Original Article Ca2/Calmodulin-Dependent Protein Kinase Kinase- Regulates Skeletal Muscle Glucose Uptake Independent of AMP-Activated Protein Kinase and Akt Activation

Studies in nonmuscle cells have demonstrated that Ca2/ calmodulin-dependent protein kinase kinases (CaMKKs) are upstream regulators of AMP-activated protein kinase (AMPK) and Akt. In skeletal muscle, activation of AMPK and Akt has been implicated in the regulation of glucose uptake. The objective of this study was to determine whether CaMKK regulates skeletal muscle glucose up-take, and whether it is dependent on AMPK and/or Akt activation. Expression vectors containing constitutively active CaMKK (caCaMKK) or empty vector were trans-fected into mouse muscles by in vivo electroporation. After 2 weeks, caCaMKK was robustly expressed and increased CaMKI (Thr177/180) phosphorylation, a known CaMKK sub-strate. In muscles from wild-type mice, caCaMKK in-creased in vivo [3H]-2-deoxyglucose uptake 2.5-fold and AMPK1 and-2 activities 2.5-fold. However, in muscles from AMPK2 inactive mice (AMPK2i), caCaMKK di