The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery
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<sup>+</sup>-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.
Authors
- Annapaola Andolfo (ORCID: https://orcid.org/0000-0002-0566-2391)
- Emilio Clementi (ORCID: https://orcid.org/0000-0001-7333-8270)
- Cristiana Perrotta (ORCID: https://orcid.org/0000-0001-6680-4536)
- Matteo Giovarelli (ORCID: https://orcid.org/0000-0002-9083-4935)
- Silvia Zecchini (ORCID: https://orcid.org/0000-0001-6416-327X)
- Davide Cervia (ORCID: https://orcid.org/0000-0002-2727-9449)
- Giacomo Clerici (ORCID: https://orcid.org/0000-0002-3287-1105)
- Anne Bigot (ORCID: https://orcid.org/0000-0003-0337-5425)
- Ornella Cappellari (ORCID: https://orcid.org/0000-0002-1882-3502)
- Chiara De Santis
- Simona Del Quondam
- Cristina Banfi (ORCID: https://orcid.org/0000-0003-3346-9879)
- Clarissa Braccia (ORCID: https://orcid.org/0000-0002-6343-9614)
- Clara De Palma (ORCID: https://orcid.org/0000-0003-0365-7414)
- Silvia Rosanna Casati (ORCID: https://orcid.org/0000-0002-4393-7691)
- Luca Mollica
- Emanuele Mocciaro (ORCID: https://orcid.org/0000-0002-4287-8933)
- Elisabetta Pisanu
- Elisabetta Catalani (ORCID: https://orcid.org/0000-0002-1210-6836)
- Annamaria De Luca (ORCID: https://orcid.org/0000-0002-5652-7341)
- Dario Brunetti (ORCID: https://orcid.org/0000-0002-2740-9370)
- Maria Grazia Cattaneo
- Laura Lociuro (ORCID: https://orcid.org/0009-0008-8023-593X)
- Alessandro Arcari
- Oriola Gjana
- Harcel Djaya Mbissam
Institutions
- Università degli Studi della Tuscia (IT)
- Vita-Salute San Raffaele University (IT)
- Inserm (FR)
- University of Milan (IT)
- Sorbonne Université (FR)
- Centro Cardiologico Monzino (IT)
- Institut de Myologie (FR)
- Human Technopole (IT)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Centre de Recherche en Myologie
- University of Bari Aldo Moro (IT)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-04-07
- DOI
- https://doi.org/10.1038/s41419-025-07595-z
- Citations
- 7
- Primary Topic
- Sirtuins and Resveratrol in Medicine
- Type
- article
- Field-Weighted Citation Impact
- 8.57
Funders
- Università degli Studi di Milano
- Ministero della Salute
- AFM-Téléthon