Green Tea component EGCG Insulin and IGF-1 promote nuclear efflux of atrophy associated transcription factor Foxo1 in skeletal muscle fibers

摘要

Prevention and slowing of skeletal muscle atrophy with nutritional approaches offers the potential to provide far reaching improvements in the quality of life for our increasingly aging population. Here we show polyphenol flavonoid Epigallocatechin 3-gallate (EGCG), found in the popular beverage green tea (Camellia sinensis), demonstrates similar effects as the endogenous hormones IGF-1 and insulin in the ability to suppress action of the atrophy-promoting transcription factor Foxo1 through a net translocation of Foxo1 out of the nucleus as monitored by nucleo-cytoplasmic movement of Foxo1-GFP in live skeletal muscle fibers. Foxo1-GFP nuclear efflux is rapid in IGF-1 or insulin, but delayed by an additional 30 min for EGCG. Once activated, kinetic analysis with a simple mathematical model shows EGCG, IGF-1 and insulin all produce similar apparent rate constants for Foxo1-GFP unidirectional nuclear influx and efflux. Interestingly, EGCG appears to have its effect at least partially via parallel signaling pathways that are independent of IGF-1’s (and insulin’s) downstream PI3K/Akt/Foxo1 signaling axis. Using the live fiber model system, we also determine the dose-response curve for both IGF-1 and insulin on Foxo1 nucleo-cytoplasmic distribution. The continued understanding of the activation mechanisms of EGCG could allow for nutritional promotion of Green Tea’s anti-atrophy skeletal muscle benefits and have implications in development of a clinically significant parallel pathway for new drugs to target muscle wasting and the reduced insulin receptor sensitivity which causes Type II Diabetes Mellitus.