Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Japan; Department of Cell Physiology, The Jikei University School of Medicine, Minato, Japan.
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Japan.
Biochem Biophys Res Commun. 2018 Oct 20;505(1):51-59. doi: 10.1016/j.bbrc.2018.09.039. Epub 2018 Sep 17.
Duchenne muscular dystrophy (DMD) and the less severe Becker muscular dystrophy (BMD) are due to mutations in the DMD gene. Previous reports show that in-frame deletion of exons 45-55 produces an internally shorted, but functional, dystrophin protein resulting in a very mild BMD phenotype. In order to elucidate the molecular mechanism leading to this phenotype, we generated exon 45-55 deleted dystrophin transgenic/mdx (Tg/mdx) mice. Muscular function of Tg/mdx mice was restored close to that of wild type (WT) mice but the localization of the neuronal type of nitric oxide synthase was changed from the sarcolemma to the cytosol. This led to hyper-nitrosylation of the ryanodine receptor 1 causing increased Ca release from the sarcoplasmic reticulum. On the other hand, Ca reuptake by the sarcoplasmic/endoplasmic reticulum Ca-ATPase (SERCA) was restored to the level of WT mice, suggesting that the Ca dysregulation had been compensated by SERCA activation. In line with this, expression of sarcolipin (SLN), a SERCA-inhibitory peptide, was upregulated in mdx mice, but strongly reduced in Tg/mdx mice. Furthermore, knockdown of SLN ameliorated the cytosolic Ca homeostasis and the dystrophic phenotype in mdx mice. These findings suggest that SLN may be a novel target for DMD therapy.
杜氏肌营养不良症（DMD）和较轻的贝克肌营养不良症（BMD）是由于 DMD 基因突变引起的。以前的报告表明，外显子 45-55 的框内缺失会产生内部缩短但功能正常的肌营养不良蛋白，导致非常轻微的 BMD 表型。为了阐明导致这种表型的分子机制，我们生成了缺失外显子 45-55 的肌营养不良蛋白转基因/mdx（Tg/mdx）小鼠。Tg/mdx 小鼠的肌肉功能恢复到接近野生型（WT）小鼠的水平，但神经元型一氧化氮合酶的定位从肌膜转移到细胞质。这导致肌浆网钙释放通道 1 的过度亚硝基化，导致肌浆网钙离子释放增加。另一方面，肌浆网/内质网 Ca-ATP 酶（SERCA）的 Ca 摄取恢复到 WT 小鼠的水平，这表明 Ca 失调已通过 SERCA 激活得到补偿。与此一致的是，肌浆网钙结合蛋白（SLN），一种 SERCA 抑制肽，在 mdx 小鼠中表达上调，但在 Tg/mdx 小鼠中强烈下调。此外，SLN 的敲低改善了 mdx 小鼠的细胞质 Ca 稳态和肌营养不良表型。这些发现表明，SLN 可能是 DMD 治疗的一个新靶点。
