Inhibition of extracellular signal-regulated kinase 1/2 signaling has beneficial effects on skeletal muscle in a mouse model of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutation.
Inhibition of extracellular signal-regulated kinase 1/2 signaling has beneficial effects on skeletal muscle in a mouse model of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutation.
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DOI：
10.1186/2044-5040-3-17
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发表时间：
2013-07-01
期刊：
影响因子：
4.9
通讯作者：
Worman HJ
中科院分区：
文献类型：
--
作者：
Muchir A;Kim YJ;Reilly SA;Wu W;Choi JC;Worman HJ
常染色体emry - dreifuss肌营养不良症是由编码A型核层蛋白（核膜的中间丝蛋白）的核层蛋白A/C基因（LMNA）突变引起的。典型表现为肩胛骨-肱骨-腓骨肌萎缩和无力，早期关节挛缩和扩张性心肌病伴传导阻滞；然而，移动可变骨骼肌受累可能存在。之前，我们证明了细胞外信号调节激酶（ERK） 1/2在LmnaH222P/H222P小鼠（常染色体emry - dreifuss肌营养不良模型）心脏中的活性增加，并且阻断其激活可改善心功能。因此，我们研究了ERK1/2活性在骨骼肌病理中的作用。对LmnaH222P/H222P小鼠骨骼肌切片进行苏木精和伊红染色，光镜下进行组织学分析。通过免疫印迹和实时聚合酶链反应检测ERK1/2在小鼠组织和培养细胞中的活性，测定下游靶基因的表达。LmnaH222P/H222P小鼠在16 ~ 20周龄时接受selumetinib治疗，以评估治疗对肌肉组织学、ERK1/2活性和肢体抓力的影响。selumetinib阻断有丝分裂原激活的蛋白激酶/细胞外信号调节激酶激酶1/2，激活ERK1/2。我们检测到LmnaH222P/H222P小鼠骨骼肌中ERK1/2的激活增强。selumetinib治疗改善了骨骼肌组织病理学，降低了血清肌酸磷酸激酶和天冬氨酸转氨酶活性。通过体内握力测试评估，塞鲁美替尼治疗也改善了肌肉功能。我们的研究结果表明，ERK1/2在LmnaH222/H222P小鼠骨骼肌病理发展中起作用。他们进一步提供了第一个证据，证明小分子药物可能对常染色体emory - dreifuss肌营养不良患者的骨骼肌有益。
Autosomal Emery-Dreifuss muscular dystrophy is caused by mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. Classically, the disease manifests as scapulo-humeroperoneal muscle wasting and weakness, early joint contractures and dilated cardiomyopathy with conduction block; however, move variable skeletal muscle involvement can be present. Previously, we demonstrated increased activity of extracellular signal-regulated kinase (ERK) 1/2 in hearts of LmnaH222P/H222P mice, a model of autosomal Emery-Dreifuss muscular dystrophy, and that blocking its activation improved cardiac function. We therefore examined the role of ERK1/2 activity in skeletal muscle pathology. Sections of skeletal muscle from LmnaH222P/H222P mice were stained with hematoxylin and eosin and histological analysis performed using light microscopy. ERK1/2 activity was assessed in mouse tissue and cultured cells by immunoblotting and real-time polymerase chain reaction to measure expression of downstream target genes. LmnaH222P/H222P mice were treated with selumetinib, which blocks mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 that activates ERK1/2, from 16 to 20 weeks of age to assess the effects of treatment on muscle histology, ERK1/2 activity and limb grip strength. We detected enhanced activation of ERK1/2 in skeletal muscle of LmnaH222P/H222P mice. Treatment with selumetinib ameliorated skeletal muscle histopathology and reduced serum creatine phosphokinase and aspartate aminotransferase activities. Selumetinib treatment also improved muscle function as assessed by in vivo grip strength testing. Our results show that ERK1/2 plays a role in the development of skeletal muscle pathology in LmnaH222/H222P mice. They further provide the first evidence that a small molecule drug may be beneficial for skeletal muscle in autosomal Emery-Dreifuss muscular dystrophy.
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影响因子：
37.8
作者：
Brodsky, GL;Muntoni, F;Mestroni, L
通讯作者：
Mestroni, L
影响因子：
3.5
作者：
Kumar, Ajay;Yamauchi, Jenny;Girgenrath, Mahasweta
通讯作者：
Girgenrath, Mahasweta
影响因子：
3.5
作者：
Arimura, T;Helbling-Leclerc, A;Bonne, G
通讯作者：
Bonne, G
DOI：
10.1073/pnas.83.17.6450
发表时间：
1986-09-01
影响因子：
11.1
作者：
FISHER, DZ;CHAUDHARY, N;BLOBEL, G
通讯作者：
BLOBEL, G
影响因子：
4
作者：
Griffin, MA;Feng, HS;Discher, DE
通讯作者：
Discher, DE