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

Sci Rep. 2015 Jun 26;5:11632. doi: 10.1038/srep11632.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Atrial Natriuretic Factor
  • Blotting, Western
  • Diaphragm / diagnostic imaging
  • Diaphragm / metabolism
  • Diaphragm / physiopathology*
  • Disease Models, Animal*
  • Dystrophin / genetics
  • Dystrophin / metabolism
  • Gene Expression / drug effects
  • Heart / physiopathology*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Morpholinos / chemistry
  • Morpholinos / pharmacology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / physiopathology
  • Muscular Dystrophy, Duchenne / genetics
  • Muscular Dystrophy, Duchenne / physiopathology*
  • NADPH Oxidase 4
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Natriuretic Peptide, C-Type / genetics
  • Natriuretic Peptide, C-Type / metabolism
  • Peptides / chemistry
  • Peptides / pharmacology
  • Physical Conditioning, Animal / physiology
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • Radiography
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Dystrophin
  • Morpholinos
  • Nppa protein, mouse
  • Peptides
  • Protein Precursors
  • Natriuretic Peptide, C-Type
  • Atrial Natriuretic Factor
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse