دورية أكاديمية
MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model
| العنوان: | MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model |
|---|---|
| المؤلفون: | William E. Tidyman, Alice F. Goodwin, Yoshiko Maeda, Ophir D. Klein, Katherine A. Rauen |
| المصدر: | Disease Models & Mechanisms, Vol 15, Iss 2 (2022) |
| بيانات النشر: | The Company of Biologists, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Medicine LCC:Pathology |
| مصطلحات موضوعية: | costello syndrome, hypotonia, mek inhibitor, myogenesis, rasopathies, ras/mapk, Medicine, Pathology, RB1-214 |
| الوصف: | Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes caused by mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due, in part, to inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction in myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction in p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1754-8403 1754-8411 |
| العلاقة: | http://dmm.biologists.org/content/15/2/dmm049166Test; https://doaj.org/toc/1754-8403Test; https://doaj.org/toc/1754-8411Test |
| DOI: | 10.1242/dmm.049166 |
| الوصول الحر: | https://doaj.org/article/95451ead71bc4f67bb310aa0bc0dee2bTest |
| رقم الانضمام: | edsdoj.95451ead71bc4f67bb310aa0bc0dee2b |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17548403 17548411 |
|---|---|
| DOI: | 10.1242/dmm.049166 |