NF1 is a critical regulator of muscle development and metabolism
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.
|ISBN||1460-2083 (Electronic) 0964-6906 (Linking)|
|Authors||Sullivan, K.; El-Hoss, J.; Quinlan, K. G.; Deo, N.; Garton, F.; Seto, J. T.; Gdalevitch, M.; Turner, N.; Cooney, G. J.; Kolanczyk, M.; North, K. N.; Little, D. G.; Schindeler, A.;|
|Publisher Name||HUMAN MOLECULAR GENETICS|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/24163128|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12444|