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PMID:25014022

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Citation

Nicks, J, Lee, S, Harris, A, Falk, DJ, Todd, AG, Arredondo, K, Dunn, WA Jr and Notterpek, L (2014) Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice. Neurobiol. Dis. 70:224-36

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 4months of age and tested monthly on the rotarod. While neither long-term feeding (8 or 10months) on rapamycin-enriched diet, or short-term injection (2months) 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.

Links

PubMed PMC4532623 Online version:10.1016/j.nbd.2014.06.023

Keywords

Animals; Charcot-Marie-Tooth Disease; Cohort Studies; Dietary Supplements; Female; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Motor Activity/drug effects; Motor Activity/physiology; Muscle, Skeletal/drug effects; Muscle, Skeletal/pathology; Muscle, Skeletal/physiopathology; Mutation; Myelin Sheath/drug effects; Myelin Sheath/pathology; Myelin Sheath/physiology; Neurons/drug effects; Neurons/pathology; Neurons/physiology; Neuroprotective Agents/administration & dosage; Peripheral Nervous System Diseases/drug therapy; Peripheral Nervous System Diseases/pathology; Peripheral Nervous System Diseases/physiopathology; Random Allocation; Rotarod Performance Test; Schwann Cells/drug effects; Schwann Cells/pathology; Schwann Cells/physiology; Sirolimus/administration & dosage; Tissue Culture Techniques

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PMP22

acts_upstream_of_or_within

GO:0022011: myelination in peripheral nervous system

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856217

P

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0048936: peripheral nervous system neuron axonogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856217

P

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0098529: neuromuscular junction development, skeletal muscle fiber

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856217

P

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0006914: autophagy

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856217

P

Seeded From UniProt

complete

MOUSE:PMP22

acts_upstream_of_or_within

GO:0008344: adult locomotory behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1856217

P

Seeded From UniProt

complete

Notes

See also

References

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