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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Autor*in:	William E. Tidyman [verfasserIn] Alice F. Goodwin [verfasserIn] Yoshiko Maeda [verfasserIn] Ophir D. Klein [verfasserIn] Katherine A. Rauen [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	costello syndrome hypotonia mek inhibitor myogenesis rasopathies ras/mapk

Übergeordnetes Werk:	In: Disease Models & Mechanisms - The Company of Biologists, 2011, 15(2022), 2
Übergeordnetes Werk:	volume:15 ; year:2022 ; number:2

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.1242/dmm.049166

Katalog-ID:	DOAJ02761042X

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520			\|a 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.
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language	English
source	In Disease Models & Mechanisms 15(2022), 2 volume:15 year:2022 number:2
sourceStr	In Disease Models & Mechanisms 15(2022), 2 volume:15 year:2022 number:2
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institution	findex.gbv.de
topic_facet	costello syndrome hypotonia mek inhibitor myogenesis rasopathies ras/mapk Medicine R Pathology
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container_title	Disease Models & Mechanisms
authorswithroles_txt_mv	William E. Tidyman @@aut@@ Alice F. Goodwin @@aut@@ Yoshiko Maeda @@aut@@ Ophir D. Klein @@aut@@ Katherine A. Rauen @@aut@@
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callnumber-first	R - Medicine
author	William E. Tidyman
spellingShingle	William E. Tidyman misc RB1-214 misc costello syndrome misc hypotonia misc mek inhibitor misc myogenesis misc rasopathies misc ras/mapk misc Medicine misc R misc Pathology MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model
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topic_title	RB1-214 MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model costello syndrome hypotonia mek inhibitor myogenesis rasopathies ras/mapk
topic	misc RB1-214 misc costello syndrome misc hypotonia misc mek inhibitor misc myogenesis misc rasopathies misc ras/mapk misc Medicine misc R misc Pathology
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title	MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model
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title_full	MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model
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title_sort	mek-inhibitor-mediated rescue of skeletal myopathy caused by activating hras mutation in a costello syndrome mouse model
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title_auth	MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model
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MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

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