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Introduction: Numerous synthetic, hybrid, and biological grafts and conduits have been deployed to facilitate axonal regeneration across peripheral nerve gaps. Though some strategies have showed promise, larger gaps continue to be an unsolved clinical challenge. Recent evidence suggests that tension-based strategies offer a promising alternative approach to nerve repair. However, whether and to what degree severed peripheral nerves tolerate and accommodate tension, especially in the critical early stages of intervention, is less clear.Methods: In this study, we evaluated a number of immuno-histochemical outcomes to test the hypothesis that injured rat sciatic nerves accommodate strains of up to 20%, a deformation magnitude that exceeds oft-quoted thresholds for nerve damage. We also assessed the possibility of integrating tension with conduit-based approaches for nerve repair.Results and Discussion: There were no deficits in axonal, basal laminar, or extracellular matrix morphology with tension, though proximal and distal stumps of nerves in all experimental groups displayed abnormal morphology in proximity to the site of injury. Axons of stretched nerves successfully grew through guidance conduits into the distal stump within 6 weeks of repair, thus demonstrating the feasibility of combining tension- and conduit-based regenerative strategies.

Supplemental material, DS_10.1177_0363546518769267 for Fatty Infiltration Is a Prognostic Marker of Muscle Function After Rotator Cuff Tear by Ana P. Valencia, Jim K. Lai, Shama R. Iyer, Katherine L. Mistretta, Espen E. Spangenburg, Derik L. Davis, Richard M. Lovering and Mohit N. Gilotra in The American Journal of Sports Medicine

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 β-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 β3-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.