Acute tear versus chronic-degenerated rotator cuff pathologies are associated with divergent tendon metabolite profiles

Metabolic disorders are risk factors for rotator cuff injuries, which suggests that the rotator cuff is sensitive to local metabolic fluctuations. However, the link between the metabolic microenvironment and pathologic features of acute tear versus chronic degeneration is currently unknown. The overarching goal of this study was to evaluate alterations in tendon metabolite profiles following acute tear or chronic degeneration of the rotator cuff. We hypothesized that injury types (acute tear vs. chronic degeneration) would result in distinct metabolite profiles relative to clinically unaffected tendon controls. We utilized untargeted metabolomics to identify pathways that were altered at the time of rotator cuff repair (RCR; acute tear) or reverse total shoulder arthroplasty (rTSA; chronic degeneration) relative to total shoulder arthroplasty controls (TSA; tendon clinically unaffected). Acute tears to the rotator cuff were associated with an overall decrease in tendon metabolites. This global decrease was primarily associated with glycolic acid and decreased tricarboxylic acid (TCA) cycle activity. Conversely, chronic tendon specimens from patients undergoing rTSA showed an overall increase in metabolites. Most notably, chronic injury was associated with increased levels of multiple amino acids including alanine, aspartate, lysine, and proline. Overall, this study demonstrates that distinct metabolite profiles are associated with injury types, and that therapeutic strategies should address both cellular and matrix components regardless of injury induction. The specific pathways identified paired with validated, established, treatment methods may serve as novel therapeutic targets for patients who suffer from rotator cuff injuries.代谢紊乱（metabolic disorders）是肩袖（rotator cuff）损伤的危险因素，提示肩袖对局部代谢波动具有敏感性。但目前代谢微环境与肩袖急性撕裂、慢性退变的病理特征之间的关联尚不明确。本研究的总体目标是评估肩袖急性撕裂或慢性退变后肌腱代谢组谱的变化。我们提出假说：相较于临床未受累的肌腱对照组，损伤类型（急性撕裂vs慢性退变）会导致截然不同的代谢组谱。我们采用非靶向代谢组学（untargeted metabolomics）技术，以全肩关节置换术（total shoulder arthroplasty, TSA）患者的肌腱样本作为对照组（对应临床未受累肌腱），识别肩袖修补术（rotator cuff repair, RCR，对应急性撕裂）或反向全肩关节置换术（reverse total shoulder arthroplasty, rTSA，对应慢性退变）患者术中肌腱样本的差异代谢通路。肩袖急性撕裂与肌腱代谢物整体水平降低相关，这一整体下降主要与乙醇酸（glycolic acid）水平降低及三羧酸（tricarboxylic acid, TCA）循环活性降低有关。与之相反，接受反向全肩关节置换术的慢性肩袖损伤患者的肌腱标本，其代谢物整体水平呈升高趋势。尤为值得关注的是，慢性损伤与丙氨酸（alanine）、天冬氨酸（aspartate）、赖氨酸（lysine）及脯氨酸（proline）等多种氨基酸水平升高密切相关。综上，本研究证实不同类型的肩袖损伤对应截然不同的代谢组谱，且无论损伤诱因如何，治疗策略均应兼顾细胞与细胞外基质组分。本研究明确的特异性代谢通路结合已验证的成熟治疗手段，有望成为肩袖损伤患者的新型治疗靶点。