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

From the Research Division, Joslin Diabetes Center; Department of Medicine, Brigham and Women's Hospital; and Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Laurie J. Goodyear, Metabolism Section, Joslin Diabetes Center, Research Division, One Joslin Place, Boston, MA, 02215. E-mail: laurie.goodyear{at}joslin.harvard.edu

Abbreviations: ACC, acetyl-CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranotide; AMPK, AMP-activated protein kinase; CaMK, Ca²⁺/calmodulin-dependent protein kinase; CaMKK, CaMK kinase; KRB, Krebs-Ringer bicarbonate; PAS, phospho-AS160

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 uptake, and whether it is dependent on AMPK and/or Akt activation. Expression vectors containing constitutively active CaMKK (caCaMKK) or empty vector were transfected into mouse muscles by in vivo electroporation. After 2 weeks, caCaMKK was robustly expressed and increased CaMKI (Thr^177/180) phosphorylation, a known CaMKK substrate. In muscles from wild-type mice, caCaMKK increased 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 did not increase AMPK1 or -2 activities, but it did increase glucose uptake 2.5-fold, demonstrating that caCaMKK stimulates glucose uptake independent of AMPK. Akt (Thr³⁰⁸) phosphorylation was not altered by CaMKK, and caCaMKK plus insulin stimulation did not increase the insulin-induced phosphorylation of Akt (Thr³⁰⁸). These results suggest that caCaMKK stimulates glucose uptake via insulin-independent signaling mechanisms. To assess the role of CaMKK in contraction-stimulated glucose uptake, isolated muscles were treated with or without the CaMKK inhibitor STO-609 and then electrically stimulated to contract. Contraction increased glucose uptake 3.5-fold in muscles from both wild-type and AMPK2i mice, but STO-609 significantly decreased glucose uptake (24%) only in AMPK2i mice. Collectively, these results implicate CaMKK in the regulation of skeletal muscle glucose uptake independent of AMPK and Akt activation.

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