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Glucose uptake was measured in WT and KO muscles from the 2-KO and 1-KO mouse strains. The upper panels show 2DG uptake in muscles incubated either with basal medium or with a similar medium in addition containing 2.0 mM AICAR. The lower panels show 2DG uptake in muscles either kept at basal conditions or electrically stimulated to contraction. †, Significantly different from basal value in the same genotype (p 0.05); *, significantly different from WT value at the same intervention (p 0.05); horizontal line, main effect. Data are presented as means S.E., n 7-8 for all groups.
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We investigated the importance of the two catalytic alpha-isoforms of the 5'-AMP-activated protein kinase (AMPK) in 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) and contraction-induced glucose uptake in skeletal muscle. Incubated soleus and EDL muscle from whole-body alpha2- or alpha1-AMPK knockout (KO) and wild type (WT) mice wer...
Contexts in source publication
Context 1
... Uptake-In both mouse strains, AICAR increased 2DG uptake by 40 -50% in WT soleus and by 100 - 130% in WT EDL (Fig. 4, upper panels). Remarkably, knockout of the 2 -subunit completely abolished the effect of AICAR on 2DG uptake in both EDL and soleus muscles. In contrast, knockout of the 1 -subunit did not affect AICAR-induced 2DG uptake in either of the muscles (Fig. 4, upper ...
Context 2
... mouse strains, AICAR increased 2DG uptake by 40 -50% in WT soleus and by 100 - 130% in WT EDL (Fig. 4, upper panels). Remarkably, knockout of the 2 -subunit completely abolished the effect of AICAR on 2DG uptake in both EDL and soleus muscles. In contrast, knockout of the 1 -subunit did not affect AICAR-induced 2DG uptake in either of the muscles (Fig. 4, upper ...
Context 3
... both mice strains, muscle contraction increased 2DG up- take by 200 -270% in WT EDL and by 240 -370% in WT soleus (Fig. 4, lower panels). Surprisingly, knockout of the 2 isoform significantly increased contraction-stimulated glucose uptake by 25% compared with WT in EDL, whereas the 2 -KO did not affect contraction-stimulated glucose uptake in soleus. The 1 -KO did not affect contraction-stimulated glucose uptake in EDL, but in soleus, the 1 -KO decreased glucose uptake ...
Context 4
... knockout of the 2 isoform significantly increased contraction-stimulated glucose uptake by 25% compared with WT in EDL, whereas the 2 -KO did not affect contraction-stimulated glucose uptake in soleus. The 1 -KO did not affect contraction-stimulated glucose uptake in EDL, but in soleus, the 1 -KO decreased glucose uptake by 25% during contraction (Fig. 4, lower panels). AMPK Signaling-In an effort to elucidate the underlying signaling events that might explain the effect of the -subunit knockout on glucose uptake, various measures of AMPK sig- naling were ...
Context 5
... Glycogen Content-The potential of insulin, AICAR, and muscle contraction to stimulate glucose uptake is inversely correlated to muscle glycogen content (6, 47, 48). The 2 -KO EDL had a decreased resting level of glycogen (40%) whereas 2 -KO soleus had a normal resting glycogen content (Table III). ...
Context 6
... muscles lacking the 2 - isoform, -AMPK Thr 172 phosphorylation was markedly re- duced in the EDL but not in the soleus. Thus, as judged by -AMPK Thr 172 phosphorylation, the lack of 2 -AMPK was not fully compensated for in the EDL, whereas it was in the soleus. Nevertheless, glucose transport was not decreased compared with WT in either muscle (Fig. 4). However, if one considers phosphorylation of ACC, a downstream target of AMPK, a better index of total endogenous AMPK activity, then compen- sation for the lack of the 2 -AMPK isoform was essentially complete during contraction in both muscle fiber types (Fig. ...
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AMP-activated protein kinase (AMPK), which functions as a sensor of cellular energy homeostasis, was phosphorylated after norepinephrine stimulation in L6 skeletal muscle cells. This effect was mediated by alpha1-adrenoceptors, with no stimulatory effects due to interactions at alpha2- or beta-adrenoceptors. Alpha1-adrenoceptors are Gq-coupled rece...
Background:
Glucose homeostasis is maintained by a balance between hepatic glucose production and peripheral glucose utilization. In skeletal muscle cells, glucose utilization is primarily regulated by glucose uptake. Deprivation of cellular energy induces the activation of regulatory proteins and thus glucose uptake. AMP-activated protein kinase...
Citations
... However, additional research presents a somewhat inconclusive view of the function of AMPK in glucose uptake stimulated by exercise. While AICAR-stimulated glucose transport was indeed abolished in knockout and transgenic mouse models of the AMPK α2 subunit, it was found that contraction-stimulated glucose uptake in vitro remained unaffected in both the extensor digitorum longus (EDL) and soleus muscle throughout these studies [50,54]. Additionally, muscle glucose uptake during in vivo exercise remained unaltered in mice with muscle-specific knockout of AMPKα1 and -α2 [55], as did muscle glucose clearance in those mice and in mice with functional depletion of AMPKα2. ...
... Stimulus/Model Observation References AMPK AICAR treatment in rat Increased glucose uptake in hindlimb muscles in vivo [45,46] Increased glucose uptake in epitrochlearis ex vivo [47] PF-739 treatment in: -mice -Cynomolgus monkeys -Lowered blood glucose levels -Increased glucose uptake in EDL -Increased TBC1D1 Ser237 phosphorylation in EDL and gastrocnemius [48] Lowered blood glucose levels [48] Muscle AMPKα2 KD mice Reduced contraction-stimulated glucose uptake in EDL and soleus ex vivo [49] No effect on contraction-stimulated glucose transport in EDL in vitro and in EDL, TA, gastrocnemius muscle in vivo [50] Muscle AMPKα1 KD or KO mice Reduced twitch-contraction-stimulated glucose uptake soleus ex vivo [52] Simultaneous muscle AMPKβ1 and β2 KO in mice Reduced contraction-stimulated glucose uptake in EDL and soleus ex vivo [53] Muscle AMPKα1 KO mice No reduction of contraction stimulated glucose uptake in EDL in vitro [54] Muscle AMPKα2 KO mice No reduction of contraction stimulated glucose uptake in EDL and soleus in vitro [54] Simultaneous muscle AMPKα1 and α2 KO in mice -No reduction of treadmill exercise-induced glucose uptake and unchanged glucose clearance in EDL, soleus, TA, quadriceps in vivo -Abolished TBC1D1 Ser231 phosphorylation after exercise in soleus and quadriceps [55] Muscle AMPKα2 KD mice -No reduction of treadmill exercise-induced glucose clearance in soleus, gastrocnemius, quadriceps in vivo -Increased surface membrane GLUT4 content after exercise normalized to GLUT4 abundance [56] -Unchanged treadmill exercise-stimulated glucose uptake in EDL, soleus, TA, quadriceps in vivo -Unchanged contraction-stimulated glucose uptake in EDL and soleus ex vivo -Abolished TBC1D1 Ser231 phosphorylation after exercise in quadriceps and after contraction in EDL [57] AMPKα2 KO mice -Reduced TBC1D1 Ser231, Thr590 and Ser600 phosphorylation after contraction in EDL ex vivo -Reduced TBC1D4 Ser588 and Thr704 phosphorylation after contraction in soleus ex vivo [58] AMPKα2 KD mice Abolished TBC1D1 Thr590 and Ser700 phosphorylation after contraction in EDL ex vivo [58] Muscle AMPKα2 KD mice Reduced TBC1D1 S231, S660 and S700 phosphorylation after contraction in TA in vivo [60] Muscle AMPKα2 KD mice Abolished TBC1D1 Ser231 and Thr590 phosphorylation after contraction in EDL ex vivo [59] Kinase assay Phosphorylation of TBC1D1 Ser231, Ser660 and Ser700 in vitro [63] TA muscle mtARK5 mice Unchanged contraction-stimulated glucose uptake in TA in situ ...
... Stimulus/Model Observation References AMPK AICAR treatment in rat Increased glucose uptake in hindlimb muscles in vivo [45,46] Increased glucose uptake in epitrochlearis ex vivo [47] PF-739 treatment in: -mice -Cynomolgus monkeys -Lowered blood glucose levels -Increased glucose uptake in EDL -Increased TBC1D1 Ser237 phosphorylation in EDL and gastrocnemius [48] Lowered blood glucose levels [48] Muscle AMPKα2 KD mice Reduced contraction-stimulated glucose uptake in EDL and soleus ex vivo [49] No effect on contraction-stimulated glucose transport in EDL in vitro and in EDL, TA, gastrocnemius muscle in vivo [50] Muscle AMPKα1 KD or KO mice Reduced twitch-contraction-stimulated glucose uptake soleus ex vivo [52] Simultaneous muscle AMPKβ1 and β2 KO in mice Reduced contraction-stimulated glucose uptake in EDL and soleus ex vivo [53] Muscle AMPKα1 KO mice No reduction of contraction stimulated glucose uptake in EDL in vitro [54] Muscle AMPKα2 KO mice No reduction of contraction stimulated glucose uptake in EDL and soleus in vitro [54] Simultaneous muscle AMPKα1 and α2 KO in mice -No reduction of treadmill exercise-induced glucose uptake and unchanged glucose clearance in EDL, soleus, TA, quadriceps in vivo -Abolished TBC1D1 Ser231 phosphorylation after exercise in soleus and quadriceps [55] Muscle AMPKα2 KD mice -No reduction of treadmill exercise-induced glucose clearance in soleus, gastrocnemius, quadriceps in vivo -Increased surface membrane GLUT4 content after exercise normalized to GLUT4 abundance [56] -Unchanged treadmill exercise-stimulated glucose uptake in EDL, soleus, TA, quadriceps in vivo -Unchanged contraction-stimulated glucose uptake in EDL and soleus ex vivo -Abolished TBC1D1 Ser231 phosphorylation after exercise in quadriceps and after contraction in EDL [57] AMPKα2 KO mice -Reduced TBC1D1 Ser231, Thr590 and Ser600 phosphorylation after contraction in EDL ex vivo -Reduced TBC1D4 Ser588 and Thr704 phosphorylation after contraction in soleus ex vivo [58] AMPKα2 KD mice Abolished TBC1D1 Thr590 and Ser700 phosphorylation after contraction in EDL ex vivo [58] Muscle AMPKα2 KD mice Reduced TBC1D1 S231, S660 and S700 phosphorylation after contraction in TA in vivo [60] Muscle AMPKα2 KD mice Abolished TBC1D1 Ser231 and Thr590 phosphorylation after contraction in EDL ex vivo [59] Kinase assay Phosphorylation of TBC1D1 Ser231, Ser660 and Ser700 in vitro [63] TA muscle mtARK5 mice Unchanged contraction-stimulated glucose uptake in TA in situ ...
Impaired skeletal muscle glucose uptake is a key feature in the development of insulin resistance and type 2 diabetes. Skeletal muscle glucose uptake can be enhanced by a variety of different stimuli, including insulin and contraction as the most prominent. In contrast to the clearance of glucose from the bloodstream in response to insulin stimulation, exercise-induced glucose uptake into skeletal muscle is unaffected during the progression of insulin resistance, placing physical activity at the center of prevention and treatment of metabolic diseases. The two Rab GTPase-activating proteins (RabGAPs), TBC1D1 and TBC1D4, represent critical nodes at the convergence of insulin- and exercise-stimulated signaling pathways, as phosphorylation of the two closely related signaling factors leads to enhanced translocation of glucose transporter 4 (GLUT4) to the plasma membrane, resulting in increased cellular glucose uptake. However, the full network of intracellular signaling pathways that control exercise-induced glucose uptake and that overlap with the insulin-stimulated pathway upstream of the RabGAPs is not fully understood. In this review, we discuss the current state of knowledge on exercise- and insulin-regulated kinases, hypoxia, nitric oxide (NO) and bioactive lipids that may be involved in the regulation of skeletal muscle glucose uptake.
... WT, muscle creatine kinase (CKMM) cre mice, and alpha myosin heavy chain (Myh6) cre mice were obtained from Jackson Laboratories (Bar Harbor, ME). AMPKα1 -/and AMPKα2 -/mice were generated as previously described 53,54 . www.nature.com/scientificreports/ ...
Ketone bodies serve as an energy source, especially in the absence of carbohydrates or in the extended exercise. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a crucial energy sensor that regulates lipid and glucose metabolism. However, whether AMPK regulates ketone metabolism in whole body is unclear even though AMPK regulates ketogenesis in liver. Prolonged resulted in a significant increase in blood and urine levels of ketone bodies in wild-type (WT) mice. Interestingly, fasting AMPKα2–/– and AMPKα1–/– mice exhibited significantly higher levels of ketone bodies in both blood and urine compared to fasting WT mice. BHB tolerance assays revealed that both AMPKα2–/– and AMPKα1–/– mice exhibited slower ketone consumption compared to WT mice, as indicated by higher blood BHB or urine BHB levels in the AMPKα2–/– and AMPKα1–/– mice even after the peak. Interestingly, fasting AMPKα2–/– and AMPKα1–/– mice exhibited significantly higher levels of ketone bodies in both blood and urine compared to fasting WT mice. . Specifically, AMPKα2ΔMusc mice showed approximately a twofold increase in blood BHB levels, and AMPKα2ΔMyo mice exhibited a 1.5-fold increase compared to their WT littermates after a 48-h fasting. However, blood BHB levels in AMPKα1ΔMusc and AMPKα1ΔMyo mice were as same as in WT mice. Notably, AMPKα2ΔMusc mice demonstrated a slower rate of BHB consumption in the BHB tolerance assay, whereas AMPKα1ΔMusc mice did not show such an effect. Declining rates of body weights and blood glucoses were similar among all the mice. Protein levels of SCOT, the rate-limiting enzyme of ketolysis, decreased in skeletal muscle of AMPKα2–/– mice. Moreover, SCOT protein ubiquitination increased in C2C12 cells either transfected with kinase-dead AMPKα2 or subjected to AMPKα2 inhibition. AMPKα2 physiologically binds and stabilizes SCOT, which is dependent on AMPKα2 activity.
... Twelve-week-old male whole-body CD36 KO mice and WT littermates were used as previously described [12,35]. Genotyping was performed by polymerase chain reaction analysis as described [25]. Mice were housed in temperature-controlled (22 ± 1 °C) facilities, maintained on a 12 h:12 h light-dark cycle, and received standard chow (Altromin, cat. ...
Several proteins are implicated in transmembrane fatty acid transport. The purpose of this study was to quantify the variation in fatty acid oxidation rates during exercise explained by skeletal muscle proteins involved in fatty acid transport. Seventeen endurance-trained males underwent a (i) fasted, incremental cycling test to estimate peak whole-body fatty acid oxidation rate (PFO), (ii) resting vastus lateralis microbiopsy, and (iii) 2 h of fed-state, moderate-intensity cycling to estimate whole-body fatty acid oxidation during fed-state exercise (FO). Bivariate correlations and stepwise linear regression models of PFO and FO during 0–30 min (early FO) and 90–120 min (late FO) of continuous cycling were constructed using muscle data. To assess the causal role of transmembrane fatty acid transport in fatty acid oxidation rates during exercise, we measured fatty acid oxidation during in vivo exercise and ex vivo contractions in wild-type and CD36 knock-out mice. We observed a novel, positive association between vastus lateralis FATP1 and PFO and replicated work reporting a positive association between FABPpm and PFO. The stepwise linear regression model of PFO retained CD36, FATP1, FATP4, and FABPpm, explaining ~87% of the variation. Models of early and late FO explained ~61 and ~65% of the variation, respectively. FATP1 and FATP4 emerged as contributors to models of PFO and FO. Mice lacking CD36 had impaired whole-body and muscle fatty acid oxidation during exercise and muscle contractions, respectively. These data suggest that substantial variation in fatty acid oxidation rates during exercise can be explained by skeletal muscle proteins involved in fatty acid transport.
... Compelling evidence suggests that AMPK contributes also to mediate the actions of metabolic cues on the central regulation of the reproductive axis. In this context, it has been demonstrated that (i) icv administration of 5aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR), an AMPK activator, delays puberty onset [32] and affects ovarian cyclicity in adult rats [83], (ii) delayed puberty in female rats subjected to chronic subnutrition is associated with increased levels of phosphorylated (activated) AMPK (pAMPK) in the hypothalamus [32], and (iii) mice with global deletion of AMPKa 1 subunit exhibit subfertility, which is not secondary to any metabolic alteration [84]. AMPK signaling might be mediating these effects by acting, at least partially, directly in GnRH neurons. ...
Gonadotropin-releasing hormone (GnRH) neurons are the final output pathway for the brain control of reproduction. The activity of this neuronal population, mainly located at the preoptic area of the hypothalamus, is controlled by a plethora of metabolic signals. However, it has been documented that most of these signal impact on GnRH neurons through indirect neuronal circuits, Kiss1, proopiomelanocortin, and neuropeptide Y/agouti-related peptide neurons being some of the most prominent mediators. In this context, compelling evidence has been gathered in recent years on the role of a large range of neuropeptides and energy sensors in the regulation of GnRH neuronal activity through both direct and indirect mechanisms. The present review summarizes some of the most prominent recent advances in our understanding of the peripheral factors and central mechanisms involved in the metabolic control of GnRH neurons.
... In the presence of low glucose, aldolase is unbound to fructose-1,6-bisphosphate and activates lysosomal AMPK via the recruitment of LKB1 (5,100,105). In skeletal and cardiac muscle, activation of AMPK stimulates glucose transporter 4 (GLUT4) translocation and glucose uptake (106)(107)(108), partly via the RAB GTPase-activating proteins TBC1D1/4 (TBC1 domain family member 1/4; (109)(110)(111)(112)(113). Importantly, like rodents (114)(115)(116)(117), small molecule selective AMPK-activators also stimulate glucose uptake and lowers blood glucose in nonhuman primates and humans with type 2 diabetes (114,115,(118)(119)(120). Interestingly, these effects on blood glucose are replicated by an aldolase inhibitor that activates AMPK via the lysosomal pathway (105). ...
Complex multi-cellular organisms require a coordinated response from multiple tissues to maintain whole-body homeostasis in the face of energetic stressors like fasting, cold and exercise. It is also essential that energy is stored efficiently with feeding and the chronic nutrient surplus that occurs with obesity. Mammals have adapted several endocrine signals that regulate metabolism in response to changes in nutrient availability and energy demand. These include hormones altered by fasting and refeeding including insulin, glucagon, GLP-1 (glucagon like peptide-1), catecholamines, ghrelin and FGF21 (fibroblast growth factor 21); adipokines such as leptin and adiponectin; cell stress-induced cytokines like TNFα (tumor necrosis factor alpha) and GDF15 (growth differentiating factor 15), and lastly exerkines such as IL-6 (interleukin-6) and irisin. Over the last two decades, it has become apparent that many of these endocrine factors control metabolism by regulating the activity of the AMPK (AMP-activated protein kinase). AMPK is a master regulator of nutrient homeostasis, phosphorylating over 100-distinct substrates that are critical for controlling autophagy, carbohydrate, fatty acid, cholesterol and protein metabolism. In this review we discuss how AMPK integrates endocrine signals to maintain energy balance in response to diverse homeostatic challenges. We also present some considerations with respect to experimental design which should enhance reproducibility and the fidelity of the conclusions.
... Insulin-and AICAR-stimulated glucose uptake was determined in isolated skeletal muscle using a previously described technique (34). Although AICAR is an unspecific AMPK activator that promotes intracellular accumulation of ZMP (AICAR monophosphate), the effect of AICAR on muscle glucose uptake has repeatedly been shown to be dependent on AMPK (35)(36)(37). Fed animals were anesthetized by a single intraperitoneal injection of pentobarbital and xylocain (100 and 5 mg/kg, respectively) after which soleus and extensor digitorum longus (EDL) were removed and suspended in heated (30 C) In situ contraction-stimulated muscle glucose uptake was determined as previously described (26,38). In short, an electrode was placed on the common peroneal nerve of one leg of fed mice that had been anesthetized by a single intraperitoneal injection of pentobarbital and xylocain (100 and 5 mg/kg, respectively). ...
The ability of insulin to stimulate glucose uptake in skeletal muscle is important for whole-body glycemic control. Insulin-stimulated skeletal muscle glucose uptake is improved in the period after a single bout of exercise and accumulating evidence suggests that phosphorylation of TBC1D4 by the protein kinase AMPK is the primary mechanism responsible for this phenomenon. To investigate this, we generated a TBC1D4 knock-in mouse model with a serine-to-alanine point mutation at residue 711 that is phosphorylated in response to both insulin and AMPK activation. Female TBC1D4-S711A mice exhibited normal growth and eating behavior as well as intact wholebody glycemic control on chow and high-fat diets. Moreover, muscle contraction increased glucose uptake, glycogen utilization and AMPK activity similarly in wild-type and TBC1D4-S711A mice. In contrast, improvements in whole-body and muscle insulin sensitivity after exercise and contractions were only evident in wild-type mice and occurred concomitantly with enhanced phosphorylation of TBC1D4-S711. These results provide genetic evidence to support that TBC1D4-S711 serves as a major point of convergence for AMPK- and insulin-induced signaling that mediates the insulin-sensitizing effect of exercise and contractions on skeletal muscle glucose uptake.
... Mice with a whole-body KO of AMPKα2 were hyperglycaemic, probably due to increased adrenergic signalling [144], whereas deletion of AMPKα1 resulted in no significant metabolic phenotype [195]. Interestingly, when AMPKα2 was deleted specifically in liver, increased HGP was also observed [106,147], supporting a direct link between hepatic AMPK and GNG. ...
Is there a role for AMPK in the control of hepatic gluconeogenesis and could targeting AMPK in liver be a viable strategy for treating type 2 diabetes? These are frequently asked questions this review tries to answer. After describing properties of AMPK and different small-molecule AMPK activators, we briefly review the various mechanisms for controlling hepatic glucose production, mainly via gluconeogenesis. The different experimental and genetic models that have been used to draw conclusions about the role of AMPK in the control of liver gluconeogenesis are critically discussed. The effects of several anti-diabetic drugs, particularly metformin, on hepatic gluconeogenesis are also considered. We conclude that the main effect of AMPK activation pertinent to the control of hepatic gluconeogenesis is to antagonize glucagon signalling in the short-term and, in the long-term, to improve insulin sensitivity by reducing hepatic lipid content.
... Wild-type C57BL/6J mice were obtained from Charles River. For experiments using AMPKa1 KO mice, these animals and their littermate controls have been described previously [22]. Briefly, PRKAA1 À/À and PRKAA1 þ/þ mice produced in the F1 generation of breedings of heterozygous parents were crossed with PRKAA1 þ/À and PRKAA1 þ/þ respectively to generate homozygous and control mice. ...
Objective:
Previous mechanistic studies on immunometabolism have focused on metabolite-based paradigms of regulation, such as itaconate. Here, we, demonstrate integration of metabolite and kinase-based immunometabolic control by AMP kinase.
Methods:
We combined whole cell quantitative proteomics with gene knockout of AMPKα1.
Results:
Comparing macrophages with AMPKα1 catalytic subunit deletion with wild-type, inflammatory markers are largely unchanged in unstimulated cells, but with an LPS stimulus, AMPKα1 knockout leads to a striking M1 hyperpolarisation. Deletion of AMPKα1 also resulted in increased expression of rate-limiting enzymes involved in itaconate synthesis, metabolism of glucose, arginine, prostaglandins and cholesterol. Consistent with this, we observed functional changes in prostaglandin synthesis and arginine metabolism. Selective AMPKα1 activation also unlocks additional regulation of IL-6 and IL-12 in M1 macrophages.
Conclusions:
Together, our results validate AMPK as a pivotal immunometabolic regulator in macrophages.
... Several studies suggest that AMPKα2 plays a more important role in metabolism than AMPKα1 (Jorgensen et al. 2004;Sakamoto et al. 2006). Consistently, we observed a significant decrease in AMPKα2 and p-AMPKα2 levels in mice from the BCAS group than those from the sham group; however, there were no significant differences in AMPKα1 and p-AMPKα1 levels between the two groups. ...
AMP-activated protein kinase (AMPK) is a regulator of cellular energy metabolism. Long-term use of metformin, an AMPK activator, was previously reported to be neuroprotective, as it promotes behavioral improvement and angiogenesis following an acute ischemic injury of the brain. However, only a few studies have demonstrated the role of AMPK in alleviating chronic cerebral ischemia (CCI) in mice models in the long-term (over 3 months). Therefore, we established a mouse model of CCI via bilateral carotid artery stenosis (BCAS) to explore the effect of AMPK on CCI. We used four groups of 3-month-old male C57BL/6 mice labeled as Sham, BCAS, BCAS + metformin treatment (BCAS + Met) and BCAS + AMPKα2 gene knockout (BCAS + KO). Three months after BCAS, we measured the AMPK protein expression, spatial learning and memory, Nissl bodies, cell apoptosis, astrocyte activation, and oligodendrocyte maturation. Additionally, we observed the brain tissues for changes in cell morphology. We observed that mice in the BCAS group had impaired spatial learning and memory compared with those in the sham group. The brain tissues of mice with CCI injury showed altered cell morphology, fewer Nissl bodies, cerebral cells apoptosis, and astrocyte activation. Interestingly, compared with mice from the BCAS group, the brains of mice from BCAS + Met group suffered lesser damage, whereas those of mice from the BCAS + KO group suffered more damage. The activation of AMPK, especially AMPKα2, plays a neuroprotective role during CCI in a mouse model of BCAS.
... The energy sensing AMP-activated protein kinase (AMPK) has long been suggested to play a role in exercise induced skeletal muscle signaling and glucose uptake (Mu et al., 2001;O'Neill et al., 2011;Winder and Hardie, 1996); however, this has been controversial, and some have shown AMPK is dispensable for exercise-stimulated glucose uptake (Jorgensen et al., 2004;Kjobsted et al., 2019;Lantier et al., 2014). AMPK is a heterotrimeric protein kinase that is activated both allosterically and by phosphorylation by events that change cellular energy state, such as exercise, and can then phosphorylate key proteins involved in energy consuming and producing pathways to restore cellular energy balance (Calabrese et al., 2014;Hardie, 2014). ...
The AMP-activated protein kinase (AMPK) is a cellular sensor of energetics and when activated in skeletal muscle during contraction can impart changes in skeletal muscle metabolism. Therapeutics that selectively activate AMPK have been developed to lower glucose levels through increased glucose disposal rates as an approach to abrogate the hyperglycemic state of diabetes; however, the metabolic fate of glucose following AMPK activation remains unclear. We have used a combination of in vivo evaluation of glucose homeostasis and ex vivo skeletal muscle incubation to systematically evaluate metabolism following pharmacological activation of AMPK with PF-739, comparing this with AMPK activation through sustained intermittent electrical stimulation of contraction. These methods to activate AMPK result in increased glucose uptake but divergent metabolism of glucose: pharmacological activation results in increased glycogen accumulation while contraction-induced glucose uptake results in increased lactate formation and glucose oxidation. These results provide additional evidence to support a role for AMPK in control of skeletal muscle metabolism and additional insight into the potential for AMPK stimulation with small molecule direct activators.
