Skeletal Muscle Raptor And Tsc1/2 Differential Responses To Activity And Fasting In The Tumor Environment

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Cancer is a debilitating disease that is often accompanied by decreased physical activity and chronic energetic stress that disrupts muscle proteostasis. Skeletal muscle protein turnover is highly sensitive to changes in feeding and activity. Raptor serine 792 and TSC1/2 serine 1387 phosphorylation sites, when activated, can inhibit mTORC1 activation leading to suppressed anabolic signaling, and has been implicated in the regulation of skeletal muscle wasting with cancer. PURPOSE: To examine the effect of a 12-hour fast on the phosphorylation of Raptor and TSC1/2 in male ApcMin/+ mice, and if voluntary wheel activity can alter the fasting response. METHODS: Male C57BL/6 (B6, N=24) and ApcMin/+ (MIN, N=31) mice were either sacrificed under ad libitum conditions (B6-fed, M-fed), fasted for 12hrs (B6-fast, M-fast), or fasted for 12hrs following 4wks of voluntary wheel running (B6+W, M+W). TSC1/2 serine 1387 and Raptor serine 792 were measured in the gastrocnemius muscle as phosphorylation to total ratio by western blot. Protein synthesis was measured by puromycin incorporation. RESULTS: All MIN mice exhibited body weight loss (p<0.001) and reduced gastrocnemius mass (p<0.001) when compared to all B6 mice. Raptor phosphorylation (pRaptor) was induced in M-fast compared to M-fed (p=0.019), but there was no change in B6+fast compared to B6-fed (p=0.414). TSC1/2 phosphorylation was induced in M-fast compared to M-fed (p=0.001) and in B6-fast to B6-fed (p=0.039). Puromycin was trending to be reduced in M-fast compared to MIN-fed (p=0.070), but there was no change in B6-fast to B6-fed (p=0.323). Raptor phosphorylation was not different in M-fast compared to M+W (p=0.302), however pRaptor was reduced in B6+W compared B6-fast (p=0.028). TSC1/2 phosphorylation (p=0.001) and puromycin (p=0.016) were induced in MIN+W compared to M-fast, with no changes in the B6-fast to B6+W (p=0.360, p=0.196; respectively). CONCLUSIONS: Our results provide evidence that the cancer environment disrupts anabolic suppression of mTORC1 in skeletal muscle. Interestingly, TSC1/2 phosphorylation was sensitive to fasting independent of the tumor environment. Wheel activity induced protein synthesis independent of Raptor phosphorylation therefore, further studies are warranted to determine this specific mechanism.