Truncated dystrophin ameliorates the dystrophic phenotype of mdx mice by reducing sarcolipin-mediated SERCA inhibition
Truncated dystrophin ameliorates the dystrophic phenotype of mdx mice by reducing sarcolipin-mediated SERCA inhibition
复制标题
截短的肌营养不良蛋白通过减少肌磷脂介导的 SERCA 抑制来改善 mdx 小鼠的营养不良表型
DOI：
10.1016/j.bbrc.2018.09.039
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发表时间：
2018
影响因子：
3.1
通讯作者：
Takeda Shin'ichi
中科院分区：
文献类型：
--
作者：
Tanihata Jun;Nagata Tetsuya;Ito Naoki;Saito Takashi;Nakamura Akinori;Minamisawa Susumu;Aoki Yoshitsugu;Ruegg Urs T.;Takeda Shin'ichi
杜氏肌营养不良症（DMD）和不太严重的贝克肌营养不良症（BMD）是由于DMD基因突变。先前的报道显示，外显子45-55的框内缺失产生内部短的但功能性的肌营养不良蛋白，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，我们产生了外显子45-55缺失的抗肌萎缩蛋白转基因/mdx（Tg/mdx）小鼠。Tg/mdx小鼠的肌肉功能恢复接近野生型（WT）小鼠，但神经元型的一氧化氮合酶的定位从肌膜的胞质溶胶的改变。这导致ryanodine受体1的超亚硝基化，引起肌浆网中Ca 2+释放增加。另一方面，肌质/内质网Ca ~（2+）-ATP酶（SERCA）的Ca ~（2+）再摄取恢复到WT小鼠的水平，表明Ca ~（2+）失调已被SERCA激活补偿。与此相一致的是，肌磷脂（SLN），一种SERCA抑制肽的表达，在mdx小鼠中上调，但在Tg/mdx小鼠中强烈降低。此外，SLN的敲除改善了mdx小鼠细胞内Ca 2+稳态和营养不良表型。这些结果表明，SLN可能是DMD治疗的新靶点。
Duchenne muscular dystrophy (DMD) and the less severe Becker muscular dystrophy (BMD) are due to mutations in theDMDgene. 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/mdxmice 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 Ca2+release from the sarcoplasmic reticulum. On the other hand, Ca2+reuptake by the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) was restored to the level of WT mice, suggesting that the Ca2+dysregulation had been compensated by SERCA activation. In line with this, expression of sarcolipin (SLN), a SERCA-inhibitory peptide, was upregulated inmdxmice, but strongly reduced in Tg/mdxmice. Furthermore, knockdown of SLN ameliorated the cytosolic Ca2+homeostasis and the dystrophic phenotype inmdxmice. These findings suggest that SLN may be a novel target for DMD therapy.