{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T16:08:30Z","timestamp":1791562110195,"version":"4.3.4"},"reference-count":40,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273070"],"award-info":[{"award-number":["82273070"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32171178"],"award-info":[{"award-number":["32171178"]}],"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":[[2026,4]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Cancer cachexia is a multifactorial wasting syndrome marked by profound skeletal muscle loss. Tumours can release high levels of Activin A (ActA), which activates the ubiquitin\u2010proteasome pathway (UPP) and drives muscle wasting. Systemic blockade of the ActA pathway is associated with inflammatory adverse effects, and tumour\u2010restricted targeting alone often fails to reverse cachexia. We asked whether ActA produced by host (nontumour) organs contributes to circulating ActA and muscle wasting.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We profiled ActA across tissues and in serum in Lewis lung carcinoma (LLC) cancer cachexia mice to generate an organ\u2010wide expression map. Functional studies were then performed using adeno\u2010associated\u2010virus (AAV)\u2010knockdown in the heart (cTnT\/hTCF21 promoters) and kidney (CMV promoter), followed by cachexia induction. Body weight (BW), food intake, skeletal muscle mass, muscle function and muscle histomorphology were assessed. Mitochondrial ultrastructure and lipid metabolic pathways in muscle and adipose tissue were also examined.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n LLC cachexia mice exhibited significant reductions in body weight (\n \u2212<\/jats:bold>\n 6.0%,\n p<\/jats:italic>\n \u2009<\u20090.05), food intake (\u22129.9%,\n p<\/jats:italic>\n \u2009<\u20090.05), quadriceps mass (\u221215.3%,\n p<\/jats:italic>\n \u2009<\u20090.05) and grip strength (\u221213.0%,\n p<\/jats:italic>\n \u2009<\u20090.0001) compared with non\u2013tumour\u2010bearing (NTB) mice (\n n<\/jats:italic>\n \u2009=\u20096\u201312\/group). ActA expression was markedly increased in the host organs, particularly in the kidney (2.8\u2010fold vs. NTB,\n p<\/jats:italic>\n \u2009<\u20090.001) and heart (2.7\u2010fold vs. NTB,\n p<\/jats:italic>\n \u2009<\u20090.05) (\n n<\/jats:italic>\n \u2009=\u200910\/group). Compared with the sh\u2010NC, organ\u2010targeted ActA knockdown restored body weight (+6.1%,\n p<\/jats:italic>\n \u2009<\u20090.05) and food intake (+8.4%\n ,<\/jats:bold>\n p<\/jats:italic>\n \u2009<\u20090.05), increased quadriceps mass (+17.2%,\n p<\/jats:italic>\n \u2009<\u20090.05) and grip strength (+10.7%,\n p<\/jats:italic>\n \u2009<\u20090.01), reduced intramuscular fat infiltration and attenuated UPP signalling (\n n<\/jats:italic>\n \u2009=\u20098\u201316\/group). These effects were accompanied by increased expression of the mitochondrial fatty\u2010acid oxidation regulator carnitine palmitoyltransferase 1B (CPT1B) (+42.3% of mRNA level; +30.9% of protein level; both\n p<\/jats:italic>\n \u2009<\u20090.05) and CPT2 (+57.7% of mRNA level,\n p<\/jats:italic>\n \u2009<\u20090.05), improved mitochondrial ultrastructure and partial restoration of adipose mass.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Simultaneous downregulation of Activin A in the kidney and heart attenuates skeletal muscle atrophy and intramuscular adipogenesis, improves muscle mass and function and mitigates adipose tissue mass loss in cancer cachexia mice. These findings identify heart\u2010 and kidney\u2010derived Activin A as a key driver of cachexia, which acts through a combinatorial effect rather than an isolated contribution from either one alone, highlighting its potential as a therapeutic target.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70237","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T07:36:06Z","timestamp":1773214566000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Downregulation of Organ\u2010Derived Activin A Attenuates Muscle Atrophy and Intramuscular Fat Infiltration in Cancer Cachexia Mice"],"prefix":"10.1002","volume":"17","author":[{"given":"Cui","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Basic Medicine, School of Basic Medicine and Forensic Medicine North Sichuan Medical College Nanchong Sichuan China"},{"name":"Department of Medical Research Center Yuebei People's Hospital Affiliated to Shantou University Medical College Shaoguan China"},{"name":"Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Medical Research Center Yuebei People's Hospital Affiliated to Shantou University Medical College Shaoguan China"},{"name":"Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital Shenzhen China"},{"name":"Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Xue","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital Shenzhen China"},{"name":"Department of Nephrology The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Medical Research Center Yuebei People's Hospital Affiliated to Shantou University Medical College Shaoguan China"},{"name":"Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honghui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Research Center Yuebei People's Hospital Affiliated to Shantou University Medical College Shaoguan China"},{"name":"Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital Shenzhen 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihang","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Nephrology The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Min","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changyong","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurology Third Affiliated Hospital of Sun Yat\u2010Sen University Guangzhou Guangdong Province 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Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital Shenzhen 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Role and Therapeutic Implication of CPTs in Fatty Acid Oxidation and Cancers Progression","volume":"11","author":"Wang J.","year":"2021","journal-title":"American Journal of Cancer 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