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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.

Type Journal
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.;
Published Date 2014-01-01
Published Volume 23
Published Issue 5
Published Pages 1250-9
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version