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>

scholarly journals AMPK and PPARβ positive feedback loop regulates endurance exercise training-mediated GLUT4 expression in skeletal muscle

2019 ◽  
Vol 316 (5) ◽  
pp. E931-E939 ◽  
Author(s):  
Jin-Ho Koh ◽  
Chad R. Hancock ◽  
Dong-Ho Han ◽  
John O. Holloszy ◽  
K. Sreekumaran Nair ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glut4 Expression ◽  
Amp Activated Protein Kinase ◽  
Response To Exercise ◽  
Glucose Transporter Type 4

The objective of this study is to determine whether AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), or peroxisome proliferator-activated receptor β (PPARβ) can independently mediate the increase of glucose transporter type 4 (GLUT4) expression that occurs in response to exercise training. We found that PPARβ can regulate GLUT4 expression without PGC-1α. We also found AMPK and PPARβ are important for maintaining normal physiological levels of GLUT4 protein in the sedentary condition as well following exercise training. However, AMPK and PPARβ are not essential for the increase in GLUT4 protein expression that occurs in response to exercise training. We discovered that AMPK activation increases PPARβ via myocyte enhancer factor 2A (MEF2A), which acted as a transcription factor for PPARβ. Furthermore, exercise training increases the cooperation of AMPK and PPARβ to regulate glucose uptake. In conclusion, cooperation between AMPK and PPARβ via NRF-1/MEF2A pathway enhances the exercise training mediated adaptive increase in GLUT4 expression and subsequent glucose uptake in skeletal muscle.

scholarly journals Glucose-transporter (GLUT4) protein content in oxidative and glycolytic skeletal muscles from calf and goat

1995 ◽  
Vol 305 (2) ◽  
pp. 465-470 ◽  
Author(s):  
J F Hocquette ◽  
F Bornes ◽  
M Balage ◽  
P Ferre ◽  
J Grizard ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Skeletal Muscles ◽  
Glucose Transporter ◽  
Transporter Protein ◽  
Rat Muscle ◽  
Glucose Transporter Glut4

It is well accepted that skeletal muscle is a major glucose-utilizing tissue and that insulin is able to stimulate in vivo glucose utilization in ruminants as in monogastrics. In order to determine precisely how glucose uptake is controlled in various ruminant muscles, particularly by insulin, this study was designed to investigate in vitro glucose transport and insulin-regulatable glucose-transporter protein (GLUT4) in muscle from calf and goat. Our data demonstrate that glucose transport is the rate-limiting step for glucose uptake in bovine fibre strips, as in rat muscle. Insulin increases the rate of in vitro glucose transport in bovine muscle, but to a lower extent than in rat muscle. A GLUT4-like protein was detected by immunoblot assay in all insulin-responsive tissues from calf and goat (heart, skeletal muscle, adipose tissue) but not in liver, brain, erythrocytes and intestine. Unlike the rat, bovine and goat GLUT4 content is higher in glycolytic and oxido-glycolytic muscles than in oxidative muscles. In conclusion, using both a functional test (insulin stimulation of glucose transport) and an immunological approach, this study demonstrates that ruminant muscles express GLUT4 protein. Our data also suggest that, in ruminants, glucose is the main energy-yielding substrate for glycolytic but not for oxidative muscles, and that insulin responsiveness may be lower in oxidative than in other skeletal muscles.

Role of Akt substrate of 160 kDa in insulin-stimulated and contraction-stimulated glucose transport

2007 ◽  
Vol 32 (3) ◽  
pp. 557-566 ◽  
Author(s):  
Gregory D. Cartee ◽  
Jørgen F.P. Wojtaszewski
Keyword(s):  
Skeletal Muscle ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Contractile Activity ◽  
Glut4 Translocation ◽  
Amp Activated Protein Kinase ◽  
Glucose Transporter Proteins ◽  
Response To Exercise

Insulin and exercise, the most important physiological stimuli to increase glucose transport in skeletal muscle, trigger a redistribution of GLUT4 glucose transporter proteins from the cell interior to the cell surface, thereby increasing glucose transport capacity. The most distal insulin signaling protein that has been linked to GLUT4 translocation, Akt substrate of 160 kDa (AS160), becomes phosphorylated in insulin-stimulated 3T3-L1 adipocytes; this is im​portant for insulin-stimulated GLUT4 translocation and glucose transport. Insulin also induces a rapid and dose-dependent increase in AS160 phosphorylation in skeletal muscle. Available data from skeletal muscle support the concepts developed in adipocytes with regard to the role AS160 plays in the regulation of insulin-stimulated glucose transport. In vivo exercise, in vitro contractions, or in situ contractions can also stimulate AS160 phosphorylation. AMP-activated protein kinase (AMPK) is likely important for phosphorylating AS160 in response to exercise/contractile activity, whereas Akt2 appears to be important for insulin-stimulated AS160 phosphorylation in muscle. Evidence of a role for AS160 in exercise/contraction-stimulated glucose uptake is currently inconclusive. The distinct signaling pathways that are stimulated by insulin and exercise/contraction converge at AS160. Although AS160 phosphorylation is apparently important for insulin-stimulated GLUT4 translocation and glucose transport, it is uncertain whether elevated AS160 phosphorylation plays a similar role with exercise/contraction.

Effects of epinephrine on insulin-stimulated glucose uptake and GLUT-4 phosphorylation in muscle

1997 ◽  
Vol 273 (3) ◽  
pp. C1082-C1087 ◽  
Author(s):  
A. D. Lee ◽  
P. A. Hansen ◽  
J. Schluter ◽  
E. A. Gulve ◽  
J. Gao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Inhibitory Effect ◽  
Phosphate Concentration ◽  
Intrinsic Activity ◽  
Adrenergic Stimulation ◽  
Beta Adrenergic ◽  
Glut 4

beta-Adrenergic stimulation has been reported to inhibit insulin-stimulated glucose transport in adipocytes. This effect has been attributed to a decrease in the intrinsic activity of the GLUT-4 isoform of the glucose transporter that is mediated by phosphorylation of GLUT-4. Early studies showed no inhibition of insulin-stimulated glucose transport by epinephrine in skeletal muscle. The purpose of this study was to determine the effect of epinephrine on GLUT-4 phosphorylation, and reevaluate the effect of beta-adrenergic stimulation on insulin-activated glucose transport, in skeletal muscle. We found that 1 microM epinephrine, which raised adenosine 3',5'-cyclic monophosphate approximately ninefold, resulted in GLUT-4 phosphorylation in rat skeletal muscle but had no inhibitory effect on insulin-stimulated 3-O-methyl-D-glucose (3-MG) transport. In contrast to 3-MG transport, the uptakes of 2-deoxyglucose and glucose were markedly inhibited by epinephrine treatment. This inhibitory effect was presumably mediated by stimulation of glycogenolysis, which resulted in an increase in glucose 6-phosphate concentration to levels known to severely inhibit hexokinase. We conclude that 1) beta-adrenergic stimulation decreases glucose uptake by raising glucose 6-phosphate concentration, thus inhibiting hexokinase, but does not inhibit insulin-stimulated glucose transport and 2) phosphorylation of GLUT-4 has no effect on glucose transport in skeletal muscle.

scholarly journals Noradrenaline increases glucose transport into brown adipocytes in culture by a mechanism different from that of insulin

1996 ◽  
Vol 314 (2) ◽  
pp. 485-490 ◽  
Author(s):  
Yasutake SHIMIZU ◽  
Danuta KIELAR ◽  
Yasuhiko MINOKOSHI ◽  
Takashi SHIMAZU
Keyword(s):  
Cyclic Amp ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Sympathetic Nerves ◽  
Intrinsic Activity ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Km Value ◽  
Glucose Transporter Glut4

Glucose uptake into brown adipose tissue has been shown to be enhanced directly by noradrenaline (norepinephrine) released from sympathetic nerves. In this study we characterized the glucose transport system in cultured brown adipocytes, which responds to noradrenaline as well as insulin, and analysed the mechanism underlying the noradrenaline-induced increase in glucose transport. Insulin increased 2-deoxyglucose (dGlc) uptake progressively at concentrations from 10-11 to 10-6 M, with maximal stimulation at 10-7 M. Noradrenaline concentrations ranging from 10-8 to 10-6 M also enhanced dGlc uptake, even in the absence of insulin. The effects of noradrenaline and insulin on dGlc uptake were additive. The stimulatory effect of noradrenaline was mimicked by the β3-adrenergic agonist, BRL37344, at concentrations two orders lower than noradrenaline. Dibutyryl cyclic AMP also mimicked the stimulatory effect of noradrenaline, and the antagonist of cyclic AMP, cyclic AMP-S Rp-isomer, blocked the enhancement of glucose uptake due to noradrenaline. Furthermore Western blot analysis with an anti-phosphotyrosine antibody revealed that, in contrast with insulin, noradrenaline apparently does not stimulate intracellular phosphorylation of tyrosine, suggesting that the noradrenaline-induced increase in dGlc uptake depends on elevation of the intracellular cyclic AMP level and not on the signal chain common to insulin. When cells were incubated with insulin, the content of the muscle/adipocyte type of glucose transporter (GLUT4) in the plasma membrane increased, with a corresponding decrease in the amount in the microsomal membrane. In contrast, noradrenaline did not affect the subcellular distribution of GLUT4 or that of the HepG2/erythrocyte type of glucose transporter. Although insulin increased Vmax. and decreased the Km value for glucose uptake, the effect of noradrenaline was restricted to a pronounced decrease in Km. These results suggest that the mechanism by which noradrenaline stimulates glucose transport into brown adipocytes is not due to translocation of GLUT but is probably due to an increase in the intrinsic activity of GLUT, which is mediated by a cyclic AMP-dependent pathway.

Characterization of the role of the AMP-activated protein kinase in the stimulation of glucose transport in skeletal muscle cells

2002 ◽  
Vol 363 (1) ◽  
pp. 167-174 ◽  
Author(s):  
Lee G.D. FRYER ◽  
Fabienne FOUFELLE ◽  
Kay BARNES ◽  
Stephen A. BALDWIN ◽  
Angela WOODS ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Phorbol Ester ◽  
Hyperosmotic Stress ◽  
Amp Activated Protein Kinase ◽  
Stimulation Of ◽  
Constitutively Active

Stimulation of AMP-activated protein kinase (AMPK) in skeletal muscle has been correlated with an increase in glucose transport. Here, we demonstrate that adenoviral-mediated expression of a constitutively active mutant of AMPKα leads to activation of glucose transport in a skeletal-muscle cell line, similar to that seen following treatment with 5-amino-imidazolecarboxamide (AICA) riboside, hyperosmotic stress or insulin. In contrast, expression of a dominant-negative form of AMPK blocked the stimulation of glucose transport by both AICA riboside and hyperosmotic stress, but was without effect on either insulin or phorbol-ester-stimulated transport. These results demonstrate that activation of AMPK is sufficient for stimulation of glucose uptake into muscle cells, and is a necessary component of the AICA riboside- and hyperosmotic-stress-induced pathway leading to increased glucose uptake. On the other hand, AMPK is not required in the insulin- or phorbol-ester-mediated pathways. Long-term (5 days) expression of the constitutively active AMPK mutant increased protein expression of GLUT1, GLUT4 and hexokinase II, consistent with previous reports on the chronic treatment of rats with AICA riboside. Expression of constitutively active AMPK had no detectable effect on p38 mitogen-activated protein kinase levels, although interestingly the level of protein kinase B was decreased. These results demonstrate that long-term activation of AMPK is sufficient to cause increased expression of specific proteins in muscle. Our results add further support to the hypothesis that long-term activation of AMPK is involved in the adaptive response of muscle to exercise training.

scholarly journals Identification of a novel phosphorylation site on TBC1D4 regulated by AMP-activated protein kinase in skeletal muscle

2010 ◽  
Vol 298 (2) ◽  
pp. C377-C385 ◽  
Author(s):  
Jonas T. Treebak ◽  
Eric B. Taylor ◽  
Carol A. Witczak ◽  
Ding An ◽  
Taro Toyoda ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Vastus Lateralis ◽  
Phosphorylation Site ◽  
Rab Gtpase ◽  
Vastus Lateralis Muscle ◽  
Phosphorylation Sites ◽  
Amp Activated Protein Kinase

TBC1D4 (also known as AS160) regulates glucose transporter 4 (GLUT4) translocation and glucose uptake in adipocytes and skeletal muscle. Its mode of action involves phosphorylation of serine (S)/threonine (T) residues by upstream kinases resulting in inactivation of Rab-GTPase-activating protein (Rab-GAP) activity leading to GLUT4 mobilization. The majority of known phosphorylation sites on TBC1D4 lie within the Akt consensus motif and are phosphorylated by insulin stimulation. However, the 5′-AMP-activated protein kinase (AMPK) and other kinases may also phosphorylate TBC1D4, and therefore we hypothesized the presence of additional phosphorylation sites. Mouse skeletal muscles were contracted or stimulated with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), and muscle lysates were subjected to mass spectrometry analyses resulting in identification of novel putative phosphorylation sites on TBC1D4. The surrounding amino acid sequence predicted that S711 would be recognized by AMPK. Using a phosphospecific antibody against S711, we found that AICAR and contraction increased S711 phosphorylation in mouse skeletal muscle, and this increase was abolished in muscle-specific AMPKα2 kinase-dead transgenic mice. Exercise in human vastus lateralis muscle also increased TBC1D4 S711 phosphorylation. Recombinant AMPK, but not Akt1, Akt2, or PKCζ, phosphorylated purified muscle TBC1D4 on S711 in vitro. Interestingly, S711 was also phosphorylated in response to insulin in an Akt2- and rapamycin-independent, but a wortmannin-sensitive, manner, suggesting this site is regulated by one or more additional upstream kinases. Despite increased S711 phosphorylation with AICAR, contraction, and insulin, mutation of S711 to alanine did not alter glucose uptake in response to these stimuli. S711 is a novel TBC1D4 phosphorylation site regulated by AMPK in skeletal muscle.

Insulin, Muscle Glucose Uptake, and Hexokinase: Revisiting the Road Not Taken

Physiology ◽  
2021 ◽  
Author(s):  
David H. Wasserman
Keyword(s):  
Skeletal Muscle ◽  
Cell Membrane ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Hexokinase Ii ◽  
The Road ◽  
Glucose Phosphorylation ◽  
Skeletal Muscle Glucose Uptake ◽  
Cell Membrane Transport ◽  
Glucose Transporter Glut4

Research conducted over the last 50 years has provided insight into the mechanisms by which insulin stimulates glucose transport across the skeletal muscle cell membrane. Transport alone, however, does not result in net glucose uptake as freeglucose equilibrates across the cell membrane and is not metabolized. Glucose uptake requires that glucose is phosphorylated by hexokinases. Phosphorylated glucosecannot leave the cell and is the substrate for metabolism. It is indisputable that glucose phosphorylation is essential for glucose uptake. Major advances have been made in defining the regulation of the insulin-stimulated glucose transporter, GLUT4, in skeletalmuscle. By contrast, the insulin-regulated hexokinase, hexokinase II parallels RobertFrost's Road Not Taken. Here the case is made that an understanding of glucosephosphorylation by hexokinase II is necessary to define the regulation of skeletal muscle glucose uptake in health and insulin resistance. Results of studies from different physiological disciplines that have elegantly described how hexokinase II can beregulated are summarized to provide a framework for potential application to skeletal muscle. Mechanisms by which hexokinase II is regulated in skeletal muscle await rigorous examination.

Skeletal muscle plasma membrane glucose transport and glucose transporters after exercise

1990 ◽  
Vol 68 (1) ◽  
pp. 193-198 ◽  
Author(s):  
L. J. Goodyear ◽  
M. F. Hirshman ◽  
P. A. King ◽  
E. D. Horton ◽  
C. M. Thompson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Time Course ◽  
Plasma Membranes ◽  
Glucose Transporter ◽  
Male Rats ◽  
Intrinsic Activity ◽  
Plasma Membrane Vesicles

Recent reports have shown that immediately after an acute bout of exercise the glucose transport system of rat skeletal muscle plasma membranes is characterized by an increase in both glucose transporter number and intrinsic activity. To determine the duration of the exercise response we examined the time course of these changes after completion of a single bout of exercise. Male rats were exercised on a treadmill for 1 h (20 m/min, 10% grade) or allowed to remain sedentary. Rats were killed either immediately or 0.5 or 2 h after exercise, and red gastrocnemius muscle was used for the preparation of plasma membranes. Plasma membrane glucose transporter number was elevated 1.8- and 1.6-fold immediately and 30 min after exercise, although facilitated D-glucose transport in plasma membrane vesicles was elevated 4- and 1.8-fold immediately and 30 min after exercise, respectively. By 2 h after exercise both glucose transporter number and transport activity had returned to nonexercised control values. Additional experiments measuring glucose uptake in perfused hindquarter muscle produced similar results. We conclude that the reversal of the increase in glucose uptake by hindquarter skeletal muscle after exercise is correlated with a reversal of the increase in the glucose transporter number and activity in the plasma membrane. The time course of the transport-to-transporter ratio suggests that the intrinsic activity response reverses more rapidly than that involving transporter number.

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