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

Duchenne Muscular Dystrophy (DMD) is a degenerative disorder caused by mutations in the DMD gene encoding dystrophin. Despite remarkable progress has been made in genetic approaches to restore dystrophin or its function, targeting secondary pathological mechanisms remains an important issue. Sirtuin 1 (SIRT1) is a NAD+-dependent class III histone deacetylase that controls several key cellular processes. Different attempts have been done to increase SIRT1 expression or activation in mdx mice, and to date, the most promising one seems to be resveratrol. However, more potent and selective activators exist, and among these SRT2104 is the most promising one. We performed molecular dynamics simulations on SIRT1 available structures, proving that a conformational selection mechanism was responsible for the activity of SRT2104, i.e., the open inactive conformation of SIRT1 explored a more compact intermediate state that is stabilized by the drug, then converted into its active form. Even more potent and specific than resveratrol, it has never been tested in DMD therefore we challenged SRT2104 effects in mdx mice. We orally administered SRT2104 for 12 weeks in 8-week-old mdx/PhAM mice [generated crossing C57BL/10ScSnDmdmdx/J with PhAM mice (C57BL6/129SV)] obtaining promising results (n35 each group, analyzed by unpaired two-tailed t-test). SRT2104 promoted muscle OxPhos capacity and improved muscle performances and phenotype in mdx mice. The proteomic profile of SRT2104 treated muscle revealed the specific enrichment of fatty acid oxidation and mechanotransduction signals, both contributing to muscle recovery. In conclusion, SRT2104 can be considered a good metabolic enhancer and an interesting treatment for DMD.