- Background Neurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in neurofibromin 1 (NF1). Amongst other features, NF1 patients frequently show reduced muscle mass and strength, impairing patients' mobility and increasing the risk of fall. The role of Nf1 in muscle and the cause for the NF1-associated myopathy are mostly unknown. Methods To dissect the function ofNf1in muscle, we created muscle-specific knockout mouse models for NF1, inactivatingNf1in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analysed during prenatal and postnatal myogenesis and muscle growth. Results Nf1(Lbx1)and Nf1(Myf5)animals showed only mild defects in prenatal myogenesis. Nf1(Lbx1)animals were perinatally lethal, while Nf1(Myf5)animals survived only up to approximately 25 weeks. A comprehensive phenotypic characterization of Nf1(Myf5)animals showed decreased postnatal growth, reduced muscle size, and fast fibre atrophy. Proteome and transcriptome analyses of muscle tissue indicatedBackground Neurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in neurofibromin 1 (NF1). Amongst other features, NF1 patients frequently show reduced muscle mass and strength, impairing patients' mobility and increasing the risk of fall. The role of Nf1 in muscle and the cause for the NF1-associated myopathy are mostly unknown. Methods To dissect the function ofNf1in muscle, we created muscle-specific knockout mouse models for NF1, inactivatingNf1in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analysed during prenatal and postnatal myogenesis and muscle growth. Results Nf1(Lbx1)and Nf1(Myf5)animals showed only mild defects in prenatal myogenesis. Nf1(Lbx1)animals were perinatally lethal, while Nf1(Myf5)animals survived only up to approximately 25 weeks. A comprehensive phenotypic characterization of Nf1(Myf5)animals showed decreased postnatal growth, reduced muscle size, and fast fibre atrophy. Proteome and transcriptome analyses of muscle tissue indicated decreased protein synthesis and increased proteasomal degradation, and decreased glycolytic and increased oxidative activity in muscle tissue. High-resolution respirometry confirmed enhanced oxidative metabolism in Nf1(Myf5)muscles, which was concomitant to a fibre type shift from type 2B to type 2A and type 1. Moreover, Nf1(Myf5)muscles showed hallmarks of decreased activation of mTORC1 and increased expression of atrogenes. Remarkably, loss of Nf1 promoted a robust activation of AMPK with a gene expression profile indicative of increased fatty acid catabolism. Additionally, we observed a strong induction of genes encoding catabolic cytokines in muscle Nf1(Myf5)animals, in line with a drastic reduction of white, but not brown adipose tissue. Conclusions Our results demonstrate a cell autonomous role for Nf1 in myogenic cells during postnatal muscle growth required for metabolic and proteostatic homeostasis. Furthermore, Nf1 deficiency in muscle drives cross-tissue communication and mobilization of lipid reserves.…
MetadatenAuthor details: | Xiaoyan Wei, Julia Franke, Mario OstORCiD, Kristina WardelmannORCiDGND, Stefan Börno, Bernd Timmermann, David MeierhoferORCiD, Andre KleinriddersORCiDGND, Susanne KlausORCiDGND, Sigmar StrickerORCiD |
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DOI: | https://doi.org/10.1002/jcsm.12632 |
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ISSN: | 2190-5991 |
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ISSN: | 2190-6009 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/33078583 |
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Title of parent work (English): | Journal of cachexia, sarcopenia and muscle |
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Publisher: | Wiley |
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Place of publishing: | Hoboken |
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Publication type: | Article |
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Language: | English |
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Date of first publication: | 2020/10/19 |
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Publication year: | 2020 |
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Release date: | 2022/10/05 |
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Tag: | AMPK; NF1; muscle atrophy; muscle fibre type; muscle metabolism; myopathy; neurofibromatosis |
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Volume: | 11 |
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Issue: | 6 |
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Number of pages: | 21 |
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First page: | 1758 |
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Last Page: | 1778 |
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Funding institution: | Chinese Scholarship Council (CSC)China Scholarship Council; Sonnenfeld; Stiftung Berlin; German Ministry of Education and Research (BMBF)Federal; Ministry of Education & Research (BMBF); State of Brandenburg (DZD; grant) [82DZD00302] |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
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DDC classification: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
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| 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Peer review: | Referiert |
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Publishing method: | Open Access / Gold Open-Access |
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License (German): | CC-BY-NC-ND - Namensnennung, nicht kommerziell, keine Bearbeitungen 4.0 International |
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