Skeletal Muscle Development in the RASopathies

The RASopathies are caused by germline mutations which result in activation of the RAS/mitogen-activated kinase (Ras/MAPK) pathway. Although variable, hypotonia, muscle weakness, and reduced muscle mass are common clinical phenotypic features associated with the RASopathies. These features are due to a true skeletal myopathy characterized by an overall reduction in myofiber diameter. Mouse model studies for neurofibromatosis type 1 (NF1), Costello syndrome (CS), and cardio-facio-cutaneous (CFC) syndrome demonstrated that myogenesis is disrupted during embryonic development by the inhibition of myoblast differentiation. Moreover, the CS and CFC mouse models revealed that in addition to activation of the RAS/MAPK pathway, the p38 MAPK pathway, which is essential for skeletal muscle development and maintenance, is inhibited. Oral treatment of adult CS mice with the MEK inhibitor (PD03225901) was able to rescue many of the abnormal skeletal muscle features including myofiber size, muscle mass, and strength. This supports the possibility for therapeutic treatment of the skeletal myopathy even in adult RASopathy patients.