Abstract 3470: Deletion of Glycogen Synthase Kinase-3α (GKS-3α) Causes a Glycogen Storage Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jibin Zhou ◽  
Risto Kerkela ◽  
David Harris ◽  
Katrina MacAulay ◽  
Lisa Kocheritz ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Heart Development ◽  
Glycogen Synthase ◽  
Periodic Acid ◽  
Glycogen Metabolism ◽  
Glycogen Storage ◽  
Negative Regulator ◽  
Heart Weight ◽  
Lv Function ◽  
Gsk 3Β

Background: GSK-3 and its targets play critical roles in a wide array of processes including development and cancer. In mammalian cells there are two isoforms, α and β. GSK-3β is purported to be a negative regulator of cardiac hypertrophy, but this is based solely on over-expression approaches, and virtually nothing is known of the functions of GSK-3α. Methods: We generated mice deleted for GSK-3α. Heart development, as well as postnatal cardiac growth, glycogen metabolism, morphology, physiology, and ECG conduction invervals were examined. Age-matched wild type (WT) mice served as controls. Results: Heart development was normal, consistent with full compensation by GSK-3β for loss of GSK-3α during development. However, echocardiographic LV mass (in mg) was significantly increased in the KO compared to WT: 187.95 ± 35.05 vs 143.52 ± 23.94*. Heart weight (HW, mg) and HW/body weight ratio were also significantly increased in the KO: 186.73 ± 15.3* and 4.96 ± 0.38* for KO (n = 19); 146.33 ± 14.92 and 4.12 ± 0.27 for WT (n = 10). Thus deletion of GSK-3α leads to significant cardiac hypertrophy with aging. The underlying mechanism appears to be marked glycogen deposition seen with both Periodic acid-Schiff staining and transmission electron microscopy. Although LV function as assessed by echocardiography was normal at 4 months of age, invasive hemodynamic evaluation demonstrated a depressed response to isoproterenol infusion. ECG revealed a significantly shortened PR interval without pre-excitation. Conclusions: We demonstrate for the first time a striking isoform-specific role for GSK-3α in the heart, and that role is as a critical regulator of glycogen metabolism. Deletion of GSK-3α leads to a glycogen storage cardiomyopathy, sharing some features with that seen with mutations in AMP-activated protein kinase. These data suggest the possibility that mutations in, or alterations in activity of, GSK-3α could account for some cases of hypertrophic cardiomyopathy. (*, P < 0.01, KO vs. WT)

Abstract P198: Aberrant Activation of γ2-AMPK Causes Cardiac Hypertrophy Independent of Glycogen Storage

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Maengjo Kim ◽  
Roger Hunter ◽  
Kei Sakamoto ◽  
Christine E Seidman ◽  
Jonathan G Seidman ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Double Mutant ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Point Mutations ◽  
Glycogen Storage ◽  
Energy Deficit ◽  
Heart Weight ◽  
Glycogen Accumulation ◽  
Mtor Activity

AMP-activated protein kinase (AMPK) is an energy sensor and a key regulator of cell metabolism, hence a promising drug target. The cardiac functions of AMPK have not been understood. Point mutations in the regulatory γ2-subunit (encoded by PRKAG2 gene) have been shown to cause a unique form of cardiomyopathy in humans characterized by cardiac hypertrophy, arrhythmias and glycogen storage. We have previously shown that PRKAG2 mutation caused aberrant activation of AMPK in the absence of energy deficit and subsequently triggered re-routing of excessive glucose into glycogen pool. In this study, we addressed two questions: 1) whether cardiac hypertrophy in PRKAG2 cardiomyopathy was secondary of glycogen storage; 2) which hypertrophic signaling pathways are involved. We sought to reduce glycogen storage in transgenic mice expressing a mutant PRKAG2 (N488I) in the heart (TGγ2 N488I ) by crossing them to knock-in mice harboring a mutation in the muscle form of glycogen synthase (GYS1 KI ) that greatly reduced GYS activity in response to glucose-6-phosphate. Compared to TGγ2 N488I , TGγ2 N488I -GYS1-KI (double mutant) hearts showed lower GYS activity (0.7 ± 0.07 vs. 6.9 ± 0.49 nmol/min/mg, p<0.0001) and reduced glycogen content (35 ± 4.5 vs. 169 ± 40 umol/g, p<0.0001). Nonetheless, cardiac hypertrophy remained in the double mutant. The heart weight to body weight ratios were 6.8 ± 0.7 mg/g for TGγ2 N488I , 6.7 ± 0.5 mg/g for the double mutant compared to 4.0 ± 0.2 mg/g in the wild type. Furthermore, we have observed significant changes in FOXO (forkhead-O transcription factor) and mTOR (mammalian target of rapamycin) pathways in the TGγ2 N488I hearts. Increased phosphorylation of FOXO3a (Ser321, Ser253) and FoxO1a (Ser256) led to nuclear exclusion and degradation of FOXO proteins. Increased mTOR activity was evidenced by enhanced phosphorylation of Ser2448 as well as its downstream targets S6 and 4E-BP. Taken together these data indicate that aberrant γ2-AMPK activation causes cardiac hypertrophy independent of excessive glycogen accumulation. We found that increased mTOR activity and decreased FOXO signaling contributes to cardiac hypertrophy in TGγ2 N488I mice, suggesting novel mechanisms underlying cardiac hypertrophy caused by abnormal γ2-AMPK activity.

scholarly journals Transgenic overexpression of protein targeting to glycogen markedly increases adipocytic glycogen storage in mice

2007 ◽  
Vol 292 (3) ◽  
pp. E952-E963 ◽  
Author(s):  
Michael J. Jurczak ◽  
Arpad M. Danos ◽  
Victoria R. Rehrmann ◽  
Margaret B. Allison ◽  
Cynthia C. Greenberg ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Transgenic Animals ◽  
Glycogen Metabolism ◽  
Glycogen Storage ◽  
Fatty Acid Binding ◽  
Fat Depots

Adipocytes express the rate-limiting enzymes required for glycogen metabolism and increase glycogen synthesis in response to insulin. However, the physiological function of adipocytic glycogen in vivo is unclear, due in part to the low absolute levels and the apparent biophysical constraints of adipocyte morphology on glycogen accumulation. To further study the regulation of glycogen metabolism in adipose tissue, transgenic mice were generated that overexpressed the protein phosphatase-1 (PP1) glycogen-targeting subunit (PTG) driven by the adipocyte fatty acid binding protein (aP2) promoter. Exogenous PTG was detected in gonadal, perirenal, and brown fat depots, but it was not detected in any other tissue examined. PTG overexpression resulted in a modest redistribution of PP1 to glycogen particles, corresponding to a threefold increase in the glycogen synthase activity ratio. Glycogen synthase protein levels were also increased twofold, resulting in a combined greater than sixfold enhancement of basal glycogen synthase specific activity. Adipocytic glycogen levels were increased 200- to 400-fold in transgenic animals, and this increase was maintained to 1 yr of age. In contrast, lipid metabolism in transgenic adipose tissue was not significantly altered, as assessed by lipogenic rates, weight gain on normal or high-fat diets, or circulating free fatty acid levels after a fast. However, circulating and adipocytic leptin levels were doubled in transgenic animals, whereas adiponectin expression was unchanged. Cumulatively, these data indicate that murine adipocytes are capable of storing far higher levels of glycogen than previously reported. Furthermore, these results were obtained by overexpression of an endogenous adipocytic protein, suggesting that mechanisms may exist in vivo to maintain adipocytic glycogen storage at a physiological set point.

Chronic β2-adrenoceptor stimulation impairs cardiac relaxation via reduced SR Ca2+-ATPase protein and activity

2008 ◽  
Vol 294 (6) ◽  
pp. H2587-H2595 ◽  
Author(s):  
James G. Ryall ◽  
Jonathan D. Schertzer ◽  
Kate T. Murphy ◽  
Andrew M. Allen ◽  
Gordon S. Lynch
Keyword(s):  
Glycogen Synthase ◽  
Cardiovascular Effects ◽  
Negative Regulator ◽  
Initial Values ◽  
Arterial Blood ◽  
Anchoring Protein ◽  
Diastolic Relaxation ◽  
Cardiac Relaxation ◽  
Gsk 3Β

We determined the cardiovascular effects of chronic β2-adrenoceptor (β2-AR) stimulation in vivo and examined the mechanism for the previously observed prolonged diastolic relaxation. Rats (3 mo old; n = 6), instrumented with implantable radiotelemeters, received the selective β2-AR agonist formoterol (25 μg·kg−1·day−1 ip) for 4 wk, with selected cardiovascular parameters measured daily throughout this period, and for a further 7 days after cessation of treatment. Chronic β2-AR stimulation was associated with an increase in heart rate (HR) of 17% ( days 1– 14) and 5% ( days 15–28); a 11% ( days 1– 14) and 6% ( days 15– 28) decrease in mean arterial blood pressure; and a 24% ( days 1– 14) increase in the rate of cardiac relaxation (−dP/d t) compared with initial values ( P < 0.05). Cessation of β2-AR stimulation resulted in an 8% decrease in HR and a 7% decrease in −dP/d t, compared with initial values ( P < 0.05). The prolonged cardiac relaxation with chronic β2-AR stimulation was associated with a 30% decrease in the maximal rate ( Vmax) of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity, likely attributed to a 50% decrease in SERCA2a protein ( P < 0.05). glycogen synthase kinase-3β (GSK-3β) has been implicated as a negative regulator of SERCA2 gene transcription, and we observed a ∼60% decrease ( P < 0.05) in phosphorylated GSK-3β protein after chronic β2-AR stimulation. Finally, we found a 40% decrease ( P < 0.05) in the mRNA expression of the novel A kinase anchoring protein AKAP18, also implicated in β2-AR-mediated cardiac relaxation. These findings highlight some detrimental cardiovascular effects of chronic β2-AR agonist administration and identify concerns for their current and future use for treating asthma or for conditions where muscle wasting and weakness are indicated.

scholarly journals A dual role for Axin in establishing the anterior-posterior axis in the early sea urchin embryo

2020 ◽  
Author(s):  
Hongyan Sun ◽  
ChiehFu Jeff Peng ◽  
Lingyu Wang ◽  
Honglin Feng ◽  
Athula H. Wikramanayake
Keyword(s):  
Gene Expression ◽  
Sea Urchin ◽  
Glycogen Synthase ◽  
Negative Regulator ◽  
Cell Surface Receptor ◽  
Ligand Complex ◽  
Sea Urchin Embryo ◽  
Early Embryos ◽  
Gsk 3Β ◽  
Anterior Posterior

AbstractThe activation of Wnt/β-catenin (cWnt) signaling at the future posterior end of early embryos is a highly conserved mechanism for initiating pattern formation along the anterior-posterior (AP) axis in bilaterians. Moreover, in many bilaterian taxa, in addition, to activation of cWnt signaling at the posterior end, inhibition of cWnt signaling at the anterior end is required for normal development of anterior structures. In most cases, inhibition of cWnt signaling at the anterior end occurs around gastrulation and it is typically mediated by secreted factors that block signal transduction through the cWnt cell surface receptor-ligand complex. This phenomenon has been fairly well characterized, but the emerging role for intracellular inhibition of cWnt signaling in future anterior blastomeres—in cleavage stage embryos—to regulate correct AP patterning is less well understood. To investigate this process in an invertebrate deuterostome embryo we studied the function of Axin, a critical negative regulator of cWnt signaling, during early sea urchin embryogenesis. Sea urchin Axin is ubiquitously expressed in early embryos and by the blastula stage the expression of the gene becomes restricted to the posterior end of the embryo. Strikingly, knockdown of Axin protein levels using antisense Axin morpholinos (MO) led to ectopic nuclearization of β-catenin and activation of endomesoderm gene expression in anterior blastomeres in early embryos. These embryos developed a severely posteriorized phenotype that could be fully rescued by co-injection of Axin MO with wild-type Axin mRNA. Axin is known to negatively regulate cWnt by its role in mediating β-catenin stability within the destruction complex. Consistent with this function overexpression of Axin by mRNA injection led to the downregulation of nuclear β-catenin, inhibition of endomesoderm specification and a strong anteriorization of embryos. Axin has several well-defined domains that regulate its interaction with β-catenin and the key regulators of the destruction complex, Adenomatous Polyposis Coli (APC), Glycogen Synthase Kinase 3β(GSK-3β), and Dishevelled (Dvl). Using Axin constructs with single deletions of the binding sites for these proteins we showed that only the GSK-3βbinding site on Axin is required for its inhibition of cWnt in the sea urchin embryo. Strikingly, overexpression of the GSK-3β-binding domain alone led to embryos with elevated levels of endomesoderm gene expression and a strongly posteriorized phenotype. These results indicated that Axin has a critical global role in inhibiting cWnt signaling in the early sea urchin embryo, and moreover, that the interaction of Axin with GSK-3βis critical for this inhibition. These results also add to the growing body of evidence that Axin plays a global function in suppressing cWnt signaling in early embryos and indicates that modulation of Axin function may be a critical early step during patterning of the AP axis during bilaterian development

scholarly journals Abnormal glycogen storage in tuberous sclerosis complex caused by impairment of mTORC1-dependent and -independent signaling pathways

2019 ◽  
Vol 116 (8) ◽  
pp. 2977-2986 ◽  
Author(s):  
Rituraj Pal ◽  
Yan Xiong ◽  
Marco Sardiello
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Glycogen Storage ◽  
Tumor Formation ◽  
Negative Regulator ◽  
Multiple Organs ◽  
Genes Encoding

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that causes tumor formation in multiple organs. TSC is caused by inactivating mutations in the genes encoding TSC1/2, negative regulators of the mammalian target of rapamycin complex 1 (mTORC1). Diminished TSC function is associated with excess glycogen storage, but the causative mechanism is unknown. By studying human and mouse cells with defective or absent TSC2, we show that complete loss of TSC2 causes an increase in glycogen synthesis through mTORC1 hyperactivation and subsequent inactivation of glycogen synthase kinase 3β (GSK3β), a negative regulator of glycogen synthesis. Specific TSC2 pathogenic mutations, however, result in elevated glycogen levels with no changes in mTORC1 or GSK3β activities. We identify mTORC1-independent lysosomal depletion and impairment of autophagy as the driving causes underlying abnormal glycogen storage in TSC irrespective of the underlying mutation. The defective autophagic degradation of glycogen is associated with abnormal ubiquitination and degradation of essential proteins of the autophagy-lysosome pathway, such as LC3 and lysosomal associated membrane protein 1 and 2 (LAMP1/2) and is restored by the combined use of mTORC1 and Akt pharmacological inhibitors. In complementation to current models that place mTORC1 as the central therapeutic target for TSC pathogenesis, our findings identify mTORC1-independent pathways that are dysregulated in TSC and that should therefore be taken into account in the development of a therapeutic treatment.

scholarly journals Gluconeogenesis and glycogen metabolism during development of Pacific abalone, Haliotis discus hannai

2020 ◽  
Vol 318 (3) ◽  
pp. R619-R633 ◽  
Author(s):  
Mugen Koyama ◽  
Fumiya Furukawa ◽  
Yuka Koga ◽  
Shohei Funayama ◽  
Suehiro Furukawa ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Egg Yolk ◽  
Glycogen Metabolism ◽  
Glycogen Storage ◽  
Glucose Content ◽  
Pacific Abalone ◽  
Nutrient Sources ◽  
Haliotis Discus ◽  
Inhibition Of Glycolysis ◽  
Veliger Larvae

In lecithotrophic larvae, egg yolk nutrients are essential for development. Although yolk proteins and lipids are the major nutrient sources for most animal embryos and larvae, the contribution of carbohydrates to development has been less understood. In this study, we assessed glucose and glycogen metabolism in developing Pacific abalone, a marine gastropod mollusc caught and cultured in east Asia. We found that glucose and glycogen content gradually elevated in developing abalone larvae, and coincident expression increases of gluconeogenic genes and glycogen synthase suggested abalone larvae had activated gluconeogenesis and glycogenesis during this stage. At settling, however, glycogen sharply decreased, with concomitant increases in glucose content and expression of Pyg and G6pc, suggesting the settling larvae had enhanced glycogen conversion to glucose. A liquid chromatography-mass spectrometry (LC/MS)-based metabolomic approach that detected intermediates of these pathways further supported active metabolism of glycogen. Immunofluorescence staining and in situ hybridization suggested the digestive gland has an important role as glycogen storage tissue during settlement, while many other tissues also showed a capacity to metabolize glycogen. Finally, inhibition of glycolysis affected survival of the settling veliger larvae, revealing that glucose is, indeed, an important nutrient source in settling larvae. Our results suggest glucose and glycogen are required for proper energy balance in developing abalone and especially impact survival during settling.

Abstract 330: Metallothionein Preservation Of Cardiac Akt2 Signaling By Down-regulating Trb3 Prevents Diabetic Cardiomyopathy

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
YI TAN ◽  
Xiaoqing Yan ◽  
Shanshan Zhou ◽  
Yong Li ◽  
Yan Li ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Negative Regulator ◽  
H9c2 Cells ◽  
Akt Phosphorylation ◽  
Gsk 3Β

Cardiac insulin resistance is a key pathogenic factor for diabetic cardiomyopathy, but its mechanism remains largely unclear. Here we demonstrated that diabetes significantly inhibited cardiac Akt phosphorylation from 2 weeks to 2 months in wide-type (WT) mice, but not in cardiac-specific metallothionein-transgenic (MT-TG) mice. Cardiac Akt2 expression and phosphorylation was decreased and insulin-induced cardiac Akt2 and GSK-3β phosphorylation and glycogen synthase dephosphorylation were also decreased in WT, but not MT-TG, diabetic mice. Deletion of the Akt2 gene either in vitro H9c2 cells or in vivo significantly impaired cardiac glucose metabolic signaling. In addition, diabetes significantly increased cardiac Akt negative regulator tribbles (TRB)3 expression only in WT mice, suggesting the possible contribution of MT inhibition of diabetic up-regulation of TRB3 to Akt2 function preservation. Cardiac H9c2 cells with and without forced MT-overexpression (MT-H9c2) were treated with tert-butyl hydroperoxide (tBHP), which significantly reduced Akt2 phosphorylation in both basal and insulin-stimulating conditions only in H9c2 cells. Silencing TRB3 expression with SiRNA completely prevented tBHP’s inhibition of insulin-stimulated Akt2 phosphorylation in H9c2 cells, while overexpression of TRB3 in MT-H9c2 cells completely abolished MT preservation of insulin-stimulated Akt2 phosphorylation. Forced-overexpression of TRB3 by adenovirus-mediated gene delivery in MT-TG hearts also abolished MT’s preservation of cardiac insulin signaling and prevention of diabetic cardiomyopathy. These results suggest that diabetes-attenuated cardiac Akt2 function via up-regulating TRB3 plays a critical role in diabetic inhibition of insulin signaling in the heart. MT preserved cardiac Akt2-mediated insulin signaling by inhibiting TRB3, leading to the prevention of diabetic cardiomyopathy.

Abstract 072: TRIF-Pathway of Innate Immune Responses Mediates Angiotensin II Hypertension

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Madhu V Singh ◽  
Michael Z Cicha ◽  
Mark W Chapleau ◽  
François M Abboud
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Pressor Response ◽  
Weight Ratio ◽  
Negative Regulator ◽  
Heart Weight ◽  
Ang Ii ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Induced Hypertension

We tested the role of two distinct adaptors of toll-like receptor (TLR) signaling on Ang II-induced hypertension and cardiac hypertrophy. These TLR adaptors, myeloid differentiation protein 88 (MyD88) and TIR domain-containing adaptor inducing interferon β (TRIF) facilitate distinct inflammatory signaling pathways. In an earlier study, we reported that MyD88-/- mice are protected from cardiac hypertrophy and pro-inflammatory gene expression after myocardial infarction. Our current results with 3 weeks infusion of Ang II (3000 ng/kg/min) vs. saline indicate that in MyD88-/- mice, the pressor response to Ang II and cardiac hypertrophy were increased more than in wild type (WT) mice. In Ang II-infused WT, systolic blood pressure (SBP) peaked at 147 ± 4 mmHg whereas in Ang II-infused MyD88-/- mice SBP reached a peak value of 163 ± 6 mmHg. However, in mice with non-functional TRIF adaptor mutant (Trifmut), SBP did not increase during Ang II infusion and remained similar to the SBP in saline-infused mice (115 ± 3 mmHg). Baseline SBP was not different among WT, MyD88-/- and Trifmut mice. The increase in heart weight to body weight ratio (HW/BW) between saline and Ang II-infused mice was greater in MyD88-/- mice than WT mice (60% increase in MyD88-/- vs. 40% increase in WT), whereas it was less in Trifmut mice (22% increase). Accordingly, expression of several inflammatory genes (Tnfa, Nox4 and Agtr1a) was significantly greater (P< 0.05) in the heart and kidney of Ang II-infused MyD88-/- mice compared with Ang II-infused WT mice, whereas expression of these genes in Trifmut mice was either unchanged or reduced. We conclude that- (1) Ang II-induced hypertension, cardiac hypertrophy and inflammatory gene expression are mediated by activation of a TRIF-dependent pathway, but not by the MyD88-dependent pathways, and (2) Enhanced Ang II effects on SBP and hypertrophy in MyD88-/- mice suggest that MyD88 may serve as a negative regulator of the TRIF pathway in Ang II-induced hypertension. Selective targeting of these adaptor proteins may have significant therapeutic implications.

Liver and peripheral tissue glycogen metabolism in obese mice: effect of a mixed meal

1993 ◽  
Vol 265 (5) ◽  
pp. E743-E751
Author(s):  
C. Chen ◽  
P. F. Williams ◽  
I. D. Caterson
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Cardiac Muscle ◽  
White Adipose Tissue ◽  
Glycogen Content ◽  
Glycogen Synthase ◽  
Glycogen Metabolism ◽  
Glycogen Storage ◽  
Obese Mice ◽  
Entire Study

Glycogen metabolism in the liver, skeletal muscle, cardiac muscle, and white adipose tissue was studied in gold thioglucose (GTG) obese mice after fasting and during refeeding. Prolonged (48 h) fasted control and GTG mice were refed with standard laboratory diet for 24 h. During fasting and refeeding, the changes in glycogen content and the activity of glycogen synthase I and R and phosphorylase alpha in the liver were similar in lean and GTG mice. However, the glycogen storage in the livers from GTG mice was always greater than that in lean animals. In GTG mice the activity of liver glycogen synthase I and R was significantly higher than that in lean animals 3 and 6 h after refeeding. The activity of liver phosphorylase alpha in GTG mice was higher than that in lean mice after refeeding. There were no significant differences in the glycogen content of white adipose tissue, cardiac muscle, and skeletal muscle from lean and GTG mice during the entire study. The results of this study suggest that increased glycogen storage in the liver is a major alteration in nonoxidative glucose metabolism and contributes to the development of insulin resistance and glucose intolerance in GTG obese mice.

The AMPK γ1 R70Q mutant regulates multiple metabolic and growth pathways in neonatal cardiac myocytes

2007 ◽  
Vol 293 (6) ◽  
pp. H3456-H3464 ◽  
Author(s):  
Karalyn D. Folmes ◽  
Lee A. Witters ◽  
Michael F. Allard ◽  
Martin E. Young ◽  
Jason R. B. Dyck
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Myocytes ◽  
Glycogen Synthase ◽  
Neonatal Rat ◽  
Mrna Levels ◽  
Glycogen Accumulation ◽  
Regulatory Pathways ◽  
Γ Subunit ◽  
Gsk 3Β ◽  
Glycogen Synthase Activity

Although mutations in the γ-subunit of AMP-activated protein kinase (AMPK) can result in excessive glycogen accumulation and cardiac hypertrophy, the mechanisms by which this occurs have not been well defined. Because >65% of cardiac AMPK activity is associated with the γ1-subunit of AMPK, we investigated the effects of expression of an AMPK-activating γ1-subunit mutant (γ1 R70Q) on regulatory pathways controlling glycogen accumulation and cardiac hypertrophy in neonatal rat cardiac myocytes. Whereas expression of γ1 R70Q displayed the expected increase in palmitate oxidation rates, rates of glycolysis were significantly depressed. In addition, glycogen synthase activity was increased in cardiac myocytes expressing γ1 R70Q, due to both increased expression and decreased phosphorylation of glycogen synthase. The inhibition of glycolysis and increased glycogen synthase activity were correlated with elevated glycogen levels in γ1 R70Q-expressing myocytes. In association with the reduced phosphorylation of glycogen synthase, glycogen synthase kinase (GSK)-3β protein and mRNA levels were profoundly decreased in the γ1 R70Q-expressing myocytes. Consistent with GSK-3β negatively regulating hypertrophy via inhibition of nuclear factor of activated T cells (NFAT), the dramatic downregulation of GSK-3β was associated with increased nuclear activity of NFAT. Together, these data provide important new information about the mechanisms by which a mutation in the γ-subunit of AMPK causes altered AMPK signaling and identify multiple pathways involved in regulating both cardiac myocyte metabolism and growth that may contribute to the development of the γ mutant-associated cardiomyopathy.

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