{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T14:06:32Z","timestamp":1791986792848,"version":"4.4.0"},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2414102"],"award-info":[{"award-number":["2023YFC2414102"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2009502"],"award-info":[{"award-number":["2022YFC2009502"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172402"],"award-info":[{"award-number":["82172402"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,2]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Sarcopenia is a prevalent age\u2010related disorder characterized by progressive muscle atrophy. Impaired balance is one of its most critical clinical consequences, often leading to falling and even bone fractures. As the cerebellum plays a central role in regulating motor coordination, elucidating the molecular mechanisms underlying imbalance in sarcopenia, particularly those mediated by the muscle\u2013cerebellum axis, remains an important yet unresolved question.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n 4D label\u2010free proteomics was employed to identify the key secretory protein mediating the interaction between muscles and cerebellums in young and aged mice. Annexin A2 (ANXA2), the candidate protein, was subsequently overexpressed using adeno\u2010associated virus (AAV), and its effects on both muscle and cerebellum were systematically examined. RNA\u2010sequencing was conducted to elucidate the molecular mechanisms underlying ANXA2 function in muscle, while stereotactic injection was performed to investigate its impact on cerebellum and related mechanisms. Finally, we evaluated the therapeutic potential of isoliquiritigenin, an inhibitor of ANXA2, in improving motor coordination and muscle function in aged mice.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Aged mice showed obviously impaired motor coordination in the accelerated rotarod (AR) test (\n p<\/jats:italic>\n \u2009<\u20090.01) and reduced strength performance in the grip strength assay (\n p<\/jats:italic>\n \u2009<\u20090.05) compared to young mice. Proteomic analysis identified ANXA2 as a secretory protein predominantly produced by aged skeletal muscles (\n p<\/jats:italic>\n \u2009<\u20090.05 in tibialis anterior, gastrocnemius muscle and quadriceps femoris) but not by other aged organs such as heart, liver, kidney, spleen and lung (all\n p<\/jats:italic>\n \u2009>\u20090.05). Functionally, ANXA2 exacerbated muscle atrophy by upregulating atrophy\u2010related markers MuRF\u20101 and Atrogin\u20101 (both\n p<\/jats:italic>\n \u2009<\u20090.05) and reducing the myotube diameter via regulation of Neuraminidase 2 (Neu2) (\n p<\/jats:italic>\n \u2009<\u20090.05). Moreover, ANXA2 was transported into the cerebellum through the blood stream and targeted type 2 cannabinoid receptors (CB2R) in cerebellar Purkinje cells (PCs) of lobule IV\/V, thereby contributing to motor incoordination as evidenced by impaired performance in AR tests (\n p<\/jats:italic>\n \u2009<\u20090.05). Importantly, isoliquiritigenin, an extract from licorice, effectively inhibited ANXA2 expression in muscle (\n p<\/jats:italic>\n \u2009<\u20090.05), alleviated muscle atrophy (\n p<\/jats:italic>\n \u2009<\u20090.05) and motor incoordination (\n p<\/jats:italic>\n \u2009<\u20090.05), while showing no adverse effects on anxiety\u2010like behaviours associated with CB2R (\n p<\/jats:italic>\n \u2009>\u20090.05).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n ANXA2 is a key mediator of the muscle\u2013cerebellum axis in sarcopenia, contributing to muscle atrophy by downregulating Neu2 and motor incoordination by targeting CB2R. Isoliquiritigenin was identified as an effective compound targeting ANXA2 to improve motor deficits. These findings highlight ANXA2 as a potential therapeutic target and suggest isoliquiritigenin as a promising strategy for alleviating motor incoordination associated with sarcopenia.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70203","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T05:11:11Z","timestamp":1769490671000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Annexin A2 Causes Motor Incoordination via Muscle\u2013Cerebellum Axis in Sarcopenia"],"prefix":"10.1002","volume":"17","author":[{"given":"Xin","family":"Jiao","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Orthopedic Implant, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China"},{"name":"Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National\u2010Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering Shenzhen University Medical School Shenzhen China"},{"name":"Engineering Research Center of Digital Medicine and Clinical Translation, School of Biomedical Engineering & Med\u2010X Research Institute, Ministry of Education Shanghai Jiao Tong University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengguang","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Orthopedic Implant, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China"},{"name":"Engineering Research Center of Digital Medicine and Clinical Translation, School of Biomedical Engineering & Med\u2010X Research Institute, Ministry of Education Shanghai Jiao Tong University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanwen","family":"Chang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Orthopedic Implant, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China"},{"name":"Engineering Research Center of Digital Medicine and Clinical Translation, School of Biomedical Engineering & Med\u2010X Research Institute, Ministry of Education Shanghai Jiao Tong University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjin","family":"Li","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Digital Medicine and Clinical Translation, School of Biomedical Engineering & Med\u2010X Research Institute, Ministry of Education Shanghai Jiao Tong University Shanghai 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Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology; Research Unit of Oral and Maxillofacial Regenerative Medicine Chinese Academy of Medical Sciences Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Orthopedic Implant, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinlin","family":"Jia","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Orthopedic Implant, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai 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