Language

English

Publication Date

8-1-2025

Journal

PLoS Genetics

DOI

10.1371/journal.pgen.1011806

PMID

40825068

PMCID

PMC12373270

PubMedCentral® Posted Date

8-18-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Mutations in protein O-glucosyltransferase 1 (POGLUT1) cause a recessive limb-girdle muscular dystrophy (LGMDR21) with reduced satellite cell number and NOTCH1 signaling in adult patient muscles and impaired myogenic capacity of patient-derived muscle progenitors. However, the in vivo roles of POGLUT1 in the development, function, and maintenance of satellite cells are not well understood. Here, we show that conditional deletion of mouse Poglut1 in myogenic progenitors leads to early lethality, postnatal muscle growth defects, reduced Pax7 expression, abnormality in muscle extracellular matrix, and impaired muscle repair. Poglut1-deficient muscle progenitors exhibit reduced proliferation, enhanced differentiation, and accelerated fusion into myofibers. Inducible loss of Poglut1 in adult satellite cells leads to their loss of quiescence and precocious differentiation, and impairs muscle repair upon serial injury. Cell-based signaling assays and mass spectrometric analysis indicate that POGLUT1 is required for the activation of NOTCH1, NOTCH2, and NOTCH3 in myoblasts and that NOTCH3 is a target of POGLUT1 like NOTCH1 and NOTCH2. These observations provide insight into the roles of POGLUT1 in muscle development and repair and the pathophysiology of LGMDR21.

Keywords

Animals, Mice, Muscle Development, Satellite Cells, Skeletal Muscle, Receptor, Notch1, Cell Differentiation, Glucosyltransferases, PAX7 Transcription Factor, Muscle, Skeletal, Signal Transduction, Receptor, Notch2, Cell Proliferation, Receptor, Notch3, Glycosyltransferases, Stem Cells, Myoblasts, Humans

Published Open-Access

yes

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