Green Tea (EGCG), Insulin, IGF-1 Suppression of Atrophy Associated Transcription Factor Foxo1 Activity in Skeletal Muscle and Mathematical Modeling of Nuclear Influx Efflux of Foxo1 in Skeletal Muscle

Abstract

Preventing, slowing and reversing skeletal muscle atrophy offers the potential to substantially improve the quality of life for our increasingly aging population. In addition to the primary function of force generation for movement, skeletal muscle plays an equally important role in maintenance of homeostasis through regulation of metabolic critical organic compounds such as amino acids, growth hormones, fatty acids, and glucose. Disruption of the body's homeostasis during diseases such as cancer, renal failure, sepsis, or diabetes leads to significant skeletal muscle atrophy. Our study utilizes over-expression of a skeletal muscle atrophy associated transcription factor, Foxo1, tagged with a green fluorescent protein (GFP) to provide a visual indication where within the muscle fiber (Nucleus or Cytoplasm) Foxo1 is located. This provides an indication of the activation status of the Foxo1 by comparing nuclear to cytoplasmic ratios with time. A two state mathematical model was created to account for the observed Foxo1-GFP nuclear concentration time course and presented here in Chapter 2. This model made two interesting observations, one implying that the kinase Akt not the predominant enzyme that phosphorylates Foxo1 in the nucleus prior to Foxo1 nuclear efflux. The second indicates that in the presence of IGF, intra-nuclear Akt activity, or possibly the activity of another kinase, has become strongly activated with the presence of IGF within the muscle fiber nuclei. EGCG is found in green tea, the most popularly consumed beverage in the world after water. Presented in Chapter 3, we show results of reduced Foxo1 activation induced by EGCG which are similar to the effects of well established endogenous growth hormones, IGF-1 and insulin. 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. Future work to further understand EGCG's parallel signaling pathways could have implications both in slowing muscle atrophy as it relates to Foxo1 or, more broadly in providing a clinical parallel pathway to IGF-1 and/or insulin.