Retinoic Acid Leads to Cytoskeletal Rearrangement through AMPK-Rac1 and Stimulates Glucose Uptake through AMPK-p38 MAPK in Skeletal Muscle Cells

Abstract

Retinoic acid (RA) is one of the major components of vitamin A.In the present study, we found that retinoic acid activated AMPactivated protein kinase (AMPK). RA induced Rac1-GTP formation and phosphorylation of its downstream target, p21-activated kinase (PAK), whereas the inhibition of AMPK blocked RA-induced Rac1 activation. Moreover, cofilin, an actin polymerization regulator, was activated when incubated with RA. We then showed that inhibition of AMPK by compound C, a selective inhibitor of AMPK, or small interfering RNA of AMPK ␣1 blocked RA-induced cofilin phosphorylation. Additionally, we found that retinoic acid-stimulated glucose uptake in differentiated C2C12 myoblast cells and activated p38 mitogen-activated protein kinase (MAPK). Finally, the inhibition of AMPK and p38 MAPK blocked retinoic acid-induced glucose uptake. In summary, our results suggest that retinoic acid may have cytoskeletal roles in skeletal muscle cells via stimulation of the AMPK-Rac1-PAK-cofillin pathway and may also have beneficial roles in glucose metabolism via stimulation of the AMPK-p38 MAPK pathway.Retinoids are important regulators of differentiation and cell proliferation. Induction of differentiation by retinoic acid has been observed in various cell systems, such as endothelial, neuronal, and lung cancers (1). Retinoic acid has been shown to inhibit the growth of breast cancer cells and to reduce the number of tumors in animal models (2, 3). The anti-tumor potential of retinoids has been demonstrated by their ability to inhibit the growth of several human cancers, including colon cancer, prostate cancer, and melanoma (4, 5). Retinoic acid mediates its effects by binding to its receptors, retinoid acid receptor, or retinoid X receptor, followed by heterodimerization of the receptors and their recognition of binding to retinoid acid receptor element-containing promoters.AMP-activated protein kinase (AMPK) 2 is a phylogenetically conserved intracellular energy sensor that plays a central role in the regulation of glucose and lipid metabolism. AMPK, a heterotrimeric complex comprised of a catalytic subunit and two regulatory subunits, is activated when cellular energy is depleted (6). Upon activation by allosteric binding of AMP or phosphorylation at Thr 172 of the catalytic subunit by AMPK kinase, AMPK accelerates ATP-generating catabolic pathways, including glucose and fatty acid oxidation (7-9) while simultaneously reducing ATP-consuming anabolic pathways including cholesterol, fatty acid, and triacylglycerol synthesis (10). In addition to its roles in energy homeostasis, AMPK also has been shown to regulate the endothelial nitric-oxide synthase pathway through Rac1 (11). The involvement of interaction of Rac1 with AMPK has been implicated in many of the biological effects of AMPK in cytoskeletal remodeling.Small GTPases of the Rho family have diverse effects on cellular structure and function. Depending on the cell type, specific Rho GTPases induce particular surface protrusions generated by actin-remodeling reactions t...

AMPK inhibitor Compound C stimulates ceramide production and promotes Bax redistribution and apoptosis in MCF7 breast carcinoma cells

“…Compound C has been used primarily as an inhibitor of AMPK in a number of cellular systems (38)(39)(40). It has also been shown to inhibit ACC inactivation by AICAR in cultured rat hepatocytes ( 7 ).…”

Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake

“…5,22). Knowing that these actors are also regulated by AMPK (20,24,30), it is tempting to postulate a possible action of one or several of these partners in the effect of AMPK activators in the insulin-mediated stimulation of glucose uptake. For instance, the fact that the insulininduced actin cytoskeleton rearrangement is impaired in insulin-resistant conditions (18) reenforces such hypothesis.…”

Effects of conjugated linoleic acid on the expression levels of miR-27 and miR-143 in pig adipose tissue

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