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Dystrophin Deficiency Causes Progressive Depletion of Cardiovascular Progenitor Cells in the Heart

S. Jelinkova, Y. Sleiman, P. Fojtík, F. Aimond, A. Finan, G. Hugon, V. Scheuermann, D. Beckerová, O. Cazorla, M. Vincenti, P. Amedro, S. Richard, J. Jaros, P. Dvorak, A. Lacampagne, G. Carnac, V. Rotrekl, AC. Meli

. 2021 ; 22 (9) : . [pub] 20210510

Language English Country Switzerland

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc21018623

Grant support
20225 Association Française contre les Myopathies

Duchenne muscular dystrophy (DMD) is a devastating condition shortening the lifespan of young men. DMD patients suffer from age-related dilated cardiomyopathy (DCM) that leads to heart failure. Several molecular mechanisms leading to cardiomyocyte death in DMD have been described. However, the pathological progression of DMD-associated DCM remains unclear. In skeletal muscle, a dramatic decrease in stem cells, so-called satellite cells, has been shown in DMD patients. Whether similar dysfunction occurs with cardiac muscle cardiovascular progenitor cells (CVPCs) in DMD remains to be explored. We hypothesized that the number of CVPCs decreases in the dystrophin-deficient heart with age and disease state, contributing to DCM progression. We used the dystrophin-deficient mouse model (mdx) to investigate age-dependent CVPC properties. Using quantitative PCR, flow cytometry, speckle tracking echocardiography, and immunofluorescence, we revealed that young mdx mice exhibit elevated CVPCs. We observed a rapid age-related CVPC depletion, coinciding with the progressive onset of cardiac dysfunction. Moreover, mdx CVPCs displayed increased DNA damage, suggesting impaired cardiac muscle homeostasis. Overall, our results identify the early recruitment of CVPCs in dystrophic hearts and their fast depletion with ageing. This latter depletion may participate in the fibrosis development and the acceleration onset of the cardiomyopathy.

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$a Duchenne muscular dystrophy (DMD) is a devastating condition shortening the lifespan of young men. DMD patients suffer from age-related dilated cardiomyopathy (DCM) that leads to heart failure. Several molecular mechanisms leading to cardiomyocyte death in DMD have been described. However, the pathological progression of DMD-associated DCM remains unclear. In skeletal muscle, a dramatic decrease in stem cells, so-called satellite cells, has been shown in DMD patients. Whether similar dysfunction occurs with cardiac muscle cardiovascular progenitor cells (CVPCs) in DMD remains to be explored. We hypothesized that the number of CVPCs decreases in the dystrophin-deficient heart with age and disease state, contributing to DCM progression. We used the dystrophin-deficient mouse model (mdx) to investigate age-dependent CVPC properties. Using quantitative PCR, flow cytometry, speckle tracking echocardiography, and immunofluorescence, we revealed that young mdx mice exhibit elevated CVPCs. We observed a rapid age-related CVPC depletion, coinciding with the progressive onset of cardiac dysfunction. Moreover, mdx CVPCs displayed increased DNA damage, suggesting impaired cardiac muscle homeostasis. Overall, our results identify the early recruitment of CVPCs in dystrophic hearts and their fast depletion with ageing. This latter depletion may participate in the fibrosis development and the acceleration onset of the cardiomyopathy.
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$a Beckerová, Deborah $u Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5/A3, 62500 Brno, Czech Republic $u ICRC, St Anne's University Hospital, Pekařská 53, 65691 Brno, Czech Republic
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$a Amedro, Pascal $u PhyMedExp, University of Montpellier, INSERM, CNRS, 34295 Montpellier, France $u Pediatric and Adult Congenital Cardiology Department, M3C Regional Reference CHD Center, CHU Montpellier, 371 Avenue du Doyen Giraud, 34295 Montpellier, France
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$a Richard, Sylvain $u PhyMedExp, University of Montpellier, INSERM, CNRS, 34295 Montpellier, France
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$a Dvorak, Petr $u Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5/A3, 62500 Brno, Czech Republic
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$a Carnac, Gilles $u PhyMedExp, University of Montpellier, INSERM, CNRS, 34295 Montpellier, France
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$a Rotrekl, Vladimir $u Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5/A3, 62500 Brno, Czech Republic $u ICRC, St Anne's University Hospital, Pekařská 53, 65691 Brno, Czech Republic
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$a Meli, Albano C $u PhyMedExp, University of Montpellier, INSERM, CNRS, 34295 Montpellier, France
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