Division of Newborn Medicine.
Division of Genetics and Genomics, and.
JCI Insight. 2022 Aug 8;7(15):e157336. doi: 10.1172/jci.insight.157336.
Striated preferentially expressed protein kinase (SPEG), a myosin light chain kinase, is mutated in centronuclear myopathy (CNM) and/or dilated cardiomyopathy. No precise therapies are available for this disorder, and gene replacement therapy is not a feasible option due to the large size of SPEG. We evaluated the potential of dynamin-2 (DNM2) reduction as a potential therapeutic strategy because it has been shown to revert muscle phenotypes in mouse models of CNM caused by MTM1, DNM2, and BIN1 mutations. We determined that SPEG-β interacted with DNM2, and SPEG deficiency caused an increase in DNM2 levels. The DNM2 reduction strategy in Speg-KO mice was associated with an increase in life span, body weight, and motor performance. Additionally, it normalized the distribution of triadic proteins, triad ultrastructure, and triad number and restored phosphatidylinositol-3-phosphate levels in SPEG-deficient skeletal muscles. Although DNM2 reduction rescued the myopathy phenotype, it did not improve cardiac dysfunction, indicating a differential tissue-specific function. Combining DNM2 reduction with other strategies may be needed to target both the cardiac and skeletal defects associated with SPEG deficiency. DNM2 reduction should be explored as a therapeutic strategy against other genetic myopathies (and dystrophies) associated with a high level of DNM2.
条纹肌优先表达蛋白激酶（SPEG）是一种肌球蛋白轻链激酶，在中核肌病（CNM）和/或扩张型心肌病中发生突变。由于 SPEG 基因较大，目前尚无针对这种疾病的精确治疗方法，基因替代治疗也不是可行的选择。我们评估了降低动力蛋白-2（DNM2）作为潜在治疗策略的潜力，因为它已被证明可以逆转由 MTM1、DNM2 和 BIN1 突变引起的 CNM 小鼠模型中的肌肉表型。我们确定 SPEG-β 与 DNM2 相互作用，并且 SPEG 缺乏会导致 DNM2 水平升高。Spe g-KO 小鼠中的 DNM2 降低策略与寿命、体重和运动性能的增加有关。此外，它还使三联体蛋白的分布、三联体超微结构和三联体数量正常化，并恢复 SPEG 缺乏骨骼肌中的磷脂酰肌醇-3-磷酸水平。虽然 DNM2 降低挽救了肌病表型，但它没有改善心脏功能障碍，表明存在组织特异性功能差异。可能需要将 DNM2 降低与其他策略相结合，以针对与 SPEG 缺乏相关的心脏和骨骼缺陷。应探索降低 DNM2 作为针对与高水平 DNM2 相关的其他遗传性肌病（和肌营养不良症）的治疗策略。
