PPARβ Activation Induces Rapid Changes of Both AMPK Subunit Expression and AMPK Activation in Mouse Skeletal Muscle

AMP-activated protein kinases (AMPK) are heterotrimeric, alpha beta gamma, serine/threonine kinases. The gamma 3-AMPK subunit is particularly interesting in muscle physiology because 1) it is specifically expressed in skeletal muscle, 2) alpha 2 beta 2 gamma 3 is the AMPK heterotrimer activated during exercise in humans, and 3) it is down-regulated in humans after a training period. However, mechanisms underlying this decrease of gamma 3-AMPK expression remained unknown. We investigated whether the expression of AMPK subunits and particularly that of gamma 3-AMPK are regulated by the PPAR beta pathway. We report that PPAR beta activation with GW0742 induces a rapid (2 h) and sustained down-regulation of gamma 3-AMPK expression both in mouse skeletal muscles and in culture myotubes. Concomitantly, phosphorylation levels of both AMPK and acetyl-coenzyme A carboxylase are rapidly modified. The gamma 3-AMPK down-regulation is also observed in muscles from young and adult transgenic mice with musclespecific overexpression of peroxisome proliferator-activated receptor beta (PPAR beta). We showed that gamma 3-AMPK down-regulation is a rapid physiological muscle response observed in mouse after running exercise or fasting, two situations leading to PPAR beta activation. Finally, using C2C12, we demonstrated that dose and time-dependent down-regulation of gamma 3-AMPK expression upon GW0742 treatment, is due to decrease gamma 3-AMPK promoter activity. (Molecular Endocrinology 25: 1487-1498, 2011)