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

Xiaoyan Wei, Angelos Rigopoulos, Matthias Lienhard, Sophie Pöhle-Kronawitter, Georgios Kotsaris, Julia Franke, Nikolaus Berndt, Joy Orezimena Mejedo, Hao Wu, Stefan Börno, Bernd Timmermann, Arunima Murgai, Rainer Glauben and Sigmar Stricker ()
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Xiaoyan Wei: Freie Universität Berlin
Angelos Rigopoulos: Freie Universität Berlin
Matthias Lienhard: Max Planck Institute for Molecular Genetics
Sophie Pöhle-Kronawitter: Freie Universität Berlin
Georgios Kotsaris: Freie Universität Berlin
Julia Franke: Freie Universität Berlin
Nikolaus Berndt: German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE)
Joy Orezimena Mejedo: Freie Universität Berlin
Hao Wu: Charité University Medicine Berlin
Stefan Börno: Max Planck Institute for Molecular Genetics
Bernd Timmermann: Max Planck Institute for Molecular Genetics
Arunima Murgai: Freie Universität Berlin
Rainer Glauben: Charité University Medicine Berlin
Sigmar Stricker: Freie Universität Berlin

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Patients affected by neurofibromatosis type 1 (NF1) frequently show muscle weakness with unknown etiology. Here we show that, in mice, 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 accretion 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.

Date: 2024
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DOI: 10.1038/s41467-024-45618-z

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