Dystrophin Deficiency Causes Progressive Depletion of Cardiovascular Progenitor Cells in the Heart
Sarka Jelinkova1,2, Yvonne Sleiman3, Petr Fojtík1,2
1Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5/A3, 62500 Brno, Czech Republic.
Insights
Duchenne muscular dystrophy (DMD) hearts show early cardiovascular progenitor cell (CVPC) increase, followed by rapid age-related depletion. This CVPC loss contributes to heart dysfunction and dilated cardiomyopathy (DCM) progression in DMD.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Duchenne Muscular Dystrophy Pathophysiology
Background:
- Duchenne muscular dystrophy (DMD) leads to premature death, often due to dilated cardiomyopathy (DCM).
- The role of cardiac stem cells in DMD-associated DCM progression is not well understood.
- Skeletal muscle stem cells (satellite cells) decline in DMD, suggesting potential stem cell dysfunction in other tissues.
Purpose of the Study:
- To investigate the age-dependent changes in cardiac muscle cardiovascular progenitor cells (CVPCs) in the dystrophin-deficient mdx mouse model.
- To determine if CVPC dysfunction contributes to the development and progression of DCM in DMD.
Main Methods:
- Quantitative PCR and flow cytometry to analyze CVPC populations.
- Speckle tracking echocardiography to assess cardiac function.
- Immunofluorescence to evaluate CVPC DNA damage and cardiac tissue.
Main Results:
- Young mdx mice showed an initial increase in CVPCs compared to controls.
- A rapid, age-related depletion of CVPCs was observed in mdx mice.
- MDX CVPCs exhibited increased DNA damage, indicating impaired cellular homeostasis.
- CVPC depletion coincided with the onset and progression of cardiac dysfunction and fibrosis.
Conclusions:
- Dystrophic hearts initially recruit more CVPCs, but these cells are rapidly depleted with age.
- The age-related loss of CVPCs is a potential mechanism driving cardiac fibrosis and the progression of DCM in DMD.
- Understanding CVPC dynamics is crucial for developing therapeutic strategies for DMD-associated heart disease.
Abstract:
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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