Caroline
authors.initials: C
authors.lastname: Woffindale
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Wells
authors.affiliation: Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gait
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
authors.forename: Matthew J A
authors.initials: MJ
authors.lastname: Wood
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D009320:Atrial Natriuretic Factor; D015153:Blotting, Western; D003964:Diaphragm / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D060172:Morpholinos / Q000737:chemistry / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000503:physiopathology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D020098:Natriuretic Peptide, C-Type / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D010805:Physical Conditioning, Animal / Q000502:physiology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011859:Radiography; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016189:Dystrophin; D060172:Morpholinos; C431578:Nppa protein, mouse; D010455:Peptides; D011498:Protein Precursors; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse