Journal
EMBO MOLECULAR MEDICINE
Volume 8, Issue 11, Pages 1289-1309Publisher
WILEY
DOI: 10.15252/emmm.201505815
Keywords
muscular dystrophy; Notch; O-glycosylation; POGLUT1; satellitecell
Categories
Funding
- Health Institute Carlos III
- FEDER [FIS PI10/02410, PI13-01739, BA12-00097, FIS12/2291]
- FEDER (CIBERNED)
- Andalusian Government [PI-0017-2014, P12-CTS-2232]
- Matsumae International Foundation
- NIH/NIGMS [R01GM061126, R01GM084135]
- NIH from NINDS [U54 NS078059]
- NIH from NICHD [R01 HD056103]
- MDA USA
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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.
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