Repurposed Nrf2 activator dimethyl fumarate rescues muscle inflammation and fibrosis in an aggravated mdx mouse model of Duchenne muscular dystrophy
In inherited neuromuscular disease, Duchenne muscular dystrophy (DMD), glucocorticoids significantly slow disease progression yet impart side effects severe enough to preclude use in a significant proportion of patients. Extending our findings that acute treatment with FDA approved multiple sclerosi...
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Elsevier
2025-07-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725001892 |
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| author | Stephanie Kourakis Cara A. Timpani Ryan M. Bagaric Bo Qi Benazir A. Ali Rebecca Boyer Guinevere Spiesberger Nitika Kandhari Xu Yan Jujiao Kuang Ankita Tulangekar Judy B. de Haan Deanna Deveson-Lucas Nicole Stupka Dirk Fischer Emma Rybalka |
| author_facet | Stephanie Kourakis Cara A. Timpani Ryan M. Bagaric Bo Qi Benazir A. Ali Rebecca Boyer Guinevere Spiesberger Nitika Kandhari Xu Yan Jujiao Kuang Ankita Tulangekar Judy B. de Haan Deanna Deveson-Lucas Nicole Stupka Dirk Fischer Emma Rybalka |
| author_sort | Stephanie Kourakis |
| collection | DOAJ |
| description | In inherited neuromuscular disease, Duchenne muscular dystrophy (DMD), glucocorticoids significantly slow disease progression yet impart side effects severe enough to preclude use in a significant proportion of patients. Extending our findings that acute treatment with FDA approved multiple sclerosis drug, dimethyl fumarate (DMF), rescues muscle pathology in juvenile mdx mice, we aimed to conduct tiered pre-clinical testing toward translation. To aggravate disease phenotype in adult mdx muscles that usually lack human equivalent muscle pathology, we used bi-weekly treadmill running for 4 weeks which increased plasma DMD biomarker, creatine kinase, by 2-fold and quadriceps fibrosis by ∼30 %. Using this model, we screened DMF for 5 weeks in a head-to-head comparison, and in combination, with standard-of-care prednisone (PRED), to model the most likely clinical trial scenario. We show comparable efficacy between DMF and PRED at reducing inflammation via NF-κB suppression and CD68+ macrophage infiltration. Moderate term DMF monotherapy had additional anti-fibrotic and anti-lipogenic effects on skeletal and cardiac muscle beyond those seen with PRED treatment, although combination therapy exacerbated fibrosis in quadriceps. Our study supports DMF as a repurposing candidate for DMD, especially for patients who cannot tolerate chronic glucocorticoid treatment. We also highlight the importance of evaluating combination therapy to identify potential off-target effects between emerging therapeutics and glucocorticoids towards better designed clinical trials. |
| format | Article |
| id | doaj-art-d5089dfe55b743d8939e5e10cdcdb3ce |
| institution | OA Journals |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-d5089dfe55b743d8939e5e10cdcdb3ce2025-08-20T02:31:54ZengElsevierRedox Biology2213-23172025-07-018410367610.1016/j.redox.2025.103676Repurposed Nrf2 activator dimethyl fumarate rescues muscle inflammation and fibrosis in an aggravated mdx mouse model of Duchenne muscular dystrophyStephanie Kourakis0Cara A. Timpani1Ryan M. Bagaric2Bo Qi3Benazir A. Ali4Rebecca Boyer5Guinevere Spiesberger6Nitika Kandhari7Xu Yan8Jujiao Kuang9Ankita Tulangekar10Judy B. de Haan11Deanna Deveson-Lucas12Nicole Stupka13Dirk Fischer14Emma Rybalka15Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia; Inherited and Acquired Myopathies Program, Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, AustraliaInstitute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia; Inherited and Acquired Myopathies Program, Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, Australia; Department of Medicine – Western Health, Melbourne Medical School, The University of Melbourne, St Albans, Victoria, AustraliaInstitute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia; Inherited and Acquired Myopathies Program, Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, AustraliaInstitute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia; Inherited and Acquired Myopathies Program, Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, AustraliaInstitute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia; Inherited and Acquired Myopathies Program, Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, AustraliaInstitute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, AustraliaInstitute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia; Inherited and Acquired Myopathies Program, Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, AustraliaMonash Genomics and Bioinformatics Platform, Biomedical Discovery Institute, Monash University, Clayton, Victoria, AustraliaInstitute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia; Sarcopenia Research Program, Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, AustraliaInstitute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, AustraliaInstitute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia; Inherited and Acquired Myopathies Program, Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, AustraliaBasic Science Domain, Oxidative Stress Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, Victoria, AustraliaMonash Genomics and Bioinformatics Platform, Biomedical Discovery Institute, Monash University, Clayton, Victoria, AustraliaDepartment of Medicine – Western Health, Melbourne Medical School, The University of Melbourne, St Albans, Victoria, Australia; Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, AustraliaDivision of Neuropediatric and Developmental Medicine, University Children's Hospital of Basel (UKBB), Basel, SwitzerlandInstitute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia; Inherited and Acquired Myopathies Program, Australian Institute for Musculoskeletal Science (AIMSS), St Albans, Victoria, Australia; Corresponding author. Institute for Health and Sport (IHeS), Victoria University, Melbourne, Victoria, Australia.In inherited neuromuscular disease, Duchenne muscular dystrophy (DMD), glucocorticoids significantly slow disease progression yet impart side effects severe enough to preclude use in a significant proportion of patients. Extending our findings that acute treatment with FDA approved multiple sclerosis drug, dimethyl fumarate (DMF), rescues muscle pathology in juvenile mdx mice, we aimed to conduct tiered pre-clinical testing toward translation. To aggravate disease phenotype in adult mdx muscles that usually lack human equivalent muscle pathology, we used bi-weekly treadmill running for 4 weeks which increased plasma DMD biomarker, creatine kinase, by 2-fold and quadriceps fibrosis by ∼30 %. Using this model, we screened DMF for 5 weeks in a head-to-head comparison, and in combination, with standard-of-care prednisone (PRED), to model the most likely clinical trial scenario. We show comparable efficacy between DMF and PRED at reducing inflammation via NF-κB suppression and CD68+ macrophage infiltration. Moderate term DMF monotherapy had additional anti-fibrotic and anti-lipogenic effects on skeletal and cardiac muscle beyond those seen with PRED treatment, although combination therapy exacerbated fibrosis in quadriceps. Our study supports DMF as a repurposing candidate for DMD, especially for patients who cannot tolerate chronic glucocorticoid treatment. We also highlight the importance of evaluating combination therapy to identify potential off-target effects between emerging therapeutics and glucocorticoids towards better designed clinical trials.http://www.sciencedirect.com/science/article/pii/S2213231725001892Duchenne muscular dystrophyDimethyl fumarateTherapeuticsMuscle pathology |
| spellingShingle | Stephanie Kourakis Cara A. Timpani Ryan M. Bagaric Bo Qi Benazir A. Ali Rebecca Boyer Guinevere Spiesberger Nitika Kandhari Xu Yan Jujiao Kuang Ankita Tulangekar Judy B. de Haan Deanna Deveson-Lucas Nicole Stupka Dirk Fischer Emma Rybalka Repurposed Nrf2 activator dimethyl fumarate rescues muscle inflammation and fibrosis in an aggravated mdx mouse model of Duchenne muscular dystrophy Redox Biology Duchenne muscular dystrophy Dimethyl fumarate Therapeutics Muscle pathology |
| title | Repurposed Nrf2 activator dimethyl fumarate rescues muscle inflammation and fibrosis in an aggravated mdx mouse model of Duchenne muscular dystrophy |
| title_full | Repurposed Nrf2 activator dimethyl fumarate rescues muscle inflammation and fibrosis in an aggravated mdx mouse model of Duchenne muscular dystrophy |
| title_fullStr | Repurposed Nrf2 activator dimethyl fumarate rescues muscle inflammation and fibrosis in an aggravated mdx mouse model of Duchenne muscular dystrophy |
| title_full_unstemmed | Repurposed Nrf2 activator dimethyl fumarate rescues muscle inflammation and fibrosis in an aggravated mdx mouse model of Duchenne muscular dystrophy |
| title_short | Repurposed Nrf2 activator dimethyl fumarate rescues muscle inflammation and fibrosis in an aggravated mdx mouse model of Duchenne muscular dystrophy |
| title_sort | repurposed nrf2 activator dimethyl fumarate rescues muscle inflammation and fibrosis in an aggravated mdx mouse model of duchenne muscular dystrophy |
| topic | Duchenne muscular dystrophy Dimethyl fumarate Therapeutics Muscle pathology |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725001892 |
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