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However, etiological studies are difficult to perform in patients due to the long duration of disease onset and progression. Therefore, the purpose of this study was to determine the effects of altered joint loading on the rotator cuff. Mice were subjected to one of three load\u2010dependent rotator cuff tendinopathy models: underuse loading, achieved by injecting botulinum toxin\u2010A into the supraspinatus muscle; overuse loading, achieved using downhill treadmill running; destabilization loading, achieved by surgical excision of the infraspinatus tendon. All models were compared to cage activity animals. Whole joint function was assessed longitudinally using gait analysis. Tissue\u2010scale structure and function were determined using microCT, tensile testing, and histology. The molecular response of the supraspinatus tendon and enthesis was determined by measuring the expression of 84 wound healing\u2010associated genes. Underuse and destabilization altered forepaw weight\u2010bearing, decreased tendon\u2010to\u2010bone attachment strength, decreased mineral density of the humeral epiphysis, and reduced tendon strength. Transcriptional activity of the underuse group returned to baseline levels by 4 weeks, while destabilization had significant upregulation of inflammation, growth factors, and extracellular matrix remodeling genes. Surprisingly, overuse activity caused changes in walking patterns, increased tendon stiffness, and primarily suppressed expression of wound healing\u2010related genes. In summary, the tendinopathy models demonstrated how divergent muscle loading can result in clinically relevant alterations in rotator cuff structure, function, and gene expression.<\/jats:p>","DOI":"10.1002\/jor.25113","type":"journal-article","created":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T20:18:00Z","timestamp":1622751480000},"page":"977-986","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["The role of loading in murine models of rotator cuff disease"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2131-5178","authenticated-orcid":false,"given":"Adam C.","family":"Abraham","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery University of Michigan Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery 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