Intermittent fasting alleviates the neuropathic phenotype in a mouse model of Charcot–Marie–Tooth disease

Abstract

Charcot-Marie-Tooth type 1A (CMT1A) neuropathies linked to the misexpression of peripheral myelin protein 22 (PMP22) are progressive demyelinating disorders of the peripheral nervous system. In this study we asked whether dietary restriction by intermittent fasting (IF) could alleviate the neuropathic phenotype in the Trembler J (TrJ) mouse model of CMT1A. Our results show that neuropathic mice kept on a five month long IF regimen had improved locomotor performance compared to ad libitum (AL) fed littermates. The functional benefits of this dietary intervention are associated with an increased expression of myelin proteins combined with a thicker myelin sheath, less redundant basal lamina, and a reduction in aberrant Schwann cell proliferation. These morphological improvements are accompanied by a decrease in PMP22 protein aggregates, and enhanced expression of cytosolic chaperones and constituents of the autophagy-lysosomal pathway. These results indicate that dietary restriction is beneficial for peripheral nerve function in TrJ neuropathic mice, as it promotes the maintenance of locomotor performance.

Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling

“…Our data together with studies focusing on effects of dietary modulation (9) suggest that SC metabolism could influence myelination via alterations in Sirt2 activity. These results are particularly relevant for diabetic neuropathy where it is believed that reparative responses occur in response to continual nerve damage (48).…”

“…For example, numerous studies indicate that nerve regeneration and myelination after injury are impaired in diabetic neuropathy (5)(6)(7)(8). Moreover, SC myelination can be altered by changes in nutrition (9,10). These findings give rise to the idea that abnormal metabolic conditions could lead to aberrant myelination via abnormalities in SC function.…”

Exercise, Energy Intake, Glucose Homeostasis, and the Brain

“…IER increases the resistance of hippocampal pyramidal neurons and striatal medium spiny neurons to degeneration induced by the neurotoxins kainic acid and 3-nitropropionic acid in rat models relevant to temporal lobe epilepsy and Huntington's disease, respectively (Bruce-Keller et al, 1999). IER also protects dopaminergic neurons and preserves motor function in a mitochondrial toxin-based model of Parkinson's disease (Duan and Mattson, 1999), and is also beneficial in gene mutation-based models of Alzheimer's (Halagappa et al, 2007), Huntington's (Duan et al, 2003, and Charcot-Marie-Tooth (Madorsky et al, 2009) diseases. In addition, energy restriction can protect the brain and spinal cord against acute traumatic and ischemic injury (Davis et al, 2008;Arumugam et al, 2010;Jeong et al, 2011), perhaps by bolstering neurotrophic signaling, antioxidant defenses, protein chaperones, autophagy, and DNA repair (Longo and Mattson, 2014).…”

“…For example, IER in mice results in increased levels of fibroblast growth factor 2, heme oxygenase 1 (an antioxidant enzyme), and the protein chaperones HSP70 and GRP78 in the cerebral cortex and striatum (Arumugam et al, 2010). In peripheral nerves, IER upregulates autophagy, which may protect cells against the deleterious effects of mitochondrial dysfunction (Madorsky et al, 2009).…”

Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

“…Autophagy, stimulated via fasting or rapamycin, or an increase in the heat shock response, can improve the phenotype of some PMP22-related neuropathies (Fortun et al, 2007;Rangaraju et al, 2008Rangaraju et al, , 2010Madorsky et al, 2009), and salubrinal enhancement of the integrated stress response (ISR) ameliorated hypomyelination and oligodendrocyte loss in cultured hippocampal slices exposed to IFN- (Lin et al, 2008).…”