The SIRT1 activator SRT2104 exerts exercise mimetic effects and promotes Duchenne muscular dystrophy recovery
Year: 2025
Type: article
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.
Source: Cell Death and Disease
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
Institutions: University of Milan, University of Bari Aldo Moro, Inserm, Sorbonne Université, Institut de Myologie, Centre de Recherche en Myologie, Human Technopole, Università degli Studi della Tuscia, IRCCS Ospedale San Raffaele, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Centro Cardiologico Monzino, Fondazione IRCCS Istituto Neurologico Carlo Besta
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,321
OpenAlex ID: W4409214478