title: NF1 is a critical regulator of muscle development and metabolism.
abstract: There is emerging evidence for reduced muscle function in children with neurofibromatosis type 1 (NF1). We have examined three murine models featuring NF1 deficiency in muscle to study the effect on muscle function as well as any underlying pathophysiology. The Nf1(+/-) mouse exhibited no differences in overall weight, lean tissue mass, fiber size, muscle weakness as measured by grip strength or muscle atrophy-recovery with limb disuse, although this model lacks many other characteristic features of the human disease. Next, muscle-specific knockout mice (Nf1muscle(-/-)) were generated and they exhibited a failure to thrive leading to neonatal lethality. Intramyocellular lipid accumulations were observed by electron microscopy and Oil Red O staining. More mature muscle specimens lacking Nf1 expression taken from the limb-specific Nf1Prx1(-/-) conditional knockout line showed a 10-fold increase in muscle triglyceride content. Enzyme assays revealed a significant increase in the activities of oxidative metabolism enzymes in the Nf1Prx1(-/-) mice. Western analyses showed increases in the expression of fatty acid synthase and the hormone leptin, as well as decreased expression of a number of fatty acid transporters in this mouse line. These data support the hypothesis that NF1 is essential for normal muscle function and survival and are the first to suggest a direct link between NF1 and mitochondrial fatty acid metabolism.
authors.affiliation: Orthopaedic Research & Biotechnology Unit and.
authors.forename: Kate
authors.initials: K
authors.lastname: Sullivan
authors.forename: Jad
authors.initials: J
authors.lastname: El-Hoss
authors.forename: Kate G R
authors.initials: KG
authors.lastname: Quinlan
authors.forename: Nikita
authors.initials: N
authors.lastname: Deo
authors.forename: Fleur
authors.initials: F
authors.lastname: Garton
authors.forename: Jane T C
authors.initials: JT
authors.lastname: Seto
authors.forename: Marie
authors.initials: M
authors.lastname: Gdalevitch
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.forename: Mateusz
authors.initials: M
authors.lastname: Kolanczyk
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.forename: David G
authors.initials: DG
authors.lastname: Little
authors.forename: Aaron
authors.initials: A
authors.lastname: Schindeler
mesh_terms: D000818:Animals; D001835:Body Weight; D001862:Bone Resorption / Q000235:genetics; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005804:Genes, Lethal; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D053580:Muscle Strength / Q000235:genetics; D009132:Muscles / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000378:metabolism*; D025542:Neurofibromin 1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D009929:Organ Size
chemical_list: D025542:Neurofibromin 1