PMID- 28250148 OWN - NLM STAT- MEDLINE DCOM- 20180305 LR - 20230803 IS - 1522-1598 (Electronic) IS - 0022-3077 (Print) IS - 0022-3077 (Linking) VI - 117 IP - 5 DP - 2017 May 1 TI - mTOR regulates peripheral nerve response to tensile strain. PG - 2075-2084 LID - 10.1152/jn.00257.2016 [doi] AB - While excessive tensile strain can be detrimental to nerve function, strain can be a positive regulator of neuronal outgrowth. We used an in vivo rat model of sciatic nerve strain to investigate signaling mechanisms underlying peripheral nerve response to deformation. Nerves were deformed by 11% and did not demonstrate deficits in compound action potential latency or amplitude during or after 6 h of strain. As revealed by Western blotting, application of strain resulted in significant upregulation of mammalian target of rapamycin (mTOR) and S6 signaling in nerves, increased myelin basic protein (MBP) and beta-actin levels, and increased phosphorylation of neurofilament subunit H (NF-H) compared with unstrained (sham) contralateral nerves (P < 0.05 for all comparisons, paired two-tailed t-test). Strain did not alter neuron-specific beta3-tubulin or overall nerve tubulin levels compared with unstrained controls. Systemic rapamycin treatment, thought to selectively target mTOR complex 1 (mTORC1), suppressed mTOR/S6 signaling, reduced levels of MBP and overall tubulin, and decreased NF-H phosphorylation in nerves strained for 6 h, revealing a role for mTOR in increasing MBP expression and NF-H phosphorylation, and maintaining tubulin levels. Consistent with stretch-induced increases in MBP, immunolabeling revealed increased S6 signaling in Schwann cells of stretched nerves compared with unstretched nerves. In addition, application of strain to cultured adult dorsal root ganglion neurons showed an increase in axonal protein synthesis based on a puromycin incorporation assay, suggesting that neuronal translational pathways also respond to strain. This work has important implications for understanding mechanisms underlying nerve response to strain during development and regeneration.NEW & NOTEWORTHY Peripheral nerves experience tensile strain (stretch) during development and movement. Excessive strain impairs neuronal function, but moderate strains are accommodated by nerves and can promote neuronal growth; mechanisms underlying these phenomena are not well understood. We demonstrated that levels of several structural proteins increase following physiological levels of nerve strain and that expression of a subset of these proteins is regulated by mTOR. Our work has important implications for understanding nerve development and strain-based regenerative strategies. CI - Copyright (c) 2017 the American Physiological Society. FAU - Love, James M AU - Love JM AD - Fischell Department of Bioengineering, University of Maryland, College Park, Maryland. FAU - Bober, Brian G AU - Bober BG AD - Department of Bioengineering, University of California-San Diego, La Jolla, California. FAU - Orozco, Elisabeth AU - Orozco E AD - Department of Orthopaedic Surgery, University of California-San Diego, La Jolla, California. AD - Veterans Affairs San Diego Healthcare System, San Diego, California; and. FAU - White, Amanda T AU - White AT AD - Department of Orthopaedic Surgery, University of California-San Diego, La Jolla, California. FAU - Bremner, Shannon N AU - Bremner SN AD - Department of Orthopaedic Surgery, University of California-San Diego, La Jolla, California. AD - Veterans Affairs San Diego Healthcare System, San Diego, California; and. FAU - Lovering, Richard M AU - Lovering RM AUID- ORCID: 0000-0002-9899-5071 AD - Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland. FAU - Schenk, Simon AU - Schenk S AD - Department of Orthopaedic Surgery, University of California-San Diego, La Jolla, California. FAU - Shah, Sameer B AU - Shah SB AD - Department of Bioengineering, University of California-San Diego, La Jolla, California; sbshah@ucsd.edu. AD - Department of Orthopaedic Surgery, University of California-San Diego, La Jolla, California. AD - Veterans Affairs San Diego Healthcare System, San Diego, California; and. LA - eng GR - I01 RX001471/RX/RRD VA/United States GR - R01 AR059179/AR/NIAMS NIH HHS/United States GR - T32 GM007752/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20170301 PL - United States TA - J Neurophysiol JT - Journal of neurophysiology JID - 0375404 RN - 0 (Actins) RN - 0 (Myelin Basic Protein) RN - 0 (Tubulin) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) SB - IM MH - Actins/metabolism MH - Animals MH - Cells, Cultured MH - Mechanistic Target of Rapamycin Complex 1/*metabolism MH - *Mechanotransduction, Cellular MH - Myelin Basic Protein/metabolism MH - Peripheral Nerves/cytology/*metabolism/physiology MH - Rats MH - Rats, Sprague-Dawley MH - Schwann Cells/metabolism/physiology MH - Tensile Strength MH - Tubulin/metabolism PMC - PMC5434482 OTO - NOTNLM OT - cytoskeleton OT - mTOR OT - myelin OT - neurofilament OT - peripheral nerve OT - rapamycin OT - strain EDAT- 2017/03/03 06:00 MHDA- 2018/03/06 06:00 PMCR- 2018/05/01 CRDT- 2017/03/03 06:00 PHST- 2016/03/28 00:00 [received] PHST- 2017/02/09 00:00 [revised] PHST- 2017/02/25 00:00 [accepted] PHST- 2017/03/03 06:00 [pubmed] PHST- 2018/03/06 06:00 [medline] PHST- 2017/03/03 06:00 [entrez] PHST- 2018/05/01 00:00 [pmc-release] AID - jn.00257.2016 [pii] AID - JN-00257-2016 [pii] AID - 10.1152/jn.00257.2016 [doi] PST - ppublish SO - J Neurophysiol. 2017 May 1;117(5):2075-2084. doi: 10.1152/jn.00257.2016. Epub 2017 Mar 1.