Neurofibromin 1 controls metabolic balance and Notch-dependent quiescence of juvenile myogenic progenitors

Abstract

Patients affected by neurofibromatosis type 1 (NF1) frequently show muscle weakness with unknown etiology. Here we show that Neurofibromin-1 (Nf1) is not required in muscle fibers, but specifically in early postnatal myogenic progenitors (MPs), where Nf1 loss led to cell cycle exit and differentiation blockade, depleting the MP pool resulting in reduced myonuclear accrual as well as reduced muscle stem cell numbers. This was caused by precocious induction of stem cell quiescence coupled to metabolic reprogramming of MPs impinging on glycolytic shutdown, which was conserved in muscle fibers. We show that a Mek/Erk/NOS pathway hypersensitizes Nf1-deficient MPs to Notch signaling, consequently, early postnatal Notch pathway inhibition ameliorated premature quiescence, metabolic reprogramming and muscle growth. This reveals an unexpected role of Ras/Mek/Erk signaling supporting postnatal MP quiescence in concert with Notch signaling, which is controlled by Nf1 safeguarding coordinated muscle growth and muscle stem cell pool establishment. Furthermore, our data suggest transmission of metabolic reprogramming across cellular differentiation, affecting fiber metabolism and function in NF1.

Tensor Decomposition and Principal Component Analysis-Based Unsupervised Feature Extraction Outperforms State-of-the-Art Methods When Applied to Histone Modification Profiles

“…This study comprised four H3K4me3 ChIP-seq profiles, four H3K27me3 ChIP-seq profiles, and four H4K16ac ChIP-seq profiles using mouse progenitor cells (two wild type (WT) and two neurofibromin knockouts) [20]. Among them, four H3K27me3 profiles were used and four bigWig files were downloaded from the GEO Supplementary file.…”