Macrophages producing chondroitin sulfate proteoglycan‐4 induce neuro‐cardiac junction impairment in Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is caused by the absence of the full form of the dystrophin protein, which is essential for maintaining the structural integrity of muscle cells, including those in the heart and respiratory system. Despite progress in understanding the molecular mechanisms associated with DMD, myocardial insufficiency persists as the primary cause of mortality, and existing therapeutic strategies remain limited. This study investigates the hypothesis that a dysregulation of the biological communication between infiltrating macrophages (MPs) and neurocardiac junctions exists in dystrophic cardiac tissue. In a mouse model of DMD (mdx), this phenomenon is influenced by the over-release of chondroitin sulfate proteoglycan-4 (CSPG4), a key inhibitor of nerve sprouting and a modulator of the neural function, by MPs infiltrating the cardiac tissue and associated with dilated cardiomyopathy, a hallmark of DMD. Givinostat, the histone deacetylase inhibitor under current development as a clinical treatment for DMD, is effective at both restoring a physiological microenvironment at the neuro-cardiac junction and cardiac function in mdx mice in addition to a reduction in cardiac fibrosis, MP-mediated inflammation, and tissue CSPG4 content. This study provides novel insight into the pathophysiology of DMD in the heart, identifying potential new biological targets. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Authors
- Roberto Rizzi (ORCID: https://orcid.org/0000-0001-6084-7199)
- Francesca Brambilla (ORCID: https://orcid.org/0000-0002-9532-175X)
- Yvan Torrente (ORCID: https://orcid.org/0000-0002-2705-3984)
- Chiara Parisi (ORCID: https://orcid.org/0000-0003-1350-3929)
- Elena De Falco (ORCID: https://orcid.org/0000-0002-5220-0587)
- Elisa Landoni
- Maila Chirivì (ORCID: https://orcid.org/0000-0002-7805-7993)
- Gianpietro Dotti (ORCID: https://orcid.org/0000-0002-2639-8526)
- Silvia Maiullari (ORCID: https://orcid.org/0000-0001-9240-5299)
- Dario Di Silvestre (ORCID: https://orcid.org/0000-0002-7143-6229)
- Chiara Lanzuolo (ORCID: https://orcid.org/0000-0003-2649-6334)
- Andrea Soluri (ORCID: https://orcid.org/0000-0003-4623-6839)
- Mauro Bombaci (ORCID: https://orcid.org/0000-0002-9887-4165)
- Mirco Toccafondi
- Mariacristina Crosti (ORCID: https://orcid.org/0000-0001-8314-1391)
- Fabio Maiullari (ORCID: https://orcid.org/0000-0002-3641-0031)
- Chiara Cordiglieri (ORCID: https://orcid.org/0000-0002-2013-0043)
- Veronica De Paolis (ORCID: https://orcid.org/0000-0002-7549-0572)
- Claudia Bearzi (ORCID: https://orcid.org/0000-0002-8218-9833)
- Dror Seliktar (ORCID: https://orcid.org/0000-0001-6964-8567)
- Marika Milan (ORCID: https://orcid.org/0000-0003-2535-0640)
- Pierluigi Mauri (ORCID: https://orcid.org/0000-0003-4364-0393)
- Nicole Fratini (ORCID: https://orcid.org/0009-0004-2358-7788)
- Maria Grazia Ceraolo
- Antonella Calogero
- Rebecca Zigiotto
Institutions
- University of North Carolina at Chapel Hill (US)
- University of Rome Tor Vergata (IT)
- Università Campus Bio-Medico (IT)
- Technion – Israel Institute of Technology (IL)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Institute of Biomedical Technologies (IT)
- National Research Council (IT)
- Institute of Cell Biology and Neurobiology (IT)
- Istituto Nazionale Genetica Molecolare (IT)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- The Journal of Pathology
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1002/path.6362
- Citations
- 2
- Primary Topic
- Muscle activation and electromyography studies
- Type
- article
- Field-Weighted Citation Impact
- 0.37
Funders
- European Commission
- Ministero della Salute
- Italfarmaco
- Fondazione Regionale per la Ricerca Biomedica