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AMPK signaling is dysregulated in human tendinopathy and loss of AMPKα1 leads to cell, matrix and mechanical dysfunction in mouse Achilles tendon

ABSTRACT: Tendinopathy is a tendon disorder that is caused by the failure to self-repair and has many pathological characteristics such as disorganized ECM and decreased cell viability. We have identified a possible target to combat these changes, AMPK, an energy stress sensor that was shown to maintain intracellular homeostasis. Through bulk RNA sequencing of healthy and tendinopathic tendons from humans we have identified a novel finding of downregulation of AMPK signaling in the tendinopathic samples which suggests AMPK plays a role in tendon homeostasis. Our studies utilizing a conditional knock-out of Prkaa1 in tendon in mice showed that loss of AMPK results in degenerative ECM, impaired biomechanical properties and increased cellular senescence in Achilles tendon through the lifespan. Additionally, we found that exercise can delay senescence onset independent of AMPK. These findings highlight the importance of energy metabolism in tendon health which will assist in understanding the onset and progression of tendinopathy.

ORGANISM(S): Mus musculus

PROVIDER: GSE292357 | GEO | 2026/06/01

REPOSITORIES: GEO

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AMPK signaling is dysregulated in human tendinopathy and loss of AMPKα1 leads to cell, matrix and mechanical dysfunction in mouse Achilles tendon II

Project description:Tendinopathy is a tendon disorder that is caused by the failure to self-repair and has many pathological characteristics such as disorganized ECM and decreased cell viability. We have identified a possible target to combat these changes, AMPK, an energy stress sensor that was shown to maintain intracellular homeostasis. Through bulk RNA sequencing of healthy and tendinopathic tendons from humans we have identified a novel finding of downregulation of AMPK signaling in the tendinopathic samples which suggests AMPK plays a role in tendon homeostasis. Our studies utilizing a conditional knock-out of Prkaa1 in tendon in mice showed that loss of AMPK results in degenerative ECM, impaired biomechanical properties and increased cellular senescence in Achilles tendon through the lifespan. Additionally, we found that exercise can delay senescence onset independent of AMPK. These findings highlight the importance of energy metabolism in tendon health which will assist in understanding the onset and progression of tendinopathy.

2026-06-01 | GSE293788 | GEO

AMPK signaling is dysregulated in human tendinopathy and loss of AMPKα1 leads to cell, matrix and mechanical dysfunction in mouse Achilles tendon [RNAseq_AMPK_WheelRunning]

2026-06-01 | GSE292517 | GEO

Analysis of Human Tendinopathy Gene Expression

Project description:Chronic tendon injuries, also known as tendinopathy, are common among professional and recreational athletes. These injuries result in a significant amount of morbidity and health care expenditure and yet little is known about the molecular mechanism leading to tendinopathy. We have used histological evaluation and molecular profiling to determine the gene expression changes in 23 human patients undergoing surgical procedures for the treatment of chronic tendinopathy. Diseased tendons have altered extracellular matrix, fiber disorientation, increased cellular content and vasculature and the absence of inflammatory cells. Global gene expression profiling identified 1783 transcripts with significant different expression patterns in the diseased tendons. Global pathway analysis further suggests altered expression of extracellular matrix proteins and the lack of an appreciable inflammatory response. We have identified pathways and genes regulated in tendinopathy samples that will help contribute to the understanding of the disease towards the development of novel therapeutics. A prospective study was initiated to collect tissue from patients undergoing surgery as standard of care for tendinopathy. Biopsies (~3mm^3) of diseased tendons as well as a section of grossly normal appearing tendon were collected from 23 patients. Written informed consent was obtained from all patients prior to any study related procedure.

2011-06-07 | E-GEOD-26051 | biostudies-arrayexpress

Characteristics of tendinopathy development in humans

Project description:Overuse injuries of tendon (tendinopathy) represents a significant musculoskeletal health problem, but its pathogenesis is only sparsely understood. We investigated the characteristics behind the development of tendinopathy in humans that had either early phase (1-2 months of symptoms, n=14) (ET) or more chronic (> 3 months, n=16) (CT) patella tendinopathy, vs healthy subjects (n=15) (CTRL). We found that pain symptoms rose and function declined with duration of injury, and that it was correlated to tendon size measured with MRI (3T and 7T). Tendon blood flow (US Doppler) increased gradually over the duration of tendinopathy, whereas peritendinous flow only rose in CT. Histological mapping (traditional multiplex and Cell Dive) of tendon vasculature showed marked changes only in CT, indicating that early in tendinopathy flow is increased in existing vessels whereas angiogenesis (both rise in vessel size and density) is a late phenomenon, and that tendinopathy leads to perivascular cell re-cruitment and expansion of lymphatic vessels. Further, matrisome analysis (proteomics) re-vealed that most matrix protein regulation occurs rather late in tendinopathy. It is concluded that the early phase of tendinopathy is dominated by pain symptoms that are correlated with tendon swelling together with increased blood flow due to flow regulation, whereas the more chronic state of tendinopathy is characterized by angiogenesis, and protein changes in the matrisome.

2026-03-02 | PXD062414 | Pride

CTRP3 exacerbates tendinopathy by dysregulating tendon stem cell differentiation and altering extracellular matrix composition [array]

Project description:Tendinopathy, the most common disorder affecting tendons, is characterized by chronic disorganization of the tendon matrix, which eventually leads to tendon tear and rupture. The goal of this study was to identify a rational molecular target whose blockade can serve as a potential therapeutic intervention for tendinopathy. We identified C1q/TNF-related protein-3 (CTRP3) as a markedly upregulated cytokine in human and rodent tendinopathy. Overexpression of CTRP3 enhanced the progression of tendinopathy by accumulating cartilaginous proteoglycans and degenerating collagenous fibers in the mouse tendon, whereas CTRP3 knockdown suppressed the tendinopathy pathogenesis. Functional blockade of CTRP3 using a neutralizing antibody ameliorated overuse-induced tendinopathy of the Achilles and rotator cuff tendons. Mechanistically, CTRP3 elicited a transcriptomic pattern that stimulates abnormal differentiation of tendon stem/progenitor cells (TSPCs) and ectopic chondrification in tendons, as an effect linked to activation of Akt signaling. Collectively, we reveal an essential role for CTRP3 in tendinopathy and propose a potential therapeutic strategy for the treatment of tendinopathy.

2021-10-02 | GSE180368 | GEO

CTRP3 exacerbates tendinopathy by dysregulating tendon stem cell differentiation and altering extracellular matrix composition [seq]

2021-10-02 | GSE181172 | GEO

Analysis of Human Tendinopathy Gene Expression

2011-06-07 | GSE26051 | GEO

Hypoxia-inducible factor 1a and Hypoxia in Tendon Fibroblasts

Project description:Tendons are soft, connective tissues that are essential for joint stability and mobility. Tendons are susceptible to injury, such as rupture and tendinopathy, and limited therapeutic strategies are available to restore native structure and function. The inability to restore adult tendon function is largely due to the limited capacity for tendon fibroblasts (TFs) to regenerate or remodel their surrounding extracellular matrix (ECM). Our preliminary findings show that the embryonic Achilles tendon in mice is hypoxic, suggesting low oxygen availability drives ECM deposition by TFs in the developing tendon. Postnatally, tendon structure and function rely on expression of hypoxia inducible factor-1α (HIF-1α) by TFs. Yet, overexpression of HIF-1α has been observed in biopsies of patients with tendinopathy, introducing a gap in our understanding of the role of HIF-1α and hypoxia in tendon development and disease. The overarching objective of our research is to identify how oxygen and HIF-1α contribute to tendon extracellular matrix deposition. We isolated TFs from wild-type and HIF-1α knockout transgenic murine tail tendon, then used controlled tissue culture conditions to adjust oxygen availability while measuring the temporal response of TFs. We used RNA-sequencing approaches to identify transcriptional changes in tendon cells due to oxygen and/or HIF-1α availability. Our RNA-sequencing analyses revealed hypoxia and HIF-1α contribute to tendon fibroblast gene expression of genes affiliated with cell adhesion, proliferation, angiogenesis, actin cytoskeleton, collagen fibril organization, and tendon-ECM composition and alignment.

2026-05-31 | GSE328685 | GEO

Genome-wide alterations in DNA methylation identify Leprel2, Foxf1, Mmp25, Igfbp6 and Peg12 as disease-associated genes in murine Achilles tendinopathy

Project description:We partnered with Zymo Research, Inc. to detect genome-wide methylation changes associated with the initiation and progression of tendinopathy induced by TGF-β1 in a murine Achilles tendon model. All genes identified as significantly differentially methylated were present in only one experimental group showing that both the gene identified and its modified methylation status are dependent on the injury time-course and activity level. In summary, we identified five genes (Leprel2, Foxf1, Mmp25, Igfbp6 and Peg12) which demonstrate significant relevance to tendon biology with three exhibiting functions in collagen fibril organization. We postulate that a study of the molecular genomics of these genes in animal and human tendon could further delineate the pathogenesis of this multifactorial disease.

2016-08-17 | GSE80396 | GEO

The investigation of genes among normal tenocytes and inflammtory tenocytes

Project description:Tendinopathy is a common disease of the musculoskeletal system, however, the mechanism of tendinopathy has not yet been elucidated, and there are no clear conclusions about the changes in gene expression within tendinopathy. In order to better investigate the mechanisms inherent to the development of tendinopathy, we performed RNA sequencing on normal tendon cells and inflammatory tendon cells

2024-02-05 | GSE253913 | GEO

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