MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model
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 p...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2022-02-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/15/2/dmm049166 |
| _version_ | 1811332456398192640 |
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| author | William E. Tidyman Alice F. Goodwin Yoshiko Maeda Ophir D. Klein Katherine A. Rauen |
| author_facet | William E. Tidyman Alice F. Goodwin Yoshiko Maeda Ophir D. Klein Katherine A. Rauen |
| author_sort | William E. Tidyman |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T16:37:22Z |
| format | Article |
| id | doaj.art-95451ead71bc4f67bb310aa0bc0dee2b |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-13T16:37:22Z |
| publishDate | 2022-02-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-95451ead71bc4f67bb310aa0bc0dee2b2022-12-22T02:39:23ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112022-02-0115210.1242/dmm.049166049166MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse modelWilliam E. Tidyman0Alice F. Goodwin1Yoshiko Maeda2Ophir D. Klein3Katherine A. Rauen4 Department of Pediatrics, University of California Davis, Sacramento, CA 95817, USA Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, CA 94143, USA Department of Pediatrics, University of California Davis, Sacramento, CA 95817, USA Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, CA 94143, USA Department of Pediatrics, University of California Davis, Sacramento, CA 95817, USA 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.http://dmm.biologists.org/content/15/2/dmm049166costello syndromehypotoniamek inhibitormyogenesisrasopathiesras/mapk |
| spellingShingle | William E. Tidyman Alice F. Goodwin Yoshiko Maeda Ophir D. Klein Katherine A. Rauen MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model Disease Models & Mechanisms costello syndrome hypotonia mek inhibitor myogenesis rasopathies ras/mapk |
| title | MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model |
| title_full | MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model |
| title_fullStr | MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model |
| title_full_unstemmed | MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model |
| title_short | MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model |
| title_sort | mek inhibitor mediated rescue of skeletal myopathy caused by activating hras mutation in a costello syndrome mouse model |
| topic | costello syndrome hypotonia mek inhibitor myogenesis rasopathies ras/mapk |
| url | http://dmm.biologists.org/content/15/2/dmm049166 |
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