{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:31:28Z","timestamp":1790616688901,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"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":["82470862"],"award-info":[{"award-number":["82470862"]}],"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":["82070882"],"award-info":[{"award-number":["82070882"]}],"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":["82070888"],"award-info":[{"award-number":["82070888"]}],"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":["82273116"],"award-info":[{"award-number":["82273116"]}],"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":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pathological intramuscular lipid deposition (myosteatosis) and exercise intolerance are hallmarks of metabolic disorders, including diabetes and metabolic dysfunction\u2010associated steatotic liver disease (MASLD), yet their underlying mechanisms remain unclear. Our previous work has confirmed that hypertriglyceridemia\u2010driven kallistatin (KAL) elevation is present in the peripheral blood of patients with MASLD and diabetes and is a causative factor in hepatic steatosis and MASH pathogenesis. Here, we aim to evaluate this elevated KAL on myosteatosis and exercise function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We first established rat models of myosteatosis via a high\u2010fat diet or high\u2010fructose water intake and measured serum KAL levels by immunoblotting. KAL transgenic (KAL\u2010TG) mice were generated and subjected to longitudinal analyses, including Oil Red O staining for lipid deposition, exercise tolerance tests, indirect calorimetry for energy expenditure, mitochondrial DNA copy number quantification, ATP measurement, immunoblotting and quantitative PCR. For mechanistic analyses, mouse C2C12 myotubes were treated with recombinant KAL or KAL adenovirus, with or without co\u2010treatment with AICAR, AdipoRon or AdipoR1 siRNA. Additionally, we evaluated the potential ameliorative effects of KAL knockout and target agonists on myosteatosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Serum KAL levels were significantly elevated in rat models of myosteatosis. Conversely, genetic ablation of KAL ameliorated diet\u2010induced muscle lipid deposition. KAL\u2010TG mice developed myosteatosis (muscle TG [\u03bcmol\/g]: WT: 54.26\u2009\u00b1\u200914.56 [95% CI: 38.99\u201369.54]; KAL\u2010TG: 85.13\u2009\u00b1\u200911.53 [95% CI: 73.03\u201397.24],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) and exhibited exercise intolerance (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05 for all) from 6\u2009months of age. Mechanistically, KAL bound to sarcolemmal adiponectin receptor 1 (AdipoR1), suppressing AMPK activity. This led to reduced phosphorylation of acetyl\u2010CoA carboxylase (ACC) (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), enhancing lipogenesis and downregulated the PGC\u20101\u03b1\/NRF1 axis (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), impairing mitochondrial biogenesis and reducing ATP production (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Pharmacological activation of AdipoR1 (AdipoRon) and fenofibrate attenuated myosteatosis and restored exercise capacity in KAL\u2010TG mice (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Abnormal elevation of KAL drives metabolic myopathy and exercise intolerance by antagonizing the AdipoR1\u2010AMPK axis. Our findings offer dual strategies: repurposing AdipoR1 agonists (e.g., AdipoRon) or reducing circulating KAL (e.g., via genetic ablation or triglyceride\u2010lowering agents such as fenofibrate), both applicable to diabetes\/MASLD\u2010related metabolic myopathy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70261","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T03:35:24Z","timestamp":1775100924000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Elevated Kallistatin Induces Myosteatosis and Exercise Intolerance by Antagonizing AdipoR1\u2010Mediated AMPK Signalling"],"prefix":"10.1002","volume":"17","author":[{"given":"Fuyan","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou China"},{"name":"Department of Laboratory Medicine The Second Affiliated Hospital of Guangzhou University of Chinese Medicine  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Third Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of 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