UC San Diego

The AMP-activated protein kinase (AMPK) is activated by exercise, and both pharmacological activation of AMPK and exercise robustly stimulate glucose uptake by skeletal muscle. Nevertheless, the molecular mechanisms underlying the increase in glucose uptake in response to these stimuli remain to be elucidated. Addressing this gap in knowledge, the goal of this study was to investigate the importance of the acetyltransferases, EA1 binding protein p300 (p300) and c-AMP response element-binding binding protein (CBP), to AMPK-mediated glucose uptake by skeletal muscle. Specifically, we used a radioactive 2-deoxyglucose (2DOG) uptake (2DOGU) approach to measure ex vivo glucose uptake in unstimulated and AMPK-stimulated (using the pharmacological activators, 5-Aminoimidazole-4-carboxamide ribonucleotide [AICAR] and MK-8772) in the extensor digitorum longus (EDL) and soleus from ~12-16 week old male and female mice (n=261) with skeletal muscle-specific knockout of p300 and/or CBP and their wildtype (WT) littermates. As expected in WT mice, AICAR and MK-8772 significantly increased 2DOGU in soleus and EDL, regardless of sex. Remarkably, in mice with knockout of p300 and CBP (i-mPCKO), this effect of AICAR and MK-8722 was blocked in male and female mice. Equally remarkable, AICAR-stimulated 2DOGU in mice with individual knockout of p300 or CBP, or AICAR- and MK8772-stimulated 2DOGU in mice with just one allele of p300 or CBP, was normal and not different from WT littermates. Taken together, we highlight a critical role for p300 and CBP in the regulation of AMPK-stimulated glucose transport in skeletal muscle.