Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Am J Pathol. 2020 Dec;190(12):2453-2463. doi: 10.1016/j.ajpath.2020.08.012. Epub 2020 Sep 11.
Centronuclear myopathies (CNMs) are a subtype of congenital myopathies characterized by skeletal muscle weakness and an increase in the number of central myonuclei. SPEG (striated preferentially expressed protein kinase) has been identified as the sixth gene associated with CNM, and it has been shown that striated muscle-specific Speg-knockout (KO) mice have defective triad formation, abnormal excitation-contraction coupling, and calcium mishandling. The impact of SPEG deficiency on the survival and function of myogenic cells remains to be deciphered. In this study, the authors examined the overall population, proliferation, and differentiation of myogenic cells obtained from striated muscle-specific Speg-KO mice and compared them with wild-type (WT) controls. SPEG-deficient skeletal muscles contained fewer myogenic cells, which on further study demonstrated reduced proliferation and delayed differentiation compared with those from WT muscles. Regenerative response to skeletal muscle injury in Speg-KO mice was compared with that of WT mice, leading to the identification of similar abnormalities including fewer satellite cells, fewer dividing cells, and an increase in apoptotic cells in KO mice. Overall, these results reveal specific abnormalities in myogenic cell number and behavior associated with SPEG deficiency. Similar satellite cell defects have been reported in mouse models of MTM1- and DNM2-associated CNM, suggestive of shared underlying pathways.
核纤层肌病（CNM）是一种先天性肌病，其特征为骨骼肌无力和中央核的数量增加。SPEG（条纹优先表达蛋白激酶）已被确定为与 CNM 相关的第六个基因，并且已经表明条纹肌肉特异性 Speg 敲除（KO）小鼠存在三联体形成缺陷、异常兴奋-收缩偶联和钙处理异常。SPEG 缺乏对成肌细胞的存活和功能的影响仍有待破译。在这项研究中，作者检查了来自条纹肌肉特异性 Speg-KO 小鼠的成肌细胞的总体群体、增殖和分化，并将其与野生型（WT）对照进行了比较。SPEG 缺陷的骨骼肌中含有较少的成肌细胞，进一步研究表明，与 WT 肌肉相比，这些细胞的增殖减少，分化延迟。Speg-KO 小鼠骨骼肌损伤的再生反应与 WT 小鼠进行了比较，结果发现 KO 小鼠存在类似的异常，包括卫星细胞较少、分裂细胞较少和凋亡细胞增加。总的来说，这些结果揭示了与 SPEG 缺乏相关的成肌细胞数量和行为的特定异常。在与 MTM1 和 DNM2 相关的 CNM 的小鼠模型中已经报道了类似的卫星细胞缺陷，提示存在共同的潜在途径。
