Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-10-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114001879 |
| _version_ | 1818646259575029760 |
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| author | Jessica Nicks Sooyeon Lee Andrew Harris Darin J. Falk Adrian G. Todd Karla Arredondo William A. Dunn, Jr. Lucia Notterpek |
| author_facet | Jessica Nicks Sooyeon Lee Andrew Harris Darin J. Falk Adrian G. Todd Karla Arredondo William A. Dunn, Jr. Lucia Notterpek |
| author_sort | Jessica Nicks |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T00:43:48Z |
| format | Article |
| id | doaj.art-7c67bd931cee420da5e511b0d6eb1443 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T00:43:48Z |
| publishDate | 2014-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-7c67bd931cee420da5e511b0d6eb14432022-12-21T22:09:57ZengElsevierNeurobiology of Disease1095-953X2014-10-0170224236Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic miceJessica Nicks0Sooyeon Lee1Andrew Harris2Darin J. Falk3Adrian G. Todd4Karla Arredondo5William A. Dunn, Jr.6Lucia Notterpek7Department of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USADepartment of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USADepartment of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USADepartment of Pediatrics, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USADepartment of Pediatrics, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USADepartment of Neuroscience, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USADepartment of Anatomy and Cell Biology, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USADepartment 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; Corresponding author at: Dept. of Neuroscience, McKnight Brain Institute, 1149 Newell Drive, Box 100244, Gainesville, FL 32610-0244, USA. Fax: +1 352 392 8347.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.http://www.sciencedirect.com/science/article/pii/S0969996114001879DemyelinationAutophagySchwann cellMyelinTrembler JCharcot–Marie–Tooth disease |
| spellingShingle | Jessica Nicks Sooyeon Lee Andrew Harris Darin J. Falk Adrian G. Todd Karla Arredondo William A. Dunn, Jr. Lucia Notterpek Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice Neurobiology of Disease Demyelination Autophagy Schwann cell Myelin Trembler J Charcot–Marie–Tooth disease |
| title | Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice |
| title_full | Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice |
| title_fullStr | Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice |
| title_full_unstemmed | Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice |
| title_short | Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice |
| title_sort | rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice |
| topic | Demyelination Autophagy Schwann cell Myelin Trembler J Charcot–Marie–Tooth disease |
| url | http://www.sciencedirect.com/science/article/pii/S0969996114001879 |
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