TY - JOUR

T1 - Disruption of day-to-night changes in circadian gene expression with chronic tendinopathy

AU - Yeung, Ching-Yan Chloé

AU - Svensson, René B.

AU - Yurchenko, Kateryna

AU - Malmgaard-Clausen, Nikolaj M.

AU - Tryggedsson, Ida

AU - Lendal, Marius

AU - Jokipii-Utzon, Anja

AU - Olesen, Jens L.

AU - Lu, Yinhui

AU - Kadler, Karl E.

AU - Schjerling, Peter

AU - Kjær, Michael

N1 - Publisher Copyright: © 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

PY - 2023

Y1 - 2023

N2 - Abstract: Overuse injury in tendon tissue (tendinopathy) is a frequent and costly musculoskeletal disorder and represents a major clinical problem with unsolved pathogenesis. Studies in mice have demonstrated that circadian clock-controlled genes are vital for protein homeostasis and important in the development of tendinopathy. We performed RNA sequencing, collagen content and ultrastructural analyses on human tendon biopsies obtained 12 h apart in healthy individuals to establish whether human tendon is a peripheral clock tissue and we performed RNA sequencing on patients with chronic tendinopathy to examine the expression of circadian clock genes in tendinopathic tissues. We found time-dependent expression of 280 RNAs including 11 conserved circadian clock genes in healthy tendons and markedly fewer (23) differential RNAs with chronic tendinopathy. Further, the expression of COL1A1 and COL1A2 was reduced at night but was not circadian rhythmic in synchronised human tenocyte cultures. In conclusion, day-to-night changes in gene expression in healthy human patellar tendons indicate a conserved circadian clock as well as the existence of a night reduction in collagen I expression. (Figure presented.). Key points: Tendinopathy is a major clinical problem with unsolved pathogenesis. Previous work in mice has shown that a robust circadian rhythm is required for collagen homeostasis in tendons. The use of circadian medicine in the diagnosis and treatment of tendinopathy has been stifled by the lack of studies on human tissue. Here, we establish that the expression of circadian clock genes in human tendons is time dependent, and now we have data to corroborate that circadian output is reduced in diseased tendon tissues. We consider our findings to be of significance in advancing the use of the tendon circadian clock as a therapeutic target or preclinical biomarker for tendinopathy.

AB - Abstract: Overuse injury in tendon tissue (tendinopathy) is a frequent and costly musculoskeletal disorder and represents a major clinical problem with unsolved pathogenesis. Studies in mice have demonstrated that circadian clock-controlled genes are vital for protein homeostasis and important in the development of tendinopathy. We performed RNA sequencing, collagen content and ultrastructural analyses on human tendon biopsies obtained 12 h apart in healthy individuals to establish whether human tendon is a peripheral clock tissue and we performed RNA sequencing on patients with chronic tendinopathy to examine the expression of circadian clock genes in tendinopathic tissues. We found time-dependent expression of 280 RNAs including 11 conserved circadian clock genes in healthy tendons and markedly fewer (23) differential RNAs with chronic tendinopathy. Further, the expression of COL1A1 and COL1A2 was reduced at night but was not circadian rhythmic in synchronised human tenocyte cultures. In conclusion, day-to-night changes in gene expression in healthy human patellar tendons indicate a conserved circadian clock as well as the existence of a night reduction in collagen I expression. (Figure presented.). Key points: Tendinopathy is a major clinical problem with unsolved pathogenesis. Previous work in mice has shown that a robust circadian rhythm is required for collagen homeostasis in tendons. The use of circadian medicine in the diagnosis and treatment of tendinopathy has been stifled by the lack of studies on human tissue. Here, we establish that the expression of circadian clock genes in human tendons is time dependent, and now we have data to corroborate that circadian output is reduced in diseased tendon tissues. We consider our findings to be of significance in advancing the use of the tendon circadian clock as a therapeutic target or preclinical biomarker for tendinopathy.

KW - chronomatrix

KW - circadian clock

KW - collagen

KW - electron microscopy

KW - human

KW - RNAseq

KW - tendinopathy

KW - tendon

U2 - 10.1113/JP284083

DO - 10.1113/JP284083

M3 - Journal article

C2 - 36810732

AN - SCOPUS:85150216972

JO - The Journal of Physiology

JF - The Journal of Physiology

SN - 0022-3751

ER -