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

Betts CA, Saleh AF, Carr CA, Hammond SM, Coenen-Stass AM, Godfrey C, McClorey G, Varela MA, Roberts TC, Clarke K, Gait MJ, Wood MJ - Sci Rep (2015)

Bottom Line: Pip peptide-AOs demonstrate high activity in cardiac muscle.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.

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.

No MeSH data available.


Related in: MedlinePlus

Gene expression analysis for markers of cardiac injury in exercised mdx mice following Pip6f-PMO treatment.RT-qPCR analysis of Nppa (A) and Nox4 (B) in heart tissue normalised to C57BL/10 cohort. The untreated mdx exercised cohort reveals elevated expression of these injury markers whereas there is partial normalisation for the Pip6f-PMO cohort. Statistical significance was determined using ANOVA followed by Tukey post-hoc test (*** = P < 0.001, ** = P < 0.01, * = P < 0.05).
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f3: Gene expression analysis for markers of cardiac injury in exercised mdx mice following Pip6f-PMO treatment.RT-qPCR analysis of Nppa (A) and Nox4 (B) in heart tissue normalised to C57BL/10 cohort. The untreated mdx exercised cohort reveals elevated expression of these injury markers whereas there is partial normalisation for the Pip6f-PMO cohort. Statistical significance was determined using ANOVA followed by Tukey post-hoc test (*** = P < 0.001, ** = P < 0.01, * = P < 0.05).

Mentions: Two such markers, Nppa and Nox4, were measured 5 days following exercise in mdx mouse hearts. Atrial natriuretic peptide (Nppa) is secreted by the atria in response to haemodynamic overload or stress36. Its release results in the reduction of blood pressure and cardiac hypertrophy and is therefore considered a compensatory mechanism36 but also serves as a diagnostic measure of heart failure37. Quantitative assessment (RT-qPCR) revealed elevated expression of this gene in the untreated exercised mdx group which was significantly higher than in the C57BL/10 cohort (P < 0.05; Fig. 3A). The expression of Nppa in the Pip6f-PMO treated cohort was partially normalised.


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

Betts CA, Saleh AF, Carr CA, Hammond SM, Coenen-Stass AM, Godfrey C, McClorey G, Varela MA, Roberts TC, Clarke K, Gait MJ, Wood MJ - Sci Rep (2015)

Gene expression analysis for markers of cardiac injury in exercised mdx mice following Pip6f-PMO treatment.RT-qPCR analysis of Nppa (A) and Nox4 (B) in heart tissue normalised to C57BL/10 cohort. The untreated mdx exercised cohort reveals elevated expression of these injury markers whereas there is partial normalisation for the Pip6f-PMO cohort. Statistical significance was determined using ANOVA followed by Tukey post-hoc test (*** = P < 0.001, ** = P < 0.01, * = P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4355666&req=5

f3: Gene expression analysis for markers of cardiac injury in exercised mdx mice following Pip6f-PMO treatment.RT-qPCR analysis of Nppa (A) and Nox4 (B) in heart tissue normalised to C57BL/10 cohort. The untreated mdx exercised cohort reveals elevated expression of these injury markers whereas there is partial normalisation for the Pip6f-PMO cohort. Statistical significance was determined using ANOVA followed by Tukey post-hoc test (*** = P < 0.001, ** = P < 0.01, * = P < 0.05).
Mentions: Two such markers, Nppa and Nox4, were measured 5 days following exercise in mdx mouse hearts. Atrial natriuretic peptide (Nppa) is secreted by the atria in response to haemodynamic overload or stress36. Its release results in the reduction of blood pressure and cardiac hypertrophy and is therefore considered a compensatory mechanism36 but also serves as a diagnostic measure of heart failure37. Quantitative assessment (RT-qPCR) revealed elevated expression of this gene in the untreated exercised mdx group which was significantly higher than in the C57BL/10 cohort (P < 0.05; Fig. 3A). The expression of Nppa in the Pip6f-PMO treated cohort was partially normalised.

Bottom Line: Pip peptide-AOs demonstrate high activity in cardiac muscle.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.

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.

No MeSH data available.


Related in: MedlinePlus