Long‐term high calcium decreases AMP‐activated protein kinase (AMPK) activity via activating protein phosphatase 2A

Abstract

AMP‐activated protein kinase (AMPK) is activated by upstream kinases and negatively regulated by protein phosphatase 2A (PP2A). Calcium has recently been found to activate PP2A, which contains calcium binding sites. Our previous work has shown that chronic calcium exposure decreases AMPK activity. To define the specific molecular mechanism, activity of AMPK and PP2A was analyzed in C2C12 and skeletal muscles from mutant pigs possessing AMPKδ3 R225Q, ryanodine receptor mutation, or both. C2C12 myotubes treated with caffeine (calcium releasing agent) for 10 h decreased AICAR‐induced AMPK activity to control level and this negative effect has diminished by dantrolene (ryanodine receptor stabilizer). Interestingly, muscles from pigs with ryanodine receptor mutation and C2C12 cells administered with 10 h caffeine showed higher PP2A activity compared to control (P < 0.05). More importantly, the inhibitory effect of caffeine on AMPK activity was attenuated by PP2A inhibitor, okadaic acid or PP2A RNA interfering. These data show the inhibitory effect of chronic calcium on AMPK activity is exerted through the activation of PP2A.