{"doi":"10.1101/2025.01.31.635920","title":"AMP-activated protein kinase (AMPK) is essential for tendon homeostasis and prevents premature senescence and ectopic calcification","abstract":"Tendinopathy is a debilitating tendon disorder affecting millions of people, characterized by pain, swelling, and diminished biomechanical properties. While the precise mechanisms underlying tendon homeostasis remain unclear, metabolic regulation plays a critical role. In this study, we combine transcriptomic analysis of human tendinopathic samples with a conditional mouse model in which Prkaa1 (encoding AMPKα1) is selectively deleted in tendon progenitors to elucidate the role of AMPK signaling in tendon homeostasis. RNA sequencing of diseased human tendons revealed downregulation of key metabolic genes, including several involved in the mitochondrial electron transport chain and AMPK signaling pathways, alongside an increase in markers associated with senescence and a secretory inflammatory profile. In parallel, mice with loss of Prkaa1 function exhibited normal postnatal development; however, by one month of age, tendons demonstrated widespread transcriptional alterations related to cell cycle regulation and ECM organization. By three months, AMPKα1-deficient tendons showed significant reductions in mechanical strength and increased expression of senescence markers p21 and p16, progressing to prominent ectopic calcification with age. In vitro studies further confirmed that tendon fibroblasts lacking AMPKα1 have altered ECM substrate adhesion profiles. Importantly, voluntary exercise partially rescued these deficits by enhancing ECM organization and reducing senescence marker expression. Collectively, our findings demonstrate that AMPKα1 is critical for maintaining energy balance, regulating ECM remodeling, and preventing premature cellular senescence in tendon. These insights highlight AMPK signaling as a promising therapeutic target and underscore the beneficial role of exercise in mitigating tendinopathic changes.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":561323,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":733531,"name":"Nicole Migotsky","orcid":"0000-0002-8478-4281","position":1,"is_corresponding":false},{"id":1175147,"name":"Syeda N. 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