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1 Department of Human Physiology, Institute of Exercise and Sport Sciences, Copenhagen, Denmark
2 Department of Molecular Muscle Biology, Rigshospitalet, Copenhagen, Denmark; Department of Medical Biochemistry and Genetics, Medical Muscle Research Cluster, Copenhagen, Denmark
* To whom correspondence should be addressed. E-mail: erichter{at}ifi.ku.dk.
The Ca2+/CaM competitive inhibitor, KN93, has previously been used to evaluate AMPK-independent Ca2+-signalling to contraction-stimulated glucose uptake in muscle during intense electrical stimulation ex vivo. Using low-intensity tetanic contraction of mouse soleus and EDL muscles ex vivo, this study demonstrates that KN93 can potently inhibit AMPK phosphorylation and activity after 2 min but not 10 min of contraction, while potently inhibiting contraction-stimulated 2DG uptake at both the 2 and 10 min timepoints. These data suggest inhibition of Ca2+/CaM-dependent signaling events upstream of AMPK, the most likely candidate being the novel AMPKK, CaMKK. CaMKK protein expression was detected in mouse skeletal muscle. Similar to KN93, the CaMKK-inhibitor, STO-609, strongly reduced AMPK phosphorylation and activity at 2 min and less potently at 10 min. Pretreatment with STO-609 inhibited contraction-stimulated glucose uptake at 2 min in soleus, but not EDL, and in both muscles after 10 min. Neither KN93 nor STO-609 inhibited AICAR-stimulated glucose uptake, AMPK phosphorylation or recombinant LKB1 activity, suggestive of an LKB1-independent effect. Finally, neither KN93 nor STO-609 had effects on the reductions in glucose uptake seen in mice overexpressing a kinase-dead AMPK construct, indicating that the effects of KN93 and STO-609 on glucose uptake require inhibition of AMPK activity. We propose that CaMKKs act in mouse skeletal muscle regulating AMPK phosphorylation and glucose uptake at the onset of mild tetanic contraction and that an intensity- and/or time-dependent switch occurs in the relative importance of AMPKKs during contraction.
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