Evaluating modified diets and dietary supplement therapies for reducing muscle lipid accumulation and improving muscle function in neurofibromatosis type 1 (NF1)

Abstract

Neurofibromatosis type 1 (NF1) is a genetic disorder that affects a range of tissue systems, however the associated muscle weakness and fatigability can have a profound impact on quality of life. Prior studies using the limb-specific Nf1 knockout mouse (Nf1 Prx1-/-) revealed an accumulation of intramyocellular lipid (IMCL) that could be rescued by a diet supplemented with L-carnitine and enriched for medium-chain fatty acids (MCFAs). In this study we used the Nf1 Prx1-/mouse to model a range of dietary interventions designed to reduce IMCL accumulation, and analyze using other modalities including in situ muscle physiology and lipid mass spectrometry. Histological IMCL accumulation was significantly reduced by a range of treatments including L-carnitine and high MCFAs alone. A low-fat diet did not affect IMCL, but did provide improvements to muscle strength. Supplementation yielded rapid improvements in IMCL within 4 weeks, but were lost once treatment was discontinued. In situ muscle measurements were highly variable in Nf1 Prx1-/mice, attributable to the severe phenotype present in this model, with fusion of the hips and an overall small hind limb muscle size. Lipidome analysis enabled segregation of the normal and modified chow diets, and fatty acid data suggested increased muscle lipolysis with the intervention. Acylcarnitines were also affected, suggestive of a mitochondrial fatty acid oxidation disorder. These data support the theory that NF1 is a lipid storage disease that can be treated by dietary intervention, and encourages future human trials.

Head circumference and anthropometric changes and their relation to plexiform and skin neurofibromas in sporadic and familial neurofibromatosis 1 Brazilian adults: a cross-sectional study

“…Weight, BMI, WC, HC and WHR were not correlated with these lesions. Nevertheless, interestingly, previous studies showed that NF1-associated neurofibromas present neoplastic Schwann cells with lipid droplets accumulation, express leptin and have higher chances of having intermingled adipocytes than non NF1-associated neurofibromas [24,[69][70][71]. Lipid droplets accumulation and overexpression of fatty acid synthesis (FASN) were also found in MPNSTs [25].…”

Dietary intervention rescues a bone porosity phenotype in a murine model of Neurofibromatosis Type 1 (NF1)

“…The Nf1 Prx1 -/- muscle phenotype could be rescued using a dietary intervention enriched for medium-chain fatty acids (MCFAs) and L-carnitine, showing a dramatic decrease in muscle lipid (71%) and a partial improvement in grip strength [ 12 ]. A subsequent 2020 study trialed several variations of this dietary intervention [ 13 ]. This included L-carnitine and MCFAs separately and in combination, an intermittent dosing regimen (5/7 days), a mitochondrial cocktail (L-carnitine, CoQ10, creatine and riboflavin), and a low-fat diet.…”

“…While the NF1 bone phenotype has been correlated with deficient osteogenesis [ 8 ], microarray analysis examining cortical bone samples from Nf1 Prx1 -/- and Nf1 Col1 -/- did show a disruption of lipid metabolism genes [ 9 ]. To investigate the potential role of diet and dietary rescue on bone, spine and long bone specimens were analyzed from our prior study comparing the impact of different dietary interventions on Nf1 Prx1 -/- mouse muscle [ 13 ].…”

Characterization of health concerns in people with neurofibromatosis type 1

“…Recent reports suggest muscle weakness (Cornett et al, 2015; Stevenson et al, 2012) may be another under identified feature of NF1, that may be potentially treatable. Deficiencies in muscle function have been identified in NF1 patients, including decreased muscle size, muscle strength, and motor proficiency (Cornett et al, 2015; Stevenson et al, 2012; Vasiljevski et al, 2020). There is some evidence from mouse studies to suggest reduced muscle strength may be related to abnormal Ras or cAMP signaling (Sullivan et al, 2014).…”

“…There is some evidence from mouse studies to suggest reduced muscle strength may be related to abnormal Ras or cAMP signaling (Sullivan et al, 2014). Furthermore, murine studies have demonstrated accumulation of intramyocellular lipids that resolve with carnitine supplementation (Vasiljevski et al, 2020). Recently, treatment of a small cohort of children with L‐carnitine led to a significant improvement in muscle function including a 6‐min walk test, and dynamometry (Vasiljevski, 2020).…”