Fasting Regulation of Muscle Autophagy during CancerCachexia
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IntroductionCancer cachexia is a characterized by accelerated skeletal muscle protein turnover that contributes to muscle mass loss. The adenosine monophosphate protein kinase (AMPK) is cellular energy sensor that is activated in response to energy stress and regulates the initiation of autophagy. The autophagy process involves lysosomal removal of cellular organelles and protein aggregates through sequestration of cytosolic substrates and tagging with ubiquinationlinked proteins such as LC3 and P62. While our understanding of AMPK's role in suppressed protein synthesis during cancer cachexia has improved, the regulation of autophagic processes by AMPK during cancer cachexia requires additional work. The purpose of this study is to examine the effect of nutrient deprivation on AMPK activation and autophagy initiation during cancer cachexia.MethodsMale C57BL/6 (B6, N=16) and ApcMin/+ (Min, N=18) mice were subjected to a 12 hour fast. B6 and Min mice fed adlibitum served as controls. Following the 12hour fast, hindlimb muscles were harvested and the gastrocnemius homogenized for protein analysis.ResultsMin mice exhibited body weight loss and reduced gastrocnemius mass when compared to B6 mice. In the fed state muscle AMPK phosphorylation (T172) was induced in the Min compared to B6. Fasting did not induce AMPK phosphorylation in B6 mice; however, AMPK was induced in Min mice following a fast. AKT phosphorylation (T308) was reduced following a fast in both B6 and Min mice. Furthermore, fasting suppressed FOXO1 phosphorylation in Min mice, similarly to B6 mice. However, fasted MIN mice had a reduction in P62 expression and an induction of LC3 II/I protein expression not seen in fasted B6 mice.ConclusionsTaken together our results suggest that cachectic skeletal muscle has increased sensitivity to acute nutrient deprivation demonstrated by AMPK activation and the initiation of autophagy when compared to healthy adult skeletal muscle.Support or Funding InformationThis work was supported by NIH/NCI grant RO1CA121249 awarded to James A. CarsonThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
