Endoplasmic reticulum stress in myotonic dystrophy type 1 muscle
Endoplasmic reticulum stress in myotonic dystrophy type 1 muscle
复制标题
DOI：
10.1007/s00401-007-0267-9
复制
发表时间：
2007-11-01
影响因子：
12.7
通讯作者：
Kira, Jun-ichi
中科院分区：
文献类型：
--
作者：
Ikezoe, Koji;Nakamori, Masayuki;Kira, Jun-ichi
在强直性肌营养不良1型（DM 1）中，已报道了兰尼碱受体1（RyR 1）和肌质/内质网Ca 2 + ATP酶（SERCA）基因的选择性剪接。这些蛋白质对于维持骨骼肌中的细胞内Ca 2+是必不可少的。为了阐明DM 1肌中内质网（ER）应激的参与，我们通过免疫组织化学、蛋白质印迹分析和RT-PCR检测了ER应激相关蛋白的激活。在五份DM 1肌肉活检中的四份中，除了来自CTG扩张时间最短且无肌强直的患者的肌肉活检外，在具有肌浆团的纤维和高度萎缩的纤维中发现了GRP 78和钙连接蛋白的表达增加以及PERK和eIF-2 α的磷酸化。核固缩团。Caspase-3和Caspase-7也在这些纤维中表达。通过蛋白质印迹分析证实了这些DM 1肌肉中GRP 78的表达增加。在DM 1肌肉活检中，GRP 78 mRNA和剪接的XBP 1 mRNA亚型也增加。此外，我们证明了神经源性肌萎缩的三个肌肉活检组织中，GRP 78在高度萎缩的纤维中表达增加，核固缩。然而，五个肌肉活检中央核心疾病大概与干扰细胞内Ca 2+稳态和肌肉活检肌强直先天性副肌强直显示没有激活这些蛋白质。总之，ER应激参与DM 1的肌肉萎缩。然而，它似乎不仅是通过破坏细胞内Ca 2+稳态引起的。
In myotonic dystrophy type 1 (DM1), alternative splicing of ryanodine receptor 1 (RyR1) and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) genes has been reported. These proteins are essential for maintaining intracellular Ca2+ in skeletal muscle. To clarify involvement of endoplasmic reticulum (ER) stress in DM1 muscles, we examined the activation of ER stress-related proteins by immunohistochemistry, western blot analysis and RT-PCR. In four of five DM1 muscle biopsies, except for a muscle biopsy from a patient with the shortest CTG expansion and no myotonia, increased expression of GRP78 and calnexin, and phosphorylation of PERK and eIF-2 alpha were revealed in fibers with sarcoplasmic masses and in highly atrophic fibers with pyknotic nuclear clumps. Caspase-3 and -7 were also expressed in these fibers. Increased expression of GRP78 in these DM1 muscles was confirmed by western blot analysis. GRP78 mRNA and spliced isoform of XBP1 mRNA were also increased in DM1 muscle biopsies. Furthermore, we demonstrated increased expression of GRP78 in highly atrophic fibers with pyknotic nuclear clumps in all three muscle biopsies from neurogenic muscular atrophies. However, five muscle biopsies from central core disease presumably with disturbed intracellular Ca2+ homeostasis and a muscle biopsy from paramyotonia congenita with myotonia showed no activation of these proteins. Taken together, ER stress is involved in muscle wasting in DM1. However, it seems to be evoked not only by disrupted intracellular Ca2+ homeostasis.