AMPK and PPARβ positive feedback loop regulates endurance exercise training-mediated GLUT4 expression in skeletal muscle

The objective of this study is to determine whether AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), or peroxisome proliferator-activated receptor beta (PPAR beta) can independently mediate the increase of glucose transporter type 4 (GLUT4) expression that occurs in response to exercise training. We found that PPAR beta can regulate GLUT4 expression without PGC-1 alpha. We also found AMPK and PPAR beta are important for maintaining normal physiological levels of GLUT4 protein in the sedentary condition as well following exercise training. However, AMPK and PPAR beta are not essential for the increase in GLUT4 protein expression that occurs in response to exercise training. We discovered that AMPK activation increases PPAR beta via myocyte enhancer factor 2A (MEF2A), which acted as a transcription factor for PPAR beta. Furthermore, exercise training increases the cooperation of AMPK and PPAR beta to regulate glucose uptake. In conclusion, cooperation between AMPK and PPAR beta via NRF-1/MEF2A pathway enhances the exercise training mediated adaptive increase in GLUT4 expression and subsequent glucose uptake in skeletal muscle.