scholarly journals Calcium signaling recruits substrate transporters GLUT4 and CD36 to the sarcolemma without increasing cardiac substrate uptake

2014 ◽  
Vol 307 (2) ◽  
pp. E225-E236 ◽  
Author(s):  
Yeliz Angin ◽  
Robert W. Schwenk ◽  
Reyhan Nergiz-Unal ◽  
Nicole Hoebers ◽  
Johan W. M. Heemskerk ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Substrate Uptake ◽  
Long Chain Fatty Acid ◽  
Cardiac Stress ◽  
Ampk Signaling ◽  
Energy Demands ◽  
Separate Pathway ◽  
Glucose Transporter Glut4 ◽  
Amp Activated Protein Kinase ◽  
Lcfa Uptake

Activation of AMP-activated protein kinase (AMPK) in cardiomyocytes induces translocation of glucose transporter GLUT4 and long-chain fatty acid (LCFA) transporter CD36 from endosomal stores to the sarcolemma to enhance glucose and LCFA uptake, respectively. Ca2+/calmodulin-activated kinase kinase-β (CaMKKβ) has been positioned directly upstream of AMPK. However, it is unknown whether acute increases in [Ca2+]i stimulate translocation of GLUT4 and CD36 and uptake of glucose and LCFA or whether Ca2+ signaling converges with AMPK signaling to exert these actions. Therefore, we studied the interplay between Ca2+ and AMPK signaling in regulation of cardiomyocyte substrate uptake. Exposure of primary cardiomyocytes to inhibitors or activators of Ca2+ signaling affected neither AMPK-Thr172 phosphorylation nor basal and AMPK-mediated glucose and LCFA uptake. Despite their lack of an effect on substrate uptake, Ca2+ signaling activators induced GLUT4 and CD36 translocation. In contrast, AMPK activators stimulated GLUT4/CD36 translocation as well as glucose/LCFA uptake. When cardiomyocytes were cotreated with Ca2+ signaling and AMPK activators, Ca2+ signaling activators further enhanced AMPK-induced glucose/LCFA uptake. In conclusion, Ca2+ signaling shows no involvement in AMPK-induced GLUT4/CD36 translocation and substrate uptake but elicits transporter translocation via a separate pathway requiring CaMKKβ/CaMKs. Ca2+-induced transporter translocation by itself appears to be ineffective to increase substrate uptake but requires additional AMPK activation to effectuate transporter translocation into increased substrate uptake. Ca2+-induced transporter translocation might be crucial under excessive cardiac stress conditions that require supraphysiological energy demands. Alternatively, Ca2+ signaling might prepare the heart for substrate uptake during physiological contraction by inducing transporter translocation.

scholarly journals Signalling components involved in contraction-inducible substrate uptake into cardiac myocytes

2004 ◽  
Vol 63 (2) ◽  
pp. 251-258 ◽  
Author(s):  
Joost J. F. P. Luiken ◽  
Susan L. M. Coort ◽  
Debby P. Y. Koonen ◽  
Arend Bonen ◽  
Jan F. C. Glatz
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Cardiac Myocytes ◽  
Glucose Transporter ◽  
Contractile Activity ◽  
Mechanical Activity ◽  
Substrate Uptake ◽  
Extracellular Signal ◽  
Intracellular Compartments ◽  
Glucose Transporter Glut4

Glucose and long-chain fatty acids (LCFA) are two major substrates used by heart and skeletal muscle to support contractile activity. In quiescent cardiac myocytes a substantial portion of the glucose transporter GLUT4 and the putative LCFA transporter fatty acid translocase (FAT)/CD36 are stored in intracellular compartments. Induction of cellular contraction by electrical stimulation results in enhanced uptake of both glucose and LCFA through translocation of GLUT4 and FAT/CD36 respectively to the sarcolemma. The involvement of protein kinase A, AMP-activated protein kinase (AMPK), protein kinase C (PKC) isoforms and the extracellular signal-regulated kinases was evaluated in cardiac myocytes as candidate signalling enzymes involved in recruiting these transporters in response to contraction. The collected evidence excluded the involvement of PKA and implicated an important role for AMPK and for one (or more) PKC isoform(s) in contraction-induced translocation of both GLUT4 and FAT/CD36. The unravelling of further components along this contraction pathway can provide valuable information on the coordinated regulation of the uptake of glucose and of LCFA by an increase in mechanical activity of heart and skeletal muscle.

AMPK stimulation increases LCFA but not glucose clearance in cardiac muscle in vivo

2004 ◽  
Vol 287 (5) ◽  
pp. E871-E877 ◽  
Author(s):  
Jane Shearer ◽  
Patrick T. Fueger ◽  
Jeffrey N. Rottman ◽  
Deanna P. Bracy ◽  
Paul H. Martin ◽  
...  
Keyword(s):  
Cardiac Muscle ◽  
Sprague Dawley ◽  
Long Chain Fatty Acid ◽  
Sprague Dawley Rats ◽  
Glucose Clearance ◽  
Independent Mechanism ◽  
Amp Activated Protein Kinase ◽  
Oxide Synthase ◽  
Lcfa Uptake

AMP-activated protein kinase (AMPK) independently increases glucose and long-chain fatty acid (LCFA) utilization in isolated cardiac muscle preparations. Recent studies indicate this may be due to AMPK-induced phosphorylation and activation of nitric oxide synthase (NOS). Given this, the aim of the present study was to assess the effects of AMPK stimulation by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR; 10 mg·kg−1·min−1) on glucose and LCFA utilization in cardiac muscle and to determine the NOS dependence of any observed effects. Catheters were chronically implanted in a carotid artery and jugular vein of Sprague-Dawley rats. After 4 days of recovery, conscious, unrestrained rats were given either water or water containing 1 mg/ml nitro-l-arginine methyl ester (l-NAME) for 2.5 days. After an overnight fast, rats underwent one of four protocols: saline, AICAR, AICAR + l-NAME, or AICAR + Intralipid (20%, 0.02 ml·kg−1·min−1). Glucose was clamped at ∼6.5 mM in all groups, and an intravenous bolus of 2-deoxy-[3H]glucose and [125I]-15-( p-iodophenyl)-3- R, S-methylpentadecanoic acid was administered to obtain indexes of glucose and LCFA uptake and clearance. Despite AMPK activation, as evidenced by acetyl-CoA carboxylase (Ser221) and AMPK phosphorylation (Thr172), AICAR increased cardiac LCFA but not glucose clearance. l-NAME + AICAR established that this effect was not due to NOS activation, and AICAR + Intralipid showed that increased cardiac LCFA clearance was not LCFA-concentration dependent. These results demonstrate that, in vivo, AMPK stimulation increases LCFA but not glucose clearance by a NOS-independent mechanism.

scholarly journals Augmentedβ-Cell Function and Mass in Glucocorticoid-Treated Rodents Are Associated with Increased Islet Ir-β/AKT/mTOR and Decreased AMPK/ACC and AS160 Signaling

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
André O. P. Protzek ◽  
José M. Costa-Júnior ◽  
Luiz F. Rezende ◽  
Gustavo J. Santos ◽  
Tiago Gomes Araújo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucose Transporter ◽  
Cell Function ◽  
Cell Mass ◽  
Protein Activity ◽  
Ampk Signaling ◽  
Akt Phosphorylation ◽  
Ampk Phosphorylation ◽  
Glut 4 Translocation ◽  
Amp Activated Protein Kinase

Glucocorticoid (GC) therapies may adversely cause insulin resistance (IR) that lead to a compensatory hyperinsulinemia due to insulin hypersecretion. The increasedβ-cell function is associated with increased insulin signaling that has the protein kinase B (AKT) substrate with 160 kDa (AS160) as an important downstream AKT effector. In muscle, both insulin and AMP-activated protein kinase (AMPK) signaling phosphorylate and inactivate AS160, which favors the glucose transporter (GLUT)-4 translocation to plasma membrane. Whether AS160 phosphorylation is modulated in islets from GC-treated subjects is unknown. For this, two animal models, Swiss mice and Wistar rats, were treated with dexamethasone (DEX) (1 mg/kg body weight) for 5 consecutive days. DEX treatment induced IR, hyperinsulinemia, and dyslipidemia in both species, but glucose intolerance and hyperglycemia only in rats. DEX treatment caused increased insulin secretion in response to glucose and augmentedβ-cell mass in both species that were associated with increased islet content and increased phosphorylation of the AS160 protein. Protein AKT phosphorylation, but not AMPK phosphorylation, was found significantly enhanced in islets from DEX-treated animals. We conclude that the augmentedβ-cell function developed in response to the GC-induced IR involves inhibition of the islet AS160 protein activity.

scholarly journals Contraction-Mediated Glucose Transport in Skeletal Muscle is Regulated by a Framework of AMPK, TBC1D1/4 and Rac1

2021 ◽  
Author(s):  
Christian de Wendt ◽  
Lena Espelage ◽  
Samaneh Eickelschulte ◽  
Christian Springer ◽  
Laura Toska ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Metabolic Response ◽  
Signaling Axis ◽  
Glucose Transporter Glut4 ◽  
Amp Activated Protein Kinase ◽  
Response To Exercise ◽  
Specific Contribution

The two closely related RabGTPase-activating proteins (RabGAPs) TBC1D1 and TBC1D4, both substrates for the AMP-activated protein kinase AMPK, play important roles in exercise metabolism and contraction-dependent translocation of the glucose transporter GLUT4 in skeletal muscle. However, the specific contribution of each RabGAP in contraction signaling is mostly unknown. In this study, we investigated the cooperative AMPK/RabGAP signaling axis in the metabolic response to exercise/contraction using a novel mouse model deficient in active skeletal muscle AMPK, combined with knockout of either <i>Tbc1d1</i>, <i>Tbc1d4</i> or both RabGAPs. AMPK-deficiency in muscle reduced treadmill exercise performance. Additional deletion of <i>Tbc1d1</i> but not <i>Tbc1d4 </i>resulted in further decrease in exercise capacity. In oxidative <i>Soleus</i> muscle, AMPK deficiency reduced contraction-mediated glucose uptake and deletion of each or both RabGAPs had no further effect. In contrast, in glycolytic <i>EDL</i> muscle, AMPK deficiency reduced contraction-stimulated glucose uptake and deletion of <i>Tbc1d1 </i>but not <i>Tbc1d4 </i>led to a further decrease. Importantly, skeletal muscle deficient in AMPK and both RabGAPs still exhibited residual contraction-mediated glucose uptake, which was completely abolished by inhibition of the GTPase <i>Rac1</i>. Our results demonstrate a novel mechanistic link between glucose transport and <a></a><a>the GTPase signaling framework in skeletal muscle in response to contraction.</a>

scholarly journals Contraction-Mediated Glucose Transport in Skeletal Muscle is Regulated by a Framework of AMPK, TBC1D1/4 and Rac1

2021 ◽  
Author(s):  
Christian de Wendt ◽  
Lena Espelage ◽  
Samaneh Eickelschulte ◽  
Christian Springer ◽  
Laura Toska ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Metabolic Response ◽  
Signaling Axis ◽  
Glucose Transporter Glut4 ◽  
Amp Activated Protein Kinase ◽  
Response To Exercise ◽  
Specific Contribution

The two closely related RabGTPase-activating proteins (RabGAPs) TBC1D1 and TBC1D4, both substrates for the AMP-activated protein kinase AMPK, play important roles in exercise metabolism and contraction-dependent translocation of the glucose transporter GLUT4 in skeletal muscle. However, the specific contribution of each RabGAP in contraction signaling is mostly unknown. In this study, we investigated the cooperative AMPK/RabGAP signaling axis in the metabolic response to exercise/contraction using a novel mouse model deficient in active skeletal muscle AMPK, combined with knockout of either <i>Tbc1d1</i>, <i>Tbc1d4</i> or both RabGAPs. AMPK-deficiency in muscle reduced treadmill exercise performance. Additional deletion of <i>Tbc1d1</i> but not <i>Tbc1d4 </i>resulted in further decrease in exercise capacity. In oxidative <i>Soleus</i> muscle, AMPK deficiency reduced contraction-mediated glucose uptake and deletion of each or both RabGAPs had no further effect. In contrast, in glycolytic <i>EDL</i> muscle, AMPK deficiency reduced contraction-stimulated glucose uptake and deletion of <i>Tbc1d1 </i>but not <i>Tbc1d4 </i>led to a further decrease. Importantly, skeletal muscle deficient in AMPK and both RabGAPs still exhibited residual contraction-mediated glucose uptake, which was completely abolished by inhibition of the GTPase <i>Rac1</i>. Our results demonstrate a novel mechanistic link between glucose transport and <a></a><a>the GTPase signaling framework in skeletal muscle in response to contraction.</a>

C2C12 myocytes lack an insulin-responsive vesicular compartment despite dexamethasone-induced GLUT4 expression

2002 ◽  
Vol 283 (3) ◽  
pp. E514-E524 ◽  
Author(s):  
Lori L. Tortorella ◽  
Paul F. Pilch
Keyword(s):  
Glucose Transporter ◽  
Fold Increase ◽  
Snare Proteins ◽  
Vesicular Traffic ◽  
Glut4 Expression ◽  
Protein Receptor ◽  
Syntaxin 4 ◽  
Insulin Dependent ◽  
Glucose Transporter Glut4 ◽  
Vesicular Compartment

Insulin regulates the uptake of glucose into skeletal muscle and adipocytes by redistributing the tissue-specific glucose transporter GLUT4 from intracellular vesicles to the cell surface. To date, GLUT4 is the only protein involved in insulin-regulated vesicular traffic that has this tissue distribution, thus raising the possibility that its expression alone may allow formation of an insulin-responsive vesicular compartment. We show here that treatment of differentiating C2C12myoblasts with dexamethasone, acting via the glucocorticoid receptor, causes a ≥10-fold increase in GLUT4 expression but results in no significant change in insulin-stimulated glucose transport. Signaling from the insulin receptor to its target, Akt2, and expression of the soluble N-ethylmaleimide-sensitive factor-attachment protein receptor, or SNARE, proteins syntaxin 4 and vesicle-associated membrane protein are normal in dexamethasone-treated C2C12 cells. However, these cells show no insulin-dependent trafficking of the insulin-responsive aminopeptidase or the transferrin receptor, respective markers for intracellular GLUT4-rich compartments and endosomes that are insulin responsive in mature muscle and adipose cells. Therefore, these data support the hypothesis that GLUT4 expression by itself is insufficient to establish an insulin-sensitive vesicular compartment.

scholarly journals Antidiabetic and Antihyperlipidemic Effects ofClitocybe nudaon Glucose Transporter 4 and AMP-Activated Protein Kinase Phosphorylation in High-Fat-Fed Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Mei-Hsing Chen ◽  
Cheng-Hsiu Lin ◽  
Chun-Ching Shih
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Transporter ◽  
Body Weight Gain ◽  
Glucose Production ◽  
Hypolipidemic Effect ◽  
Glucose Transporter 4 ◽  
High Fat ◽  
Hepatic Expression ◽  
Amp Activated Protein Kinase

The objective of this study was to evaluate the antihyperlipidemic and antihyperglycemic effects and mechanism of the extract ofClitocybe nuda(CNE), in high-fat- (HF-) fed mice. C57BL/6J was randomly divided into two groups: the control (CON) group was fed with a low-fat diet, whereas the experimental group was fed with a HF diet for 8 weeks. Then, the HF group was subdivided into five groups and was given orally CNE (including C1: 0.2, C2: 0.5, and C3: 1.0 g/kg/day extracts) or rosiglitazone (Rosi) or vehicle for 4 weeks. CNE effectively prevented HF-diet-induced increases in the levels of blood glucose, triglyceride, insulin (P<0.001,P<0.01,P<0.05, resp.) and attenuated insulin resistance. By treatment with CNE, body weight gain, weights of white adipose tissue (WAT) and hepatic triacylglycerol content were reduced; moreover, adipocytes in the visceral depots showed a reduction in size. By treatment with CNE, the protein contents of glucose transporter 4 (GLUT4) were significantly increased in C3-treated group in the skeletal muscle. Furthermore, CNE reduces the hepatic expression of glucose-6-phosphatase (G6Pase) and glucose production. CNE significantly increases protein contents of phospho-AMP-activated protein kinase (AMPK) in the skeletal muscle and adipose and liver tissues. Therefore, it is possible that the activation of AMPK by CNE leads to diminished gluconeogenesis in the liver and enhanced glucose uptake in skeletal muscle. It is shown that CNE exhibits hypolipidemic effect in HF-fed mice by increasing ATGL expression, which is known to help triglyceride to hydrolyze. Moreover, antidiabetic properties of CNE occurred as a result of decreased hepatic glucose production via G6Pase downregulation and improved insulin sensitization. Thus, amelioration of diabetic and dyslipidemic states by CNE in HF-fed mice occurred by regulation of GLUT4, G6Pase, ATGL, and AMPK phosphorylation.

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