Dietary intervention rescues myopathy associated with neurofibromatosis type 1

Summers, Matthew A.; Rupasinghe, Thusitha; Vasiljevski, Emily R; Evesson, Frances J.; Mikulec, Kathy; Peacock, Lauren; Quinlan, Kate; Cooper, Sandra T.; Roessner, Ute; Stevenson, David A.; Little, David

doi:10.1093/hmg/ddx423

Cited by 27 publications

(41 citation statements)

References 45 publications

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“…In parallel we observed a fiber type shift from glycolytic type 2 fibers to oxidative type 2 and in part to type 1 fibers. In adult Nf1 Prx1 mice, no fiber type shift was reported [18], however this had not been quantified. During embryonic and fetal myogenesis, muscle fibers predominantly show oxidative-type gene and protein expression.…”

Section: Discussionmentioning

confidence: 97%

“…Inactivation of Nf1 in limb mesenchyme during development using Prx1 Cre recapitulated the skeletal manifestations of NF1 [15,16], but also caused an early-onset defect in embryonal myogenesis [17], providing the first evidence for a direct involvement of Nf1 in myogenesis. Postnatally, Nf1 Prx1 mice recapitulated Nf1 features as muscle weakness and fibro-fatty infiltration of muscle [17,18]. However, in this model, Nf1…”

Section: Introductionmentioning

confidence: 83%

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Cell autonomous requirement of Neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis

Wei

Franke

Ost

et al. 2020

Preprint

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BackgroundNeurofibromatosis 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 NF1associated myopathy is mostly unknown. MethodsTo 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. ResultsNf1 Lbx1 and Nf1 Myf5 animals showed only mild defects in prenatal myogenesis. Nf1 Lbx1 animals were perinatally lethal, while Nf1 Myf5 animals survived only up to approx. 25 weeks. A comprehensive phenotypic characterization of Nf1 Myf5 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. High-resolution respirometry confirmed enhanced oxidative metabolism in Nf1 Myf5 muscles, which was concomitant to a fiber type shift from type 2B to type 2A and type 1. Moreover, Nf1 Myf5 muscles showed hallmarks of decreased activation of mTORC1 and increased expression of atrogenes. Remarkably, loss of Nf1 promoted a robust activation of AMPK with a gene expression profile indicative of increased fatty acid catabolism. Additionally, we observed a strong induction of genes encoding catabolic cytokines in muscle Nf1 Myf5 animals, in line with a drastic reduction of white, but not brown adipose tissue. ConclusionsOur 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 drives cross-tissue communication and mobilization of lipid reserves.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 83%

Cell autonomous requirement of Neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis

Wei

Franke

Ost

et al. 2020

Preprint

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“…These novel findings led us to speculate that NF1 may have a key role in the regulation of muscle lipid metabolism. More recently, Summers et al published a report examining the IMCL found in Nf1 MyoD -/muscle [6]. Lipidomics identified an increase in triglycerides, diglycerides, and cholesterol esters containing long-chain fatty acids (LCFAs).…”

Section: Introductionmentioning

confidence: 99%

“…L-carnitine has previously been shown to treat muscle weakness in patients with other metabolic myopathies [7][8][9]. However, the mouse chow containing 70% octanoic acid as a MCFA source [6] is an approach that is not directly translational to dietary modification in humans. Moreover, it was unknown whether L-carnitine supplementation alone would be sufficient to produce significant reductions in muscle lipid and improvements in strength; an intervention that could be more readily adopted than changes in dietary fat intake.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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“…Intramyocellular lipid deposits have been found in both NF1 ‐deficient human and Nf1 ‐null mouse muscle, consistent with myopathy. Weakness and lipid buildup were rescued in a knockout mouse model with a medium‐chain fatty acid and carnitine‐enriched diet (Summers et al, ), suggesting a potential therapy for patients.…”

Section: Meeting Sessionsmentioning

confidence: 99%

From process to progress—2017 International Conference on Neurofibromatosis 1, Neurofibromatosis 2 and Schwannomatosis

Ferner

Elgersma

Evans

et al. 2019

American J of Med Genetics Pt A

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The neurofibromatoses are inherited, tumor suppressor disorders that are characterized by multiple, benign peripheral nerve sheath tumors and other nervous system tumors. Each disease is associated with a distinct genetic mutation and with a different pathogenesis and clinical course. Neurofibromatosis 1 (NF1) is common and epitomized by multiple neurofibromas with widespread complications. NF2 and schwannomatosis are rare diseases that are typified by multiple schwannomas that are particularly painful in people with schwannomatosis. Since 1985, the Children's Tumor Foundation (formerly the National Neurofibromatosis Foundation) has hosted an international Neurofibromatosis Conference, bringing together international participants who are focused on NF research and clinical care. The 2017 Conference, held in Washington, DC, was among the largest gatherings of NF researchers to date and included presentations from clinicians and basic scientists, highlighting new data regarding the molecular and cellular mechanisms underlying each of these diseases as well as results from clinical studies and clinical trials. This article summarizes the findings presented at the meeting and represents the current state-of-the art for NF research. the neurofibromatoses-neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis. The neurofibromatoses are inherited tumor predisposition diseases linked to mutations in distinct genes.NF1 has a birth incidence of 1 in 2,699 to 1 in 3,000 and a prevalence of 1 in 4,560 (Evans et al., 2010). For NF2, the birth incidence is 1 in 27,956 and prevalence is 1 in 50,000, and schwannomatosis has a birth incidence of 1 in 68,956 and a prevalence of 1 in 126,000 (Evans et al., 2018).In the early 1990s, the focus of neurofibromatosis research was on identifying the molecular pathways underpinning the pathophysiology of these disorders. However, recent advances in molecular biology, the development of animal models, and novel imaging techniques have been matched by an increased understanding of the clinical manifestations and natural history of these conditions. The advent of targeted disease therapy has highlighted the interdependence of the scientist and clinician and the importance of animal models in screening potential new treatments.

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Dietary intervention rescues myopathy associated with neurofibromatosis type 1

Cited by 27 publications

References 45 publications

Cell autonomous requirement of Neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis

Cell autonomous requirement of Neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis

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

From process to progress—2017 International Conference on Neurofibromatosis 1, Neurofibromatosis 2 and Schwannomatosis

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