SRT2104, a new SIRT1 activator, is an effective metabolic enhancer that promotes muscle recovery in DMD

Duchenne Muscular Dystrophy (DMD) is the most severe and common form of muscular dystrophy in childhood. DMD is an X-linked recessive disorder caused by mutations in the dystrophin gene. The lack of dystrophin protein disrupts the dystrophin-glycoprotein complex eliciting structural degeneration and functional impairments of myofibers. Currently, there is no cure for DMD. The standard treatment consists of the use of corticosteroids that slow down the progression of the disease, but their chronic use causes serious adverse effects. In recent years progress has been made in gene therapies to restore dystrophin. Among the different trialed strategies, micro-dystrophin (MD) approach is one of the most promising for DMD. However, at present, this approach still presents some limits. Indeed, the dystrophic muscle milieu exhibits chronic inflammatory activation and early sarcolemmal fragility that do not support MD engraftment and its preservation over time. Therefore, to enhance gene therapy efficacy, it is crucial to develop conservative therapies that improve the dystrophic phenotype by targeting secondary mechanisms of the disease. For this purpose, Sirtuin1(SIRT1) might be the suitable target. SIRT1 is a NADH-dependent class III histone deacetylase with key functions in several cellular processes. In mdx mice, SIRT1 overexpression tends to counteract the dystrophic phenotype reducing fibrosis, triggering anti-inflammatory effects, and improving muscle structure, motor performances, and heart pathology. Among the new SIRT1-activating compounds, the SRT2104 synthetic molecule is the most advanced in clinical studies. We tested its efficacy on dystrophic muscles by treating mdx mice for 12 weeks with the SRT2104 supplemented into the diet. At the endpoint, mice treated with SRT2104 performed better compared to those treated with a standard diet and, of notice, 6 weeks of SRT2104 administration were sufficient to significantly increase motor performance by whole-body tension test. Consistently, muscle cross-section analysis showed improvement in overall muscle structure and decreased fibrosis, degenerating and necrotic areas, and inflammatory infiltrate. Moreover, treatment with SRT2104 enhanced muscle regeneration, oxidative capacity, and mitochondrial activity. Overall, given its effects on crucial hallmarks of the disorder, SRT2104 could be an effective treatment for DMD and may be the proper candidate to sustain MD-based gene therapy in a combined approach.