The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery

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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Main Authors: 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
Format: Article
Language:English
Published: Nature Publishing Group 2025-04-01
Series:Cell Death and Disease
Online Access:https://doi.org/10.1038/s41419-025-07595-z
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Summary: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.
ISSN:2041-4889

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