Failure to resolve inflammation contributes to juvenile onset cardiac damage in a mouse model of Duchenne muscular dystrophy
Abstract Absence of dystrophin protein causes cardiac dysfunction in patients with Duchenne muscular dystrophy (DMD). Unlike boys with DMD, the common mouse model of DMD (B10-mdx) does not manifest cardiac deficits until late adulthood. This has limited our understanding of the mechanism and therape...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07816-5 |
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| author | James S. Novak Amy Lischin Prech Uapinyoying Ravi Hindupur Young Jae Moon Surajit Bhattacharya Sarah Tiufekchiev-Grieco Victoria Barone Davi A. G. Mázala Iteoluwakishi H. Gamu Gabriela Walters Jyoti K. Jaiswal |
| author_facet | James S. Novak Amy Lischin Prech Uapinyoying Ravi Hindupur Young Jae Moon Surajit Bhattacharya Sarah Tiufekchiev-Grieco Victoria Barone Davi A. G. Mázala Iteoluwakishi H. Gamu Gabriela Walters Jyoti K. Jaiswal |
| author_sort | James S. Novak |
| collection | DOAJ |
| description | Abstract Absence of dystrophin protein causes cardiac dysfunction in patients with Duchenne muscular dystrophy (DMD). Unlike boys with DMD, the common mouse model of DMD (B10-mdx) does not manifest cardiac deficits until late adulthood. This has limited our understanding of the mechanism and therapeutic approaches to target the pediatric onset of cardiac pathology in DMD. Here we show that the mdx mouse model on the DBA/2 J genetic background (D2-mdx) displays juvenile-onset cardiac degeneration. Molecular and histological analysis revealed that cardiac damage in this model is linked to increased leukocyte chemotactic signaling and an inability to resolve inflammation. These deficiencies result in chronic inflammation and fibrotic conversion of the extracellular matrix (ECM) in the juvenile D2-mdx heart. To address these pathologies, we tested the utility of pro-resolution therapy to clear chronic cardiac inflammation. Use of an N-formyl peptide receptor (FPR) agonist helped physiologically resolve inflammation and mitigate the downstream events that lead to fibrotic degeneration of cardiomyocytes, preventing juvenile onset cardiac muscle loss. These results establish the utility of D2-mdx model to study events associated with pediatric-onset cardiac damage and demonstrates pro-resolution therapy as an alternate to anti-inflammatory therapy for treating degenerative cardiac pathology that leads to cardiomyopathy in DMD. |
| format | Article |
| id | doaj-art-3fe864d6a9844c7eaa689288eb3e09b6 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-3fe864d6a9844c7eaa689288eb3e09b62025-08-20T03:46:28ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111110.1038/s41419-025-07816-5Failure to resolve inflammation contributes to juvenile onset cardiac damage in a mouse model of Duchenne muscular dystrophyJames S. Novak0Amy Lischin1Prech Uapinyoying2Ravi Hindupur3Young Jae Moon4Surajit Bhattacharya5Sarah Tiufekchiev-Grieco6Victoria Barone7Davi A. G. Mázala8Iteoluwakishi H. Gamu9Gabriela Walters10Jyoti K. Jaiswal11Center for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National HospitalCenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National HospitalCenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National HospitalCenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National HospitalCenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National HospitalCenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National HospitalCenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National HospitalCenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National HospitalCenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National HospitalCenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National HospitalCenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National HospitalCenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National HospitalAbstract Absence of dystrophin protein causes cardiac dysfunction in patients with Duchenne muscular dystrophy (DMD). Unlike boys with DMD, the common mouse model of DMD (B10-mdx) does not manifest cardiac deficits until late adulthood. This has limited our understanding of the mechanism and therapeutic approaches to target the pediatric onset of cardiac pathology in DMD. Here we show that the mdx mouse model on the DBA/2 J genetic background (D2-mdx) displays juvenile-onset cardiac degeneration. Molecular and histological analysis revealed that cardiac damage in this model is linked to increased leukocyte chemotactic signaling and an inability to resolve inflammation. These deficiencies result in chronic inflammation and fibrotic conversion of the extracellular matrix (ECM) in the juvenile D2-mdx heart. To address these pathologies, we tested the utility of pro-resolution therapy to clear chronic cardiac inflammation. Use of an N-formyl peptide receptor (FPR) agonist helped physiologically resolve inflammation and mitigate the downstream events that lead to fibrotic degeneration of cardiomyocytes, preventing juvenile onset cardiac muscle loss. These results establish the utility of D2-mdx model to study events associated with pediatric-onset cardiac damage and demonstrates pro-resolution therapy as an alternate to anti-inflammatory therapy for treating degenerative cardiac pathology that leads to cardiomyopathy in DMD.https://doi.org/10.1038/s41419-025-07816-5 |
| spellingShingle | James S. Novak Amy Lischin Prech Uapinyoying Ravi Hindupur Young Jae Moon Surajit Bhattacharya Sarah Tiufekchiev-Grieco Victoria Barone Davi A. G. Mázala Iteoluwakishi H. Gamu Gabriela Walters Jyoti K. Jaiswal Failure to resolve inflammation contributes to juvenile onset cardiac damage in a mouse model of Duchenne muscular dystrophy Cell Death and Disease |
| title | Failure to resolve inflammation contributes to juvenile onset cardiac damage in a mouse model of Duchenne muscular dystrophy |
| title_full | Failure to resolve inflammation contributes to juvenile onset cardiac damage in a mouse model of Duchenne muscular dystrophy |
| title_fullStr | Failure to resolve inflammation contributes to juvenile onset cardiac damage in a mouse model of Duchenne muscular dystrophy |
| title_full_unstemmed | Failure to resolve inflammation contributes to juvenile onset cardiac damage in a mouse model of Duchenne muscular dystrophy |
| title_short | Failure to resolve inflammation contributes to juvenile onset cardiac damage in a mouse model of Duchenne muscular dystrophy |
| title_sort | failure to resolve inflammation contributes to juvenile onset cardiac damage in a mouse model of duchenne muscular dystrophy |
| url | https://doi.org/10.1038/s41419-025-07816-5 |
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