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]

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.