PXD017958

PXD017958 is an original dataset announced via ProteomeXchange.

Title	Cell autonomous requirement of Neurofibrimin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis
Description	Background Neurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in Neurofibromin (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 is mostly unknown. Methods To dissect the function of Nf1 in muscle, we created muscle-specific knockout mouse models for Nf1, inactivating Nf1 in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analyzed during pre-and postnatal myogenesis and muscle growth. Results Nf1Lbx1 and Nf1Myf5 animals showed only mild defects in prenatal myogenesis. Nf1Lbx1 animals were perinatally lethal, while Nf1Myf5 animals survived up to approx. 25 weeks. Nf1Myf5 animals showed decreased postnatal growth, reduced muscle size, and fast fiber atrophy. Proteome and transcriptome analysis of muscle tissue indicated decreased protein synthesis and increased proteasomal degradation, and decreased glycolytic and increased oxidative activity in muscle tissue. Real-time respirometry demonstrated enhanced oxidative metabolism in Nf1Myf5 muscles concomitant to a fiber type shift from type 2B to type 2A and type 1. Nf1Myf5 muscles showed hallmarks of mild oxidative stress and increased activation of AMPK indicating an energy deficit, increased expression of atrogenes and decreased activation of mTORC1. Proteome and transcriptome analysis indicated that oxidative fibers mainly relied on fatty acid catabolism. Inline, Nf1Myf5 animals showed 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 leads to cross-tissue communication and mobilization of lipid reserves.
HostingRepository	PRIDE
AnnounceDate	2020-10-26
AnnouncementXML	Submission_2020-10-26_01:21:11.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	David Meierhofer
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-03-10 00:12:51	ID requested
⏵ 1	2020-10-26 01:21:12	announced

Wei X, Franke J, Ost M, Wardelmann K, B, ö, rno S, Timmermann B, Meierhofer D, Kleinridders A, Klaus S, Stricker S, Cell autonomous requirement of neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis. J Cachexia Sarcopenia Muscle, 11(6):1758-1778(2020) [pubmed]

submitter keyword: Neurofibromatosis, myopathy, muscle atrophy, muscle metabolism, muscle fiber type

Sigmar Stricker
contact affiliation	Musculoskeletal Development and Regeneration Group, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
contact email	sigmar.stricker@fu-berlin.de
lab head
David Meierhofer
contact affiliation	Mass Spectrometry Facility MPIMG
contact email	meierhof@molgen.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD017958
     1. Label: PRIDE project
     2. Name: Cell autonomous requirement of Neurofibrimin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis