Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice

Abstract

Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy characterized by progressive demyelination and distal muscle weakness. Abnormal expression of peripheral myelin protein 22 (PMP22) has been linked to CMT1A and is modeled by Trembler J (TrJ) mice, which carry the same leucine to proline substitution in PMP22 as affected pedigrees. Pharmacologic modulation of autophagy by rapamycin in neuron-Schwann cell explant cultures from neuropathic mice reduced PMP22 aggregate formation and improved myelination. Here we asked whether rapamycin administration by food supplementation, or intraperitoneal injection, could alleviate the neuropathic phenotype of affected mice and improve neuromuscular performance. Cohorts of male and female wild type (Wt) and TrJ mice were assigned to placebo or rapamycin treatment starting at 2 or 4 months of age and tested monthly on the rotarod. While neither long-term feeding (8 or 10 months) on rapamycin-enriched diet, or short term injection (2 months) of rapamycin improved locomotor performance of the neuropathic mice, both regimen benefited peripheral nerve myelination. Together, these results indicate that while treatment with rapamycin benefits the myelination capacity of neuropathic Schwann cells, this intervention does not improve neuromuscular function. The observed outcome might be the result of the differential response of nerve and skeletal muscle tissue to rapamycin.

Autophagy in Peripheral Neuropathy

“…My findings support the results of previous studies, which have shown that nerve injury upregulates LC3 [98,99]. Rapamycin has been shown to protect against neurodegeneration by activating autophagy [100], and improves myelination in PNS [101]. Proteomic study of the injured nerves of diabetic rats 4 weeks after surgery identified 798 proteins, and among these 193 proteins were differentially expressed.…”

Myelination and mTOR

“…In light of the novel data indicating a prodifferentiating effect of mTORC1 inhibition in SCs, rapamycin treatment may also be a therapeutic option in neuropathies in which SC differentiation is defective, often a clinically severe condition. Intriguingly, administration of rapamycin has already been shown to decrease p75 expression levels, a marker for immature and promyelinating SCs, and to increase myelin proteins and myelinated fibers in a mouse model of hereditary neuropathy (Nicks et al, 2014). Such a therapeutic approach would be potentially favored by the intrinsic biological plasticity of SCs, which—unlike OLs—are capable of dedifferentiation/demyelination and redifferentiation/remyelination (Kim, Mindos, & Parkinson, 2013).…”

Promoting peripheral myelin repair

“…In subsequent studies RM was administered to neuropathic mice either by dietary supplementation or i.p. injections (Nicks et al, 2014). In both paradigms, peripheral nerves of RM-treated neuropathic mice showed significant improvements in myelin, however without benefit to neuromuscular function (Nicks et al, 2014).…”

“…injections (Nicks et al, 2014). In both paradigms, peripheral nerves of RM-treated neuropathic mice showed significant improvements in myelin, however without benefit to neuromuscular function (Nicks et al, 2014). One explanation for this functional outcome might involve the distinct response of nerve and muscle tissue to the inhibition of mTOR (Quy et al, 2013).…”