Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).
AMP-activated protein kinase (AMPK) is a heterotrimericT he 5ЈAMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that is ubiquitously expressed and functions as an intracellular fuel sensor activated by depletion of highenergy phospho-compounds (1). Activation of AMPK initiates a complex series of signaling events that trigger increases in the uptake and oxidation of substrates important for ATP synthesis and decreases in ATP-consuming biosynthetic processes such as protein, lipid, and glycogen synthesis (2). Activation of AMPK has been linked to the regulation of glucose transport (3), but the substrates linking these events are elusive.AMPK regulates GLUT4-dependent glucose transport across the sarcolemma in skeletal muscle in response to diverse forms of cellular stress including exercise, hypoxia, and agents that disrupt the intracellular ATP-to-AMP ratio (4 -6). Evidence linking AMPK and glucose uptake has been provided by the use of different genetic approaches, including knockout (KO) and transgenic dominant-negative kinase mouse models (4 -6). Expression of a dominant-negative ␣2 AMPK construct in skeletal muscle suppresses ␣2 and ␣1 isoform-specific AMPK activity and completely prevents 5-aminoimidazole-4-carboxamide 1 -D-ribonucleoside (AICAR)-induced glucose transport (6). This observation was reinforced by recent reports showing that knockout of either the catalytic ␣2 (but not ␣1 AMPK isoform) or the regulatory ␥3 AMPK subunit completely abolishes AICAR-induced glucose transport (4,5). Collectively, these data provide evidence to suggest that ␣2 and ␥3 containing AMPK heterotrimeric complexes are involved in AICAR-induced glucose transport. Although AICAR-induced glucose transport in resting skeletal muscle is mediated by GLUT4 translocation to the plasma membrane (7,8), the link between AMPK signaling and GLUT4 translocation is presently unknown.AS160 is a substrate for the protein kinase Akt that links insulin signaling and GLUT4 trafficking (9 -11). AS160 contains a GTPase-activating protein homology domain that has been shown to regulate the GTPase activity of certain Rab proteins in vitro (12). Phosphorylation of AS160 by Akt is likely to inhibit its GTPase-activating protein activity, such that as a consequence, the GTP form of a Rab protein is elevated and this elevation in turn increases GLUT4 vesicle movement to, and/or fusion with, From the
We identified signaling pathways by which IL-6 regulates skeletal muscle differentiation and metabolism. Primary human skeletal muscle cells were exposed to IL-6 (25 ng/ml either acutely or for several days), and small interfering RNA gene silencing was applied to measure glucose and fat metabolism. Chronic IL-6 exposure increased myotube fusion and formation and the mRNA expression of glucose transporter 4, peroxisome proliferator activated receptor (PPAR)alpha, PPARdelta, PPARgamma, PPARgamma coactivator 1, glycogen synthase, myocyte enhancer factor 2D, uncoupling protein 2, fatty acid transporter 4, and IL-6 (P < 0.05), whereas glucose transporter 1, CCAAT/enhancer-binding protein-alpha, and uncoupling protein 3 were decreased. IL-6 increased glucose incorporation into glycogen, glucose uptake, lactate production, and fatty acid uptake and oxidation, concomitant with increased phosphorylation of AMP-activated protein kinase (AMPK), signal transducer and activator of transcription 3, and ERK1/2. IL-6 also increased phosphatidylinositol (PI) 3-kinase activity (450%; P < 0.05), which was blunted by subsequent insulin-stimulation (P < 0.05). IL-6-mediated glucose metabolism was suppressed, but lipid metabolism was unaltered, by inhibition of PI3-kinase with LY294002. The small interfering RNA-directed depletion of AMPK reduced IL-6-mediated fatty acid oxidation and palmitate uptake but did not reduce glycogen synthesis. In summary, IL-6 increases glycogen synthesis via a PI3-kinase-dependent mechanism and enhances lipid oxidation via an AMPK-dependent mechanism in skeletal muscle. Thus, IL-6 directly promotes skeletal muscle differentiation and regulates muscle substrate utilization, promoting glycogen storage and lipid oxidation.
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