Decoding skeletal muscle tissue repair dysfunction in Duchenne Muscular Dystrophy – DMDRepair
A failure to repair or regenerate tissue can result in devastating degenerative diseases. Impaired skeletal muscle repair leading to accelerated muscle loss is observed in Duchenne Muscular Dystrophy (DMD), one of the most common genetic diseases in man. There is currently no cure for DMD patients. Muscle degeneration alters all intentional movement as well as basic physiological processes such as breathing. Patients die prematurely due to cardiorespiratory failure. Skeletal muscle can be repaired by two distinct mechanisms: a fiber intrinsic one that restores damage to the muscle fiber’s membrane or contractile units, and a muscle stemcell based regeneration one that replaces dead muscle fibers. Currently, we do not know why both repair mechanisms fail in DMD. Progress in understanding the physiopathology of the disease has been slow because the available experimental models only partially recapitulate the disease, and due to the lack of appropriate experimental methods. Our proposal aims to overcome these major bottlenecks which have hampered progress in the development of new therapies. First, we have developed two new DMD models, in vivo and in vitro, that better recapitulate the human phenotype. Second, we will apply state of the art single-cell and nuclei sequencing technologies to unique patient material and to our novel DMD models to systematically compare cells and nuclei in normal and DMD muscles. State of the art computational analysis and integration of the data will allow us to define the disease trajectory at the molecular level, providing insights into the failure of muscle repair in DMD. We propose to exploit this knowledge to manipulate the cell-intrinsic repair of damaged myofibers as well as the stem cell-dependent regeneration of deteriorating muscles. Together, this will provide new insights into the repair deficits in DMD and allow the development of rational strategies targeting repair for the treatment of muscular dystrophies.
Monsieur Frédéric RELAIX (Institut Mondor de recherche biomédicale)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Ludwig Maximilian University of Munich (LMU)
Max-Delbrück-Centrum in der Helmholtz-Gemeinschaft
IMRB Institut Mondor de recherche biomédicale
Brigham and Women’s Hospital
Help of the ANR 16,814 euros
Beginning and duration of the scientific project: July 2022 - 12 Months