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Early Myocardial Dysfunction and Benefits of Cardiac Treatment in Young X-Linked Duchenne Muscular Dystrophy Mice

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Abstract

Context

Duchenne muscular dystrophy (DMD) is associated with a progressive alteration in cardiac function.

Objective

The aim of this study was to detect early cardiac dysfunction using the high sensitive two-dimensional speckle-tracking echocardiography (2D strain) in mdx mouse model and to investigate the potential preventive effects of the S107 ryanodine receptor (RyR2) stabilizer on early onset of DMD-related cardiomyopathy.

Methods and Results

Conventional echocardiography and global and segmental left ventricle (LV) 2D strains were assessed in male mdx mice and control C57/BL10 mice from 2 to 12 months of age. Up to 12 months of age, mdx mice showed preserved myocardial function as assessed by conventional echocardiography. However, global longitudinal, radial, and circumferential LV 2D strains significantly declined in mdx mice compared to controls from the 9 months of age. Segmental 2D strain analysis found a predominant alteration in posterior, inferior, and lateral LV segments, with a more marked impairment with aging. Then, mdx mice were treated with S107 in the drinking water at a dose of 250 mg/L using two different protocols: earlier therapy from 2 to 6 months of age and later therapy from 6 to 9 months of age. The treatment with S107 was efficient only when administered earlier in very young animals (from 2 to 6 months of age) and prevented the segmental alterations seen in non-treated mdx mice.

Conclusions

This is the first animal study to evaluate the therapeutic effect of a drug targeting early onset of DMD-related cardiomyopathy, using 2D strain echocardiography. Speckle-tracking analyses revealed early alterations of LV posterior segments that could be prevented by 4 months of RyR2 stabilization.

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Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Abbreviations

2D:

Two-dimensional

DMD:

Duchenne muscular dystrophy

STE:

Speckle-tracking echocardiography

LV:

Left ventricular

SR:

Sarcoplasmic reticulum

WT:

Wild-type

mdx :

X-linked muscular dystrophy

RYR2:

Ryanodine receptor type 2

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Funding

This study was supported by the Association Française contre les Myopathies (AFM) (AL N°15083).

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Authors and Affiliations

  1. PHYMEDEXP, University of Montpellier, INSERM, CNRS, University Hospital, CHU Arnaud de Villeneuve, 34295, Montpellier, France

    Marie Vincenti, Charlotte Farah, Pascal Amedro, Valerie Scheuermann, Alain Lacampagne & Olivier Cazorla

  2. Pediatric and Congenital Cardiology Department, M3C Regional Reference CHD Centre, University Hospital, Montpellier, France

    Marie Vincenti & Pascal Amedro

  3. FATH-IREC, Université Catholique de Louvain, Brussel, Belgium

    Charlotte Farah

Authors
  1. Marie Vincenti
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  2. Charlotte Farah
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  3. Pascal Amedro
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  4. Valerie Scheuermann
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  5. Alain Lacampagne
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Corresponding authors

Correspondence to Alain Lacampagne or Olivier Cazorla.

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Ethics Approval

Experiments were conducted in accordance with the European directive for the protection of animals used for scientific purposes and were approved by the ethical committee (Comité d’éthique pour l’expérimentation animale Languedoc-Roussillon, n° CEEA-LR-12078).

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The authors declare no competing interests.

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Alain Lacampagne and Olivier Cazorla jointly supervised this work.

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Vincenti, M., Farah, C., Amedro, P. et al. Early Myocardial Dysfunction and Benefits of Cardiac Treatment in Young X-Linked Duchenne Muscular Dystrophy Mice. Cardiovasc Drugs Ther 36, 793–803 (2022). https://doi.org/10.1007/s10557-021-07218-7

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