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 due to 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 an inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction of 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 of 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.

Defining RASopathy

“…Small-molecule inhibitors originally developed to treat cancer, such as farnesyl transferase inhibitors, MEK inhibitors, ERK inhibitors and several more, provide opportunities to modulate pathway activity and therapeutically treat developmental disorders caused by germline RAS/MAPK hyperactivation ( Dombi et al, 2016 ). As also shown in this Special Issue of DMM, we recently demonstrated normalization of a skeletal myopathy using a MEK inhibitor in an adult CS Hras mouse model ( Tidyman et al, 2021 ). Because many of the developmental phenotypic signs and symptoms of RASopathies are not static, the possible use of systemic therapies after birth to reduce pathway activity holds the potential to ameliorate germline syndromic disease progression.…”

How can same-gene mutations promote both cancer and developmental disorders?

“…Mutations in kinases and phosphatases may lead to divergent phenotypes by phosphorylating/dephosphorylating different substrates in different tissue types ( 126 ). Recent data suggest that HRas G12V is involved in hypotonia in CS.…”

The RASopathies: from pathogenetics to therapeutics

“…A subsequent model, CC-FR-Hras G12V , has a high perinatal mortality rate and CS-like craniofacial defects, and develops benign skin papillomas and malignant angiosarcoma ( Chen et al, 2009 ). Importantly, these mice also have a skeletal muscle myopathy, which can be reversed by postnatal treatment with the MEK inhibitor PD-0325901 ( Tidyman et al, 2021 ). A Hras G12S mouse model has also been established.…”