The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery
Abstract Duchenne muscular dystrophy (DMD) is a devastating genetic disorder, whose management is still a major challenge, despite progress in genetic and pharmacological disease-modifying treatments have been made. Mitochondrial dysfunctions contribute to DMD, however, there are no effective mitoch...
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07595-z |
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| author | Matteo Giovarelli Silvia Zecchini Silvia Rosanna Casati Laura Lociuro Oriola Gjana Luca Mollica Elena Pisanu Harcel Djaya Mbissam Ornella Cappellari Chiara De Santis Alessandro Arcari Anne Bigot Giuditta Clerici Elisabetta Catalani Simona Del Quondam Annapaola Andolfo Clarissa Braccia Maria Grazia Cattaneo Cristina Banfi Dario Brunetti Emanuele Mocciaro Annamaria De Luca Emilio Clementi Davide Cervia Cristiana Perrotta Clara De Palma |
| author_facet | Matteo Giovarelli Silvia Zecchini Silvia Rosanna Casati Laura Lociuro Oriola Gjana Luca Mollica Elena Pisanu Harcel Djaya Mbissam Ornella Cappellari Chiara De Santis Alessandro Arcari Anne Bigot Giuditta Clerici Elisabetta Catalani Simona Del Quondam Annapaola Andolfo Clarissa Braccia Maria Grazia Cattaneo Cristina Banfi Dario Brunetti Emanuele Mocciaro Annamaria De Luca Emilio Clementi Davide Cervia Cristiana Perrotta Clara De Palma |
| author_sort | Matteo Giovarelli |
| collection | DOAJ |
| description | Abstract Duchenne muscular dystrophy (DMD) is a devastating genetic disorder, whose management is still a major challenge, despite progress in genetic and pharmacological disease-modifying treatments have been made. Mitochondrial dysfunctions contribute to DMD, however, there are no effective mitochondrial therapies for DMD. SIRT1 is a NAD+-dependent deacetylase that controls several key processes and whose impairment is involved in determining mitochondrial dysfunction in DMD. In addition to well-known resveratrol, other potent selective activators of SIRT1 exist, with better pharmacokinetics properties and a safer profile. Among these, SRT2104 is the most promising and advanced in clinical studies. Here we unveil the beneficial effects of SRT2104 in flies, mice, and patient-derived myoblasts as different models of DMD, demonstrating an anti-inflammatory, anti-fibrotic, and pro-regenerative action of the drug. We elucidate, by molecular dynamics simulations, that a conformational selection mechanism is responsible for the activation of SIRT1. Further, the impact of SRT2104 in reshaping muscle proteome and acetylome profiles has been investigated, highlighting effects that mimic those induced by exercise. Overall, our data suggest SRT2104 as a possible therapeutic candidate to successfully counteract DMD progression. |
| format | Article |
| id | doaj-art-20c63607e7354b29b2fbfcfd2e5afc9b |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj-art-20c63607e7354b29b2fbfcfd2e5afc9b2025-08-20T02:11:47ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111410.1038/s41419-025-07595-zThe SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recoveryMatteo Giovarelli0Silvia Zecchini1Silvia Rosanna Casati2Laura Lociuro3Oriola Gjana4Luca Mollica5Elena Pisanu6Harcel Djaya Mbissam7Ornella Cappellari8Chiara De Santis9Alessandro Arcari10Anne Bigot11Giuditta Clerici12Elisabetta Catalani13Simona Del Quondam14Annapaola Andolfo15Clarissa Braccia16Maria Grazia Cattaneo17Cristina Banfi18Dario Brunetti19Emanuele Mocciaro20Annamaria De Luca21Emilio Clementi22Davide Cervia23Cristiana Perrotta24Clara De Palma25Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di MilanoDepartment of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di MilanoDepartment of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di MilanoDepartment of Medical Biotechnology and Translational Medicine (BioMeTra), Università degli Studi di Milano; SegrateDepartment of Medical Biotechnology and Translational Medicine (BioMeTra), Università degli Studi di Milano; SegrateDepartment of Medical Biotechnology and Translational Medicine (BioMeTra), Università degli Studi di Milano; SegrateDepartment of Medical Biotechnology and Translational Medicine (BioMeTra), Università degli Studi di Milano; SegrateDepartment of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di MilanoDepartment of Pharmacy - Drug Sciences, University of Bari Aldo MoroDepartment of Pharmacy - Drug Sciences, University of Bari Aldo MoroDepartment of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di MilanoSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieHuman TechnopoleDepartment for Innovation in Biological, Agro-Food and Forest Systems (DIBAF), Università degli Studi della TusciaDepartment for Innovation in Biological, Agro-Food and Forest Systems (DIBAF), Università degli Studi della TusciaProMeFa, Proteomics and Metabolomics Facility, Center for Omics Sciences, IRCCS San Raffaele Scientific InstituteProMeFa, Proteomics and Metabolomics Facility, Center for Omics Sciences, IRCCS San Raffaele Scientific InstituteDepartment of Medical Biotechnology and Translational Medicine (BioMeTra), Università degli Studi di Milano; SegrateUnit of Functional Proteomics, Metabolomics and Network Analysis, Centro Cardiologico Monzino IRCCSUnità di Genetica Medica e Neurogenetica, Fondazione IRCCS Istituto Neurologico Carlo BestaDepartment of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di MilanoDepartment of Pharmacy - Drug Sciences, University of Bari Aldo MoroDepartment of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di MilanoDepartment for Innovation in Biological, Agro-Food and Forest Systems (DIBAF), Università degli Studi della TusciaDepartment of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di MilanoDepartment of Medical Biotechnology and Translational Medicine (BioMeTra), Università degli Studi di Milano; SegrateAbstract Duchenne muscular dystrophy (DMD) is a devastating genetic disorder, whose management is still a major challenge, despite progress in genetic and pharmacological disease-modifying treatments have been made. Mitochondrial dysfunctions contribute to DMD, however, there are no effective mitochondrial therapies for DMD. SIRT1 is a NAD+-dependent deacetylase that controls several key processes and whose impairment is involved in determining mitochondrial dysfunction in DMD. In addition to well-known resveratrol, other potent selective activators of SIRT1 exist, with better pharmacokinetics properties and a safer profile. Among these, SRT2104 is the most promising and advanced in clinical studies. Here we unveil the beneficial effects of SRT2104 in flies, mice, and patient-derived myoblasts as different models of DMD, demonstrating an anti-inflammatory, anti-fibrotic, and pro-regenerative action of the drug. We elucidate, by molecular dynamics simulations, that a conformational selection mechanism is responsible for the activation of SIRT1. Further, the impact of SRT2104 in reshaping muscle proteome and acetylome profiles has been investigated, highlighting effects that mimic those induced by exercise. Overall, our data suggest SRT2104 as a possible therapeutic candidate to successfully counteract DMD progression.https://doi.org/10.1038/s41419-025-07595-z |
| spellingShingle | Matteo Giovarelli Silvia Zecchini Silvia Rosanna Casati Laura Lociuro Oriola Gjana Luca Mollica Elena Pisanu Harcel Djaya Mbissam Ornella Cappellari Chiara De Santis Alessandro Arcari Anne Bigot Giuditta Clerici Elisabetta Catalani Simona Del Quondam Annapaola Andolfo Clarissa Braccia Maria Grazia Cattaneo Cristina Banfi Dario Brunetti Emanuele Mocciaro Annamaria De Luca Emilio Clementi Davide Cervia Cristiana Perrotta Clara De Palma The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery Cell Death and Disease |
| title | The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery |
| title_full | The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery |
| title_fullStr | The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery |
| title_full_unstemmed | The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery |
| title_short | The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery |
| title_sort | sirt1 activator srt2104 exerts exercise mimetic effects and promotes duchenne muscular dystrophy recovery |
| url | https://doi.org/10.1038/s41419-025-07595-z |
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