Pathophysiology and Treatment of Muscle Weakness in NF1

Posted January 8, 2019

Aaron Schindeler, Ph.D., The Children's Hospital at Westmead

  Aaron Schindeler, Ph.D., The Children's Hospital at Westmead
Dr. Aaron Schindeler,
The Children's Hospital at Westmead

Neurofibromatosis type 1 (NF1) is a genetic syndrome in which neurofibromin-deficient cells are overactive in the Ras-MEK-ERK signaling pathway. Current clinical trials are focused on using MEK inhibitors for tumor treatment; however, tumors are not the only manifestation of NF1. This syndrome may also affect the musculoskeletal system and is associated with bone dysplasias, spinal malformations, failure to repair long bones after fracture, muscle weakness, and low muscle tone (hypotonia). In previous studies, mice with a loss of neurofibromin functionality (Nf1-/-) in their muscles also exhibited different metabolic levels. Dr. Aaron Schindeler received a Fiscal Year 2013 Neurofibromatosis Research Program Exploration - Hypothesis Development Award to investigate whether a MEK inhibitor or dietary changes may also have therapeutic value for the muscular issues of conditional knockout Nf1-/- mice.

The skeletal muscle knockout (Nf1MyoD-/-) and limb embryonic tissue knockout (Nf1Prx1-/-) mouse models were used in a study [1] from Dr. Schindeler’s group that focused on metabolism and intramyocellular lipids for possible dietary interventions. Muscle specimens from both versions of knockout Nf1-/- mice were found to be enriched with long-chain fatty acids (LCFA) containing neutral lipids, which suggested an impaired LCFA metabolism. A genetic profile of Nf1MyoD-/- muscle tissue extracts revealed alterations in genes associated with metabolism and cell signaling. Conversely, Nf1Prx1-/- expressed the same features as human NF1 muscle disease, including weakness and lipid storage. These different insights led to evaluating a diet of reduced LCFAs and increased medium-chained fatty acids with L-carnitine in mice. After 8 weeks of this diet, Nf1Prx1-/- mice showed a 45% increase in grip strength and a 71% decrease in intramyocellular lipid staining compared to their control-diet littermates. Furthermore, protein and histologic analysis of muscle biopsies from six individuals with NF1 confirm the presence of intramyocellular lipids in muscle tissue.

In the most recent study [2], Dr. Schindeler’s team used Nf1MyoD-/- and Nf1Prx1-/- mice to test the capacity of PD0325901, a MEK inhibitor, to influence fat droplets stored in muscle cells. Accumulation of this fat, called intramyocellular lipid, has been associated with neurofibromin-deficiency. They learned that dosing pregnant mice with PD0325901 could modify the developmental muscle phenotype of the Nf1MyoD-/- mice, but not the Nf1Prx1-/- mice. This finding supports the idea that the MEK/ERK-dependent mechanism underlies NF1 muscle metabolism during development. However, the data does not support MEK inhibitor therapy for treating individuals with established NF1-associated muscle weakness.

The collective evidence from this work provides strong proof of principle that treatments affecting lipid metabolism will be able to ameliorate the muscle symptoms of NF1. This research has yielded important insights into both the mechanisms of disease and novel therapies. There is hope to expand this research into human studies to confirm dietary influence as well as explore other lifestyle factors that may cause NF1 muscle weakness and lipid accumulation. In 2019 Dr. Schindeler’s team is commencing a small clinical trial for L-carnitine supplementation in children with NF1 to determine whether this intervention improves quality of life and functional outcomes.


[1] Summers MA, Rupasinghe T, Vasiljevski ER, et al. 2018. Dietary intervention rescues myopathy associated with neurofibromatosis type 1. Hum Mol Genet 27(4):577-588. doi: 10.1093/hmg/ddx423.

[2] Summers MA, Vasiljevski ER, Mikulec K, et al. 2018. Developmental dosing with a MEK inhibitor (PD0325901) rescues myopathic features of the muscle-specific but not limb-specific Nf1 knockout mouse. Mol Genet Metab PMID:29477258.


Public and Technical Abstracts: Pathophysiology and Treatment of Muscle Weakness in NF1

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Last updated Thursday, May 26, 2022