title: 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 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.
authors.affiliation: Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Nicks
authors.affiliation: Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Sooyeon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Harris
authors.affiliation: Department of Pediatrics, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Falk
authors.affiliation: Department of Pediatrics, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Adrian G
authors.initials: AG
authors.lastname: Todd
authors.affiliation: Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Karla
authors.initials: K
authors.lastname: Arredondo
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Dunn
authors.affiliation: Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA; Department of Neurology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA; Department of Anatomy and Cell Biology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA. Electronic address: notterpek@ufl.edu.
authors.forename: Lucia
authors.initials: L
authors.lastname: Notterpek
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease; D015331:Cohort Studies; D019587:Dietary Supplements; D005260:Female; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011897:Random Allocation; D045442:Rotarod Performance Test; D012583:Schwann Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D020123:Sirolimus / Q000008:administration & dosage*; D046509:Tissue Culture Techniques
chemical_list: D018696:Neuroprotective Agents; D020123:Sirolimus
keywords: Autophagy; Charcot–Marie–Tooth disease; Demyelination; Myelin; Schwann cell; Trembler J