A potential new role for myofibroblasts in remodeling of sub-rupture fatigue tendon injuries by exercise

Rebecca Bell,Nelly Andarawis-Puri,Evan L Flatow,Matthew Anderson,N Remi Gendron

doi:10.1038/s41598-018-27196-5

Rebecca Bell, Nelly Andarawis-Puri + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-27196-5

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Abstract

Tendons are ineffective at repairing sub-rupture fatigue injuries. Accordingly, we evaluated whether an exercise protocol that we have previously found to decrease structural damage kinks in fatigue damaged tendons, leads to improvement in mechanical properties. We hypothesized that exercise that promotes repair of fatigue damage will decrease apoptosis and increase the population of myofibroblasts. Rat patellar tendons underwent in vivo fatigue loading for 500 or 7200 cycles. Animals resumed cage activity for 2-weeks, then either remained cage active or began treadmill running until sacrifice at 4- or 10-weeks post-fatigue loading. Exercise following fatigue damage increased the stiffness back towards naïve levels, decreased apoptosis and increased the population of myofibroblasts. Next, proteins associated with inhibition of apoptosis (Collagen VI) or activation of myofibroblast (pSmad 2/3, fibrillin, integrin subunits αV and α5) were evaluated. Data suggests that collagen VI may not be integral to inhibition of apoptosis in this context. Exercise increased pSmad 2/3 and fibrillin in the insertion region for the 7200-cycles group. In addition, exercise decreased integrin αV and increased integrin α5 in fatigue damaged tendons. Data suggests that a decrease in apoptosis and an increase in population of myofibroblasts may be integral to remodeling of fatigue damaged tendons.

Highlights

Tendinopathy is a common musculoskeletal disease that affects the entire spectrum of society
We evaluated whether an exercise protocol that we have previously found to decrease structural damage kinks in fatigue damaged tendons, leads to improvement in mechanical properties
We have begun to evaluate the utility of physiological loading to promote remodeling in fatigue damaged tendons

Summary

Introduction

Tendinopathy is a common musculoskeletal disease that affects the entire spectrum of society. We have previously shown that one bout of moderate level fatigue loading leads to a 20% stiffness loss that is not recovered out to at least 6-weeks[9] This lack of repair is accompanied by an early increase in cell death, or apoptosis, suggesting that a decrease in the population of cells that can repair the induced fatigue injury may account for the compromised capacity of fatigue damaged tendons to repair[10]. Since myofibroblasts have been shown to play a critical role in contracture of wound healing, most typically through TGFβ pathways, we expect that they may play a similar role in re-tensioning the damaged matrix, albeit in this entirely distinct context[11,12] This notion is further corroborated by studies suggesting that myofibroblasts may contribute to crimp formation in healthy tendons[13]. We hypothesize that exercise modulates the population of myofibroblasts through modulation of integrin-based interactions with the matrix, namely integrin αV and α5, and through TGFβ pathways

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