{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T06:07:20Z","timestamp":1789538840630,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Cancer\u2010associated cachexia (CAC) is a multifactorial syndrome characterised by progressive loss of muscle mass with limited Food and Drug Administration treatments. Although emerging evidence suggests that <jats:sc>l<\/jats:sc>\u2010leucine and \u03b2\u2010hydroxy\u2010\u03b2\u2010methyl butyrate (HMB) have potential for treating CAC, the role of \u03b1\u2010ketoisocaproate (KIC), a metabolite of <jats:sc>l<\/jats:sc>\u2010leucine, remains unclear. Therefore, this study explored the use of KIC as a therapeutic agent for CAC\u2010induced muscle atrophy by targeting myostatin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We evaluated the effect of KIC on muscle atrophy using BALB\/c mice and C2C12 myotubes as models of C26\u2010 and 4T1\u2010induced CAC. Male and female mice were injected with C26 and 4T1 cells, respectively. Grip strength was measured weekly, and mice were sacrificed 4\u2009weeks post\u2010injection for muscle collection. C2C12 myotubes were treated with conditioned media (CM) derived from C26 or 4T1 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>KIC suppressed mRNA expression of myostatin, a key regulator of muscle atrophy, more effectively than did <jats:sc>l<\/jats:sc>\u2010leucine (\u221226.37\u2009\u00b1\u20094.11%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). KIC enhanced protein turnover in C2C12 myotubes and maintained 50% cell viability at high concentrations (KIC: 4.68\u2009mM, HMB: 3.11\u2009mM). Following CM treatment, KIC suppressed MuRF1 and MAFbx expression in a myostatin\u2010dependent manner, thereby reducing their polyubiquitination. KIC restored Akt\u2010FoxO3a phosphorylation, leading to improved myotube diameter (+63.8\u2009\u00b1\u200925.71%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and fusion index (+51.9\u2009\u00b1\u200922.6%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Immunofluorescence and nuclear fractionation revealed that KIC reduced FoxO3a nuclear accumulation. CM reduced p\u2010Akt\u2013FoxO3a interaction, which was rescued by KIC. In\u00a0vivo, KIC administration increased body weight (11.11\u2009\u00b1\u20098.53%), grip strength (24.76\u2009\u00b1\u200910.58%), and skeletal muscle mass (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) in C26 tumour\u2010bearing mice. Protein expression of myostatin in the tibialis anterior (TA) muscle (\u221223.57\u2009\u00b1\u200912.22%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and serum (\u221252.11\u2009\u00b1\u20093.56%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) was lower in KIC\u2010treated mice (<jats:italic>n<\/jats:italic>\u2009=\u200912) compared with that in the controls. KIC increased the mean fibre cross\u2010sectional area in TA (24.51\u2009\u00b1\u200914.14%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). In 4T1 tumour\u2010bearing mice, KIC improved body weight (13.10\u2009\u00b1\u200910.76%) and grip strength (7.42\u2009\u00b1\u20094.33%) (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001, <jats:italic>n<\/jats:italic>\u2009=\u200910). Serum myostatin levels (\u221257.43\u2009\u00b1\u20099.46%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and skeletal muscle weight were reduced in KIC\u2010treated mice (<jats:italic>n<\/jats:italic>\u2009=\u200910).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings demonstrate that KIC improves muscle function in CAC\u2010induced muscle atrophy by regulating myostatin expression in skeletal muscle via the Akt\u2013FoxO3a pathway. Thus, KIC has been proposed as a potential therapeutic agent against CAC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.70044","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T13:02:17Z","timestamp":1755176537000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Alpha\u2010Ketoisocaproate Attenuates Muscle Atrophy in Cancer Cachexia Models"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4209-4591","authenticated-orcid":false,"given":"Pooreum","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Anatomy Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4759-0564","authenticated-orcid":false,"given":"Sang\u00a0Woo","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Anatomy Korea University 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