\u03b21 integrin, ILK and mTOR regulate collagen synthesis in mechanically loaded tendon cells

Rouhollah Mousavizadeh,Vincent Duronio,Robert G Mccormack,Payman Hojabrpour,Seyed Mehdi Jafarnejad,Paul C Mcdonald,Shoukat Dedhar,Felipe Eltit,Alex Scott

doi:10.1038/s41598-020-69267-6

Rouhollah Mousavizadeh, Vincent Duronio + Show 7 more

Open Access

https://doi.org/10.1038/s41598-020-69267-6

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Abstract

Tendons are specialized tissues composed primarily of load-responsive fibroblasts (tenocytes) embedded in a collagen-rich extracellular matrix. Habitual mechanical loading or targeted exercise causes tendon cells to increase the stiffness of the extracellular matrix; this adaptation may occur in part through collagen synthesis or remodeling. Integrins are likely to play an important role in transmitting mechanical stimuli from the extracellular matrix to tendon cells, thereby triggering cell signaling pathways which lead to adaptive regulation of mRNA translation and protein synthesis. In this study, we discovered that mechanical stimulation of integrin β1 leads to the phosphorylation of AKT, an event which required the presence of integrin-linked kinase (ILK). Repetitive stretching of tendon cells activates the AKT and mTOR pathways, which in turn regulates mRNA translation and collagen expression. These results support a model in which integrins are an upstream component of the mechanosensory cellular apparatus, regulating fundamental tendon cell functions relevant to exercise-induced adaptation and mechanotherapy.

Highlights

Tendons are specialized tissues composed primarily of load-responsive fibroblasts embedded in a collagen-rich extracellular matrix
In certain cell types, mechanical stimulation has been shown to trigger a cascade of AKT/ mTOR signaling which regulates the rate of mRNA translation9. mTOR plays a major role in regulation of protein synthesis in mechanically induced skeletal muscles and c hondrocytes[1,2]
This study found that mechanical loading stimulates collagen synthesis in tendon cells by activating a signaling pathway involving β1 integrin, integrin-linked kinase (ILK), AKT, and mTOR

Summary

Introduction

Tendons are specialized tissues composed primarily of load-responsive fibroblasts (tenocytes) embedded in a collagen-rich extracellular matrix. Integrins are likely to play an important role in transmitting mechanical stimuli from the extracellular matrix to tendon cells, thereby triggering cell signaling pathways which lead to adaptive regulation of mRNA translation and protein synthesis. The resident fibroblasts in tendon tissue (tenocytes) respond to mechanical stimuli by altering their gene and protein expression p rofiles[1] Cell surface proteins such as integrins have been suggested to transmit physical stimuli from the tendon ECM to regulate intracellular signaling pathways and gene expression[2]. We have investigated the role of β1 integrin and ILK in the activation of the AKT/mTOR pathway, and the role of AKT/mTOR in the subsequent expression and translation of collagen in human tendon cells We found that these factors play a key role in the adaptive response of tendon cells to mechanical loading

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