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This Article Full Text (PDF) All Versions of this Article: 297/6/E1388    most recent ajpendo.00125.2009v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Deshmukh, A. S Articles by Zierath, J. R. PubMed PubMed Citation Articles by Deshmukh, A. S Articles by Zierath, J. R.

RESEARCH ARTICLE

Role of the AMPK3 isoform in hypoxia-stimulated glucose transport in glycolytic skeletal muscle

¹Karolinska Institute

Submitted 24 February 2009 ; revised 25 September 2009 ; accepted in final form 12 October 2009

Skeletal muscle glucose transport is regulated via the canonical insulin signaling cascade, as well as by energy sensing signals. 5'-AMP-activated protein kinase (AMPK) has been implicated in the energy status regulation of glucose transport. We determined the role of the AMPK3 isoform in hypoxia-mediated energy status signaling and glucose transport. Isolated mouse fast-twitch glycolytic extensor digitorum longus (EDL) muscle from AMPK3 knock-out (KO) mice and wild-type littermates were incubated under basal or hypoxic conditions. While hypoxia increased glucose transport (P<0.001) in wild-type mice, this effect was attenuated in AMPK3 KO mice (45% reduction P<0.01). The role of Ca²⁺-mediated signaling was tested using the Ca²⁺/calmodulin competitive inhibitor, KN-93. Hypoxia-mediated glucose transport in AMPK3 KO and wild-type mice was reduced in the presence of KN-93 (P<0.05). To further explore underlying signaling mechanisms, phosphorylation of AMPK, ACC and AS160 was determined under basal and hypoxic conditions, in the absence or presence of KN-93. Basal and hypoxia-mediated AMPK and ACC phosphorylation was comparable between AMPK3 KO and wild-type mice and these responses were unaltered by KN-93. Hypoxia also increased AS160 phosphorylation in AMPK3 KO and wild-type mice (P<0.001). KN-93 exposure prevented the hypoxia-mediated increase in AS160 phosphorylation in AMPK3 KO mice, but not in wild-type mice. Taken together, we provide direct evidence for a role of the AMPK3 isoform in hypoxia-mediated glucose transport in glycolytic muscle. Moreover, hypoxia-mediated AS160 phosphorylation was uncoupled from glucose transport in AMPK3 KO mice, indicating AS160-independent mechanisms contribute to glucose transport in skeletal muscle.

Signal Transduction; Calcium; Glucose Metabolism; Diabetes