Exercise Improves the Fasting Regulation of Skeletal Muscle Protein Synthesis in Tumor Bearing Mice

Abstract

IntroductionCancer 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 (Ser 792) and TSC1/2 (Ser 1387) phosphorylation can inhibit mTORC1 activation and suppress anabolic signaling, which has been implicated in cancer‐induced skeletal muscle wasting.PurposeTo examine the effect of the cancer environment on the fasting regulation of Raptor and TSC1/2 in male ApcMin/+ mice and determine if increased physical activity could alter this response.MethodsMale 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.ResultsAll 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), which was not changed by fasting in B6 mice (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).ConclusionsOur results provide evidence that the cancer environment disrupts fasting regulation of mTORC1 in skeletal muscle. Interestingly, TSC1/2 phosphorylation was sensitive to fasting independent of the tumor environment, while wheel activity induced protein synthesis independent of Raptor phosphorylation. Therefore, further study is warranted to determine physical activities regulation of fasting skeletal muscle protein synthesis in tumor bearing mice.Support or Funding InformationAcknowledgementsNCI R01‐CA121249