Servian-Morilla, Emilia , Takeuchi, Hideyuki , Lee, Tom V. , Clarimon, Jordi , Mavillard, Fabiola , Area-Gomez, Estela , Rivas, Eloy , Nieto-Gonzalez, Jose L. , Rivero, Maria C. , Cabrera-Serrano, Macarena , Gomez-Sanchez, Leonardo , MARTÍNEZ LÓPEZ, JOSÉ ANTONIO, Estrada, Beatriz , Marquez, Celedonio , Morgado, Yolanda , Suarez-Calvet, Xavier , Pita, Guillermo , Bigot, Anne , Gallardo, Eduard , Fernandez-Chacon, Rafael , Hirano, Michio , Haltiwanger, Robert S. , Jafar-Nejad, Hamed , Paradas, Carmen
Si
EMBO Mol. Med.
Article
Científica
9.249
5.138
01/11/2016
000387111900005
Skeletal muscle regeneration by muscle satellite cells is a physiological mechanism activated upon muscle damage and regulated by Notch signaling. In a family with autosomal recessive limb-girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function. In vitro and invivo experiments demonstrated that the mutation reduces O-glucosyltransferase activity on Notch and impairs muscle development. Muscles from patients revealed decreased Notch signaling, dramatic reduction in satellite cell pool and a muscle-specific -dystroglycan hypoglycosylation not present in patients' fibroblasts. Primary myoblasts from patients showed slow proliferation, facilitated differentiation, and a decreased pool of quiescent PAX7(+) cells. A robust rescue of the myogenesis was demonstrated by increasing Notch signaling. None of these alterations were found in muscles from secondary dystroglycanopathy patients. These data suggest that a key pathomechanism for this novel form of muscular dystrophy is Notch-dependent loss of satellite cells.
muscular dystrophy; Notch; O-glycosylation; POGLUT1; satellitecell