Developmental dosing with a MEK inhibitor (PD0325901) rescues myopathic features of the muscle-specific but not limb-specific Nf1 knockout mouse

• Published in: Molecular genetics and metabolism 2018-04, Vol.123 (4), p.518-525
• Main Authors: Summers, Matthew A., Vasiljevski, Emily R., Mikulec, Kathy, Peacock, Lauren, Little, David G., Schindeler, Aaron
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Benzamides - pharmacology; Diphenylamine - analogs & derivatives; Diphenylamine - pharmacology; Extremities - pathology; Female; Homeodomain Proteins - physiology; MAP Kinase Signaling System - drug effects; MEK inhibitor; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle weakness; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Diseases - metabolism; Muscular Diseases - pathology; Muscular Diseases - prevention & control; MyoD Protein - physiology; Myopathy; Neurofibromatosis 1 - physiopathology; Neurofibromatosis type 1 (NF1); Neurofibromin 1 - physiology; ras Proteins - antagonists & inhibitors; ras Proteins - metabolism; Signal Transduction
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2018.02.009

Neurofibromatosis Type 1 (NF1) is a common autosomal dominant genetic disorder While NF1 is primarily associated with predisposition for tumor formation, muscle weakness has emerged as having a significant impact on quality of life. NF1 inactivation is linked with a canonical upregulation Ras-MEK-ERK signaling. This in this study we tested the capacity of the small molecule MEK inhibitor PD0325901 to influence the intramyocellular lipid accumulation associated with NF1 deficiency. Established murine models of tissue specific Nf1 deletion in skeletal muscle (Nf1MyoD−/−) and limb mesenchyme (Nf1Prx1−/−) were tested. Developmental PD0325901 dosing of dams pregnant with Nf1MyoD−/− progeny rescued the phenotype of day 3 pups including body weight and lipid accumulation by Oil Red O staining. In contrast, PD0325901 treatment of 4 week old Nf1Prx1−/− mice for 8 weeks had no impact on body weight, muscle wet weight, activity, or intramyocellular lipid. Examination of day 3 Nf1Prx1−/− pups showed differences between the two tissue-specific knockout strains, with lipid staining greatest in Nf1MyoD−/− mice, and fibrosis higher in Nf1Prx1−/− mice. These data show that a MEK/ERK dependent mechanism underlies NF1 muscle metabolism during development. However, crosstalk from Nf1-deficient non-muscle mesenchymal cells may impact upon muscle metabolism and fibrosis in neonatal and mature myofibers. •Neurofibromatosis type 1 (NF1) features lipid droplets in muscle fibers.•Canonical NF1-Ras-MAPK signaling was disrupted with MEK inhibitor PD0325901.•PD0325901 rescued lipid droplet accumulation in neonatal muscle-specific Nf1 knockout mice.•PD0325901 was ineffective in neonatal or adult limb-specific Nf1 knockout mice.