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RESEARCH ARTICLE

AICAR and metformin, but not exercise, increase muscle glucose transport through AMPK- , ERK- and PDK1-dependent activation of atypical PKC.

¹James A. Haley Veterans Hospital ²The University of California, San Diego ³Roskamp Institute ⁴INSERM U145 ⁵INSERM UMRS872, Centre de Recherches Biomedicales des Cordeliers ⁶Joslin Diabetes Center ⁷Max Plank Institute

Submitted 19 June 2009 ; revised 26 October 2009 ; accepted in final form 27 October 2009

Activators of 5'-AMP-activated protein kinase (AMPK), 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), metformin and exercise activate atypical protein kinase C (aPKC) and ERK, and stimulate glucose transport in muscle by uncertain mechanisms. Here, in cultured L6-myotubes: AICAR- and metformin-induced activation of AMPK was required for activation of aPKC and ERK; aPKC activation involved and required phosphoinositide kinase-dependent-1 (PDK1) phosphorylation of thr-410-PKC-; aPKC thr-410 phosphorylation and activation also required MEK1-dependent ERK; and glucose transport effects of AICAR and metformin were inhibited by expression of dominant-negative AMPK, kinase-inactive PDK1, MEK1 inhibitors, kinase-inactive PKC- and RNAi-mediated knockdown of PKC-. In mice, muscle-specific aPKC (PKC- depletion by conditional gene targeting impaired: AICAR-stimulated glucose disposal and stimulatory effects of both AICAR and metformin on 2-deoxyglucose/glucose uptake in muscle in vivo; and AICAR stimulation of [³H]2-deoxyglucose uptake in isolated extensor digitorum longus muscle. In marked contrast to AICAR and metformin, treadmill exercise-induced stimulation of 2-deoxyglucose/glucose uptake was not inhibited in aPKC knockout mice, despite normal AMPK activation. Finally, in intact rodents, AICAR and metformin activated aPKC in muscle, but not in liver, despite activating AMPK in both tissues. The findings demonstrate that, in muscle: AICAR and metformin activate aPKC via sequential activation of AMPK, ERK and PDK1; and AMPK/ERK/PDK1/aPKC pathway is required for metformin- and AICAR-stimulated increases in glucose transport. On the other hand, although aPKC is activated by treadmill exercise, this activation is not required for exercise-induced increases in glucose transport, and therefore may be a redundant mechanism.

atypical PKC; AMPK; exercise; AICAR