Endocrine Abstracts

Background: Intermittent fasting increase maximum lifespan in several species and this effect is associated with reduced protein synthesis signaling. During fasting, a progressive loss of protein in human skeletal muscle is evident. Furthermore, fasting is associated with increased lipid oxidation and insulin resistance.

Aim: To define which protein metabolic mechanisms are activated in skeletal muscle during fasting.

Methods: We investigated the response to 72 h of fasting in eight healthy men. Skeletal muscle protein metabolism was assessed using labelled phenylalanine tracer combined with arteriovenous catheterization technique. Insulin sensitivity was assessed by hyperinsulinemic–euglycemic clamp. In addition, substrate oxidation and intramyocellular signaling to protein synthesis and breakdown was assessed.

Results: Peripheral insulin sensitivity was reduced and substrate oxidation shifted toward lipid oxidation during fasting. Net muscle protein breakdown was increased, mTOR signaling to protein synthesis was reduced, and FOXO3a signaling to local protein breakdown was unaltered. Furthermore, insulin signaling to protein synthesis was impaired downstream of Akt. However, fasting did not affect the upstream kinases Akt and AMPK or amino acid sensitive phosphorylation of eIF2a.

Conclusion: This work defines the physiological adaptations to fasting. The findings suggest that the increased net protein breakdown is due to reduced mTOR mediated protein synthesis. Furthermore, impaired insulin signaling to protein synthesis is not due to amino acid deprivation or AMPK activation. Our findings suggest that inhibition of mTOR signaling is a central mechanism triggering reduction of protein synthesis in muscle during fasting – and perhaps increasing longevity in humans and other species.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.