Cho Soomin, Servián-Morilla Emilia, Navarro Victoria, Rodriguez-Gonzalez Beatriz, Yuan Youxi, Cano Raquel, Rambhiya Arjun A, Darabi Radbod, Haltiwanger Robert S, Paradas Carmen, Jafar-Nejad Hamed
Development, Disease Models & Therapeutics Graduate Program Baylor College of Medicine, Houston, Texas, United States of America.
Neuromuscular Disorders Unit, Department of Neurology, Instituto de Biomedicina de Sevilla, Hospital U. Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
PLoS Genet. 2025 Aug 18;21(8):e1011806. doi: 10.1371/journal.pgen.1011806. eCollection 2025 Aug.
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.
蛋白O-葡萄糖基转移酶1（POGLUT1）的突变会导致隐性肢带型肌营养不良（LGMDR21），成年患者肌肉中的卫星细胞数量减少、NOTCH1信号传导受损，且患者来源的肌肉祖细胞的成肌能力受损。然而，POGLUT1在卫星细胞的发育、功能和维持中的体内作用尚不清楚。在此，我们表明，在成肌祖细胞中条件性删除小鼠Poglut1会导致早期致死、出生后肌肉生长缺陷、Pax7表达降低、肌肉细胞外基质异常以及肌肉修复受损。Poglut1缺陷的肌肉祖细胞表现出增殖减少、分化增强以及加速融合成肌纤维。在成年卫星细胞中诱导性缺失Poglut1会导致它们失去静止状态并过早分化，并在连续损伤后损害肌肉修复。基于细胞的信号分析和质谱分析表明，POGLUT1是成肌细胞中NOTCH1、NOTCH2和NOTCH3激活所必需的，并且NOTCH3与NOTCH1和NOTCH2一样是POGLUT1的靶标。这些观察结果为POGLUT1在肌肉发育和修复中的作用以及LGMDR21的病理生理学提供了见解。
