Effects of Graded Levels of Calorie Restriction XXI: Impact of Short-term Graded Restriction on Gene Expression Profiles of Stomach and Skeletal Muscle

Calorie restriction (CR) extends lifespan and prevents several aging related diseases. During short-term restriction, we previously showed that lean tissues generally decrease in size, but the alimentary tract (especially the stomach) grows. To illuminate pathway alterations in these contrasting tissues we compared gene expression profiles (bulk RNAseq) of the skeletal muscle and stomach, in the same male C57BL/6J mice exposed to 3 months of graded CR (0%-40%). Transcriptomic analysis showed the numbers of differentially expressed genes relative to 12 h ad libitum (12AL) feeding increased as the level of restriction increased. We found the canonical CR and aging related pathways, eukaryotic translation initiation factor 2 (EIF2) and mammalian target of rapamycin (mTOR), were significantly up and downregulated respectively in gastrocnemius muscle, but less so in the stomach. These changes were consistent with the differential growth status of the 2 tissues under CR. However, various immune-related pathways such as pathogenesis of influenza and interferon signaling pathway were downregulated and the PD-1/PD-L1 cancer immunotherapy pathway was upregulated with increased CR level in the stomach, indicating an impaired ability of antivirus and improvement of cancer treatment. Furthermore, in the mTOR and NF-kB aging related pathways, more genes in muscle tissue were significantly correlated with CR level than in the stomach and liver. This suggests muscle is an important aging related tissue responding to caloric restriction. These 2 pathways were altered in a manner consistent with increased lifespan as CR level increased in both tissues.