ArticleJournal of cachexia, sarcopenia and muscle2025
Alpha-Ketoisocaproate Attenuates Muscle Atrophy in Cancer Cachexia Models.
Article in Journal of cachexia, sarcopenia and muscle, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
- Understanding cachexia and muscle dysfunction in the context of metastatic breast cancer.Cancer metastasis reviews · 2026Review
- The Secretome of a Cachexia-Inducing Lung Tumor Impairs Mitochondrial Function and Skeletal Muscle Differentiation.Cancers · 2026Article
- Integrative serum metabolite prioritization and functional screening identify N-acetyl-L-glutamine as a protective candidate in premature ovarian insufficiency.Frontiers in genetics · 2026Article
- Alpha-Ketoisocaproate Attenuates Muscle Atrophy in Cancer Cachexia Models.Journal of cachexia, sarcopenia and muscle · 2025Article
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12 authors.
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Abstract
backgroundCancer-associated 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 l-leucine and β-hydroxy-β-methyl butyrate (HMB) have potential for treating CAC, the role of α-ketoisocaproate (KIC), a metabolite of l-leucine, remains unclear. Therefore, this study explored the use of KIC as a therapeutic agent for CAC-induced muscle atrophy by targeting myostatin.
methodsWe evaluated the effect of KIC on muscle atrophy using BALB/c mice and C2C12 myotubes as models of C26- and 4T1-induced CAC. Male and female mice were injected with C26 and 4T1 cells, respectively. Grip strength was measured weekly, and mice were sacrificed 4 weeks post-injection for muscle collection. C2C12 myotubes were treated with conditioned media (CM) derived from C26 or 4T1 cells.
resultsKIC suppressed mRNA expression of myostatin, a key regulator of muscle atrophy, more effectively than did l-leucine (-26.37 ± 4.11%, p < 0.01). KIC enhanced protein turnover in C2C12 myotubes and maintained 50% cell viability at high concentrations (KIC: 4.68 mM, HMB: 3.11 mM). Following CM treatment, KIC suppressed MuRF1 and MAFbx expression in a myostatin-dependent manner, thereby reducing their polyubiquitination. KIC restored Akt-FoxO3a phosphorylation, leading to improved myotube diameter (+63.8 ± 25.71%, p < 0.05) and fusion index (+51.9 ± 22.6%, p < 0.05). Immunofluorescence and nuclear fractionation revealed that KIC reduced FoxO3a nuclear accumulation. CM reduced p-Akt-FoxO3a interaction, which was rescued by KIC. In vivo, KIC administration increased body weight (11.11 ± 8.53%), grip strength (24.76 ± 10.58%), and skeletal muscle mass (p < 0.001) in C26 tumour-bearing mice. Protein expression of myostatin in the tibialis anterior (TA) muscle (-23.57 ± 12.22%, p < 0.05) and serum (-52.11 ± 3.56%, p < 0.001) was lower in KIC-treated mice (n = 12) compared with that in the controls. KIC increased the mean fibre cross-sectional area in TA (24.51 ± 14.14%, p < 0.01). In 4T1 tumour-bearing mice, KIC improved body weight (13.10 ± 10.76%) and grip strength (7.42 ± 4.33%) (p < 0.001, n = 10). Serum myostatin levels (-57.43 ± 9.46%, p < 0.001) and skeletal muscle weight were reduced in KIC-treated mice (n = 10).
conclusionOur findings demonstrate that KIC improves muscle function in CAC-induced muscle atrophy by regulating myostatin expression in skeletal muscle via the Akt-FoxO3a pathway. Thus, KIC has been proposed as a potential therapeutic agent against CAC.
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