dc.contributor.author
Wei, Xiaoyan
dc.contributor.author
Franke, Julia
dc.contributor.author
Ost, Mario
dc.contributor.author
Wardelmann, Kristina
dc.contributor.author
Börno, Stefan
dc.contributor.author
Timmermann, Bernd
dc.contributor.author
Meierhofer, David
dc.contributor.author
Kleinridders, Andre
dc.contributor.author
Klaus, Susanne
dc.contributor.author
Stricker, Sigmar
dc.date.accessioned
2020-12-21T09:05:47Z
dc.date.available
2020-12-21T09:05:47Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/28822
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-28571
dc.description.abstract
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 of Nf1in 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.
en
dc.format.extent
21 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
Neurofibromatosis
en
dc.subject
Muscle atrophy
en
dc.subject
Muscle metabolism
en
dc.subject
Muscle fibre type
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::570 Biowissenschaften; Biologie
dc.title
Cell autonomous requirement of neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
JCSM12632
dcterms.bibliographicCitation.doi
10.1002/jcsm.12632
dcterms.bibliographicCitation.journaltitle
Journal of Cachexia, Sarcopenia and Muscle
dcterms.bibliographicCitation.number
6
dcterms.bibliographicCitation.pagestart
1758
dcterms.bibliographicCitation.pageend
1778
dcterms.bibliographicCitation.volume
11
dcterms.bibliographicCitation.url
https://doi.org/10.1002/jcsm.12632
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.affiliation.other
Institut für Chemie und Biochemie
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refubium.funding
DEAL Wiley
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
2190-6009
refubium.resourceType.provider
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