Sirtuin 1 as a key regulator of the myogenic program: which involvement in FSHD?

Facioscapulohumeral dystrophy (FSHD) is a genetic muscle disorder for which there is currently no curative treatment. Its progression follows a cranio-caudal pattern, and it is primarily caused by the aberrant expression of the transcription factor DUX4. Although the gene has been clearly identified, the molecular mechanisms underlying DUX4-induced muscle dysfunction remain poorly understood. This project focuses on the role of SIRT1, a NAD⁺-dependent deacetylase, in the muscular alterations observed in FSHD. SIRT1 has recently been shown to regulate myogenic differentiation, a process known to be impaired in FSHD patients. Our goal is to better understand how DUX4 and SIRT1 interact, and how this interaction affects both muscle cell differentiation and the development of muscle damage. We will use inducible cell differentiation models to study the consequences of DUX4 induction on SIRT1 expression, localization, and activity. Furthermore, our data suggest that DUX4 has an impact on the expression level and protein abundance of SIRT1 in muscle cells. These modifications are likely to alter the activity of this enzyme, with potentially harmful consequences for the muscle and its regeneration process. In addition, post-translational modifications regulating SIRT1 nuclear localization may play a crucial role in the inhibition of muscle differentiation. Investigating these regulatory mechanisms could provide new insights into the pathways altered in FSHD and identify potential therapeutic targets. Ultimately, this study aims to clarify the functional relationship between DUX4 and SIRT1 and its impact on muscle physiology in FSHD.