[Glutamine-induced autophagy exacerbates muscle atrophy in cachectic nude mice: a multi-omics analysis].

objectivesTo clarify whether glutamine induces autophagy to promote skeletal muscle atrophy in cancer cachexia through integrated transcriptomic and metabolomic analyses.

methodsTwenty male BALB/c nude mice were randomized into control and model groups (

resultsCompared with the control mice, the mice in the model group had significantly decreased tumor-free body mass, grip strength/body mass ratio and myofiber area with elevated atrogin-1 and MuRF1 expressions. The DEGs were mainly enriched in arginine/proline metabolism, AMPK, mTOR, autophagy and FOXO signaling pathways. Metabolomic analysis showed significantly increased glutamine and glutamate in the cachectic muscle. In the tumor-bearing mice, the number of autophagosomes increased significantly with blurred and fragmented myofibrils, upregulated AMPK/FOXO3a pathway proteins and ULK1, and downregulated mTOR pathway proteins and P62. In C2C12 myoblasts, treatment with glutamine obviously promoted autophagy, activated AMPK/FOXO3a signaling and inhibited the mTOR pathway, and these effects were strongly blocked by the AMPK inhibitor.

conclusionsGlutamine promotes autophagy through activation of the AMPK/FOXO3a signaling axis and suppression of the mTOR pathway, leading to skeletal muscle atrophy in cancer cachexia.