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Article ; Online: GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease.

Chown, Erin E / Wang, Peixiang / Zhao, Xiaochu / Crowder, Justin J / Strober, Jordan W / Sullivan, Mitchell A / Xue, Yunlin / Bennett, Cody S / Perri, Ami M / Evers, Bret M / Roach, Peter J / Depaoli-Roach, Anna A / Akman, H Orhan / Pederson, Bartholomew A / Minassian, Berge A

Annals of clinical and translational neurology

2020 Volume 7, Issue 11, Page(s) 2186–2198

Abstract: Objective: Adult polyglucosan body disease (APBD) is an adult-onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched ...

Abstract	Objective: Adult polyglucosan body disease (APBD) is an adult-onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched glycogen aggregates called polyglucosan bodies in the nervous system. There are presently no treatments for APBD. Here, we test whether downregulation of glycogen synthesis is therapeutic in a mouse model of the disease. Methods: We characterized the effects of knocking out two pro-glycogenic proteins in an APBD mouse model. APBD mice were crossed with mice deficient in glycogen synthase (GYS1), or mice deficient in protein phosphatase 1 regulatory subunit 3C (PPP1R3C), a protein involved in the activation of GYS1. Phenotypic and histological parameters were analyzed and glycogen was quantified. Results: APBD mice deficient in GYS1 or PPP1R3C demonstrated improvements in life span, morphology, and behavioral assays of neuromuscular function. Histological analysis revealed a reduction in polyglucosan body accumulation and of astro- and micro-gliosis in the brains of GYS1- and PPP1R3C-deficient APBD mice. Brain glycogen quantification confirmed the reduction in abnormal glycogen accumulation. Analysis of skeletal muscle, heart, and liver found that GYS1 deficiency reduced polyglucosan body accumulation in all three tissues and PPP1R3C knockout reduced skeletal muscle polyglucosan bodies. Interpretation: GYS1 and PPP1R3C are effective therapeutic targets in the APBD mouse model. These findings represent a critical step toward the development of a treatment for APBD and potentially other glycogen storage disease type IV patients.
MeSH term(s)	Animals ; Behavior, Animal/physiology ; Disease Models, Animal ; Glycogen Storage Disease/metabolism ; Glycogen Storage Disease/physiopathology ; Glycogen Storage Disease/therapy ; Glycogen Synthase/deficiency ; Intracellular Signaling Peptides and Proteins/deficiency ; Mice ; Mice, Knockout ; Nervous System Diseases/metabolism ; Nervous System Diseases/physiopathology ; Nervous System Diseases/therapy
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Ppp1r3c protein, mouse ; Glycogen Synthase (EC 2.4.1.11)
Language	English
Publishing date	2020-10-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2740696-9
ISSN	2328-9503 ; 2328-9503
ISSN (online)	2328-9503
ISSN	2328-9503
DOI	10.1002/acn3.51211
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Article ; Online: Glycogen and its metabolism: some new developments and old themes.

Roach, Peter J / Depaoli-Roach, Anna A / Hurley, Thomas D / Tagliabracci, Vincent S

The Biochemical journal

2012 Volume 441, Issue 3, Page(s) 763–787

Abstract: Glycogen is a branched polymer of glucose that acts as a store of energy in times of nutritional sufficiency for utilization in times of need. Its metabolism has been the subject of extensive investigation and much is known about its regulation by ... ...

Abstract	Glycogen is a branched polymer of glucose that acts as a store of energy in times of nutritional sufficiency for utilization in times of need. Its metabolism has been the subject of extensive investigation and much is known about its regulation by hormones such as insulin, glucagon and adrenaline (epinephrine). There has been debate over the relative importance of allosteric compared with covalent control of the key biosynthetic enzyme, glycogen synthase, as well as the relative importance of glucose entry into cells compared with glycogen synthase regulation in determining glycogen accumulation. Significant new developments in eukaryotic glycogen metabolism over the last decade or so include: (i) three-dimensional structures of the biosynthetic enzymes glycogenin and glycogen synthase, with associated implications for mechanism and control; (ii) analyses of several genetically engineered mice with altered glycogen metabolism that shed light on the mechanism of control; (iii) greater appreciation of the spatial aspects of glycogen metabolism, including more focus on the lysosomal degradation of glycogen; and (iv) glycogen phosphorylation and advances in the study of Lafora disease, which is emerging as a glycogen storage disease.
MeSH term(s)	Amino Acid Sequence ; Animals ; Biology/trends ; Carbohydrate Metabolism/genetics ; Carbohydrate Metabolism/physiology ; Concept Formation ; Gluconeogenesis/physiology ; Glycogen/chemistry ; Glycogen/metabolism ; Glycogen/physiology ; Glycogenolysis/physiology ; Humans ; Metabolic Networks and Pathways/genetics ; Metabolic Networks and Pathways/physiology ; Mice ; Models, Biological ; Models, Molecular ; Molecular Sequence Data ; Sequence Homology, Amino Acid
Chemical Substances	Glycogen (9005-79-2)
Language	English
Publishing date	2012-01-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BJ20111416
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Article ; Online: Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure.

Cordero, Pablo / Parikh, Victoria N / Chin, Elizabeth T / Erbilgin, Ayca / Gloudemans, Michael J / Shang, Ching / Huang, Yong / Chang, Alex C / Smith, Kevin S / Dewey, Frederick / Zaleta, Kathia / Morley, Michael / Brandimarto, Jeff / Glazer, Nicole / Waggott, Daryl / Pavlovic, Aleksandra / Zhao, Mingming / Moravec, Christine S / Tang, W H Wilson /

Skreen, Jamie / Malloy, Christine / Hannenhalli, Sridhar / Li, Hongzhe / Ritter, Scott / Li, Mingyao / Bernstein, Daniel / Connolly, Andrew / Hakonarson, Hakon / Lusis, Aldons J / Margulies, Kenneth B / Depaoli-Roach, Anna A / Montgomery, Stephen B / Wheeler, Matthew T / Cappola, Thomas / Ashley, Euan A

Nature communications

2019 Volume 10, Issue 1, Page(s) 2760

Abstract: Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and ... ...

Abstract	Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.
MeSH term(s)	Animals ; Benzeneacetamides ; Cells, Cultured ; Datasets as Topic ; Disease Models, Animal ; Female ; Gene Expression Profiling/methods ; Gene Expression Regulation ; Gene Knockdown Techniques ; Gene Regulatory Networks/genetics ; Genome-Wide Association Study ; Heart Failure/etiology ; Heart Failure/genetics ; Heart Failure/metabolism ; Heart Failure/pathology ; Humans ; Male ; Metabolic Networks and Pathways/genetics ; Mice ; Mice, Knockout ; Middle Aged ; Myocytes, Cardiac/pathology ; Phosphoprotein Phosphatases/genetics ; Phosphoprotein Phosphatases/metabolism ; Primary Cell Culture ; Pyridines ; Quantitative Trait Loci/genetics ; Rats ; Rats, Sprague-Dawley ; Sequence Analysis, RNA/methods
Chemical Substances	2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide ; Benzeneacetamides ; Pyridines ; PPP1R3A protein, human (EC 3.1.3.-) ; PPP1R3A protein, mouse (EC 3.1.3.-) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; Ppp1r3a protein, rat (EC 3.1.3.16)
Language	English
Publishing date	2019-06-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-10591-5
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Article ; Online: Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation.

Jeoung, Nam Ho / Wu, Pengfei / Joshi, Mandar A / Jaskiewicz, Jerzy / Bock, Cheryl B / Depaoli-Roach, Anna A / Harris, Robert A

The Biochemical journal

2006 Volume 397, Issue 3, Page(s) 417–425

Abstract: The PDC (pyruvate dehydrogenase complex) is strongly inhibited by phosphorylation during starvation to conserve substrates for gluconeogenesis. The role of PDHK4 (pyruvate dehydrogenase kinase isoenzyme 4) in regulation of PDC by this mechanism was ... ...

Abstract	The PDC (pyruvate dehydrogenase complex) is strongly inhibited by phosphorylation during starvation to conserve substrates for gluconeogenesis. The role of PDHK4 (pyruvate dehydrogenase kinase isoenzyme 4) in regulation of PDC by this mechanism was investigated with PDHK4-/- mice (homozygous PDHK4 knockout mice). Starvation lowers blood glucose more in mice lacking PDHK4 than in wild-type mice. The activity state of PDC (percentage dephosphorylated and active) is greater in kidney, gastrocnemius muscle, diaphragm and heart but not in the liver of starved PDHK4-/- mice. Intermediates of the gluconeogenic pathway are lower in concentration in the liver of starved PDHK4-/- mice, consistent with a lower rate of gluconeogenesis due to a substrate supply limitation. The concentration of gluconeogenic substrates is lower in the blood of starved PDHK4-/- mice, consistent with reduced formation in peripheral tissues. Isolated diaphragms from starved PDHK4-/- mice accumulate less lactate and pyruvate because of a faster rate of pyruvate oxidation and a reduced rate of glycolysis. BCAAs (branched chain amino acids) are higher in the blood in starved PDHK4-/- mice, consistent with lower blood alanine levels and the importance of BCAAs as a source of amino groups for alanine formation. Non-esterified fatty acids are also elevated more in the blood of starved PDHK4-/- mice, consistent with lower rates of fatty acid oxidation due to increased rates of glucose and pyruvate oxidation due to greater PDC activity. Up-regulation of PDHK4 in tissues other than the liver is clearly important during starvation for regulation of PDC activity and glucose homoeostasis.
MeSH term(s)	Animals ; Diaphragm/metabolism ; Fatty Acids/metabolism ; Glucose/metabolism ; Glycolysis ; Homeostasis ; Insulin/blood ; Isoenzymes/biosynthesis ; Isoenzymes/genetics ; Isoenzymes/physiology ; Lactic Acid/metabolism ; Liver/metabolism ; Male ; Mice ; Mice, Knockout ; Organ Specificity ; Oxidation-Reduction ; Protein Kinases/biosynthesis ; Protein Kinases/genetics ; Protein Kinases/physiology ; Protein-Serine-Threonine Kinases ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase ; Pyruvic Acid/metabolism ; Starvation/blood ; Starvation/metabolism ; Up-Regulation
Chemical Substances	Fatty Acids ; Insulin ; Isoenzymes ; Pdk4 protein, mouse ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase ; Lactic Acid (33X04XA5AT) ; Pyruvic Acid (8558G7RUTR) ; Protein Kinases (EC 2.7.-) ; pyruvate dehydrogenase kinase 4 (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2006-03-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BJ20060125
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Article: Mice with elevated muscle glycogen stores do not have improved exercise performance.

Pederson, Bartholomew A / Cope, Carlie R / Irimia, Jose M / Schroeder, Jill M / Thurberg, Beth L / Depaoli-Roach, Anna A / Roach, Peter J

Biochemical and biophysical research communications

2005 Volume 331, Issue 2, Page(s) 491–496

Abstract: Skeletal muscle glycogen is considered to be an important source of energy for contraction and increasing the level of the glucose polymer is generally thought to improve exercise performance in humans. A genetically modified mouse model (GSL30), which ... ...

Abstract	Skeletal muscle glycogen is considered to be an important source of energy for contraction and increasing the level of the glucose polymer is generally thought to improve exercise performance in humans. A genetically modified mouse model (GSL30), which overaccumulates glycogen due to overexpression of a hyperactive form of glycogen synthase, was used to examine whether increasing the level of the polysaccharide enhances the ability of mice to run on a treadmill. The skeletal muscle of the GSL30 mice had large deposits of glycogen. There were no significant increases in the work performed by GSL30 mice as compared to their respective wild type littermates when exercised to exhaustion. The amount of muscle glycogen utilized by GSL30 mice, however, was greater, while the amount of liver glycogen consumed during exhaustive exercise was less than wild type animals. This result suggests that increased muscle glycogen stores do not necessarily improve exercise performance in mice.
MeSH term(s)	Animals ; Blood Glucose/analysis ; Exercise Test ; Glycogen/metabolism ; Glycogen Synthase/genetics ; Glycogen Synthase/metabolism ; Lactic Acid/blood ; Liver/metabolism ; Mice ; Muscle, Skeletal/cytology ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/physiology ; Physical Conditioning, Animal/physiology
Chemical Substances	Blood Glucose ; Lactic Acid (33X04XA5AT) ; Glycogen (9005-79-2) ; Glycogen Synthase (EC 2.4.1.11)
Language	English
Publishing date	2005-06-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2005.03.206
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Article: Abnormal metabolism of glycogen phosphate as a cause for Lafora disease.

Tagliabracci, Vincent S / Girard, Jean Marie / Segvich, Dyann / Meyer, Catalina / Turnbull, Julie / Zhao, Xiaochu / Minassian, Berge A / Depaoli-Roach, Anna A / Roach, Peter J

The Journal of biological chemistry

2008 Volume 283, Issue 49, Page(s) 33816–33825

Abstract: Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) ... ...

Abstract	Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual specificity protein phosphatase family that is able to release the small amount of covalent phosphate normally present in glycogen. In studies of Epm2a(-/-) mice that lack laforin, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. At three months, glycogen metabolism remained essentially normal, even though the phosphorylation of glycogen has increased 4-fold and causes altered physical properties of the polysaccharide. By 9 months, the glycogen has overaccumulated by 3-fold, has become somewhat more phosphorylated, but, more notably, is now poorly branched, is insoluble in water, and has acquired an abnormal morphology visible by electron microscopy. These glycogen molecules have a tendency to aggregate and can be recovered in the pellet after low speed centrifugation of tissue extracts. The aggregation requires the phosphorylation of glycogen. The aggregrated glycogen sequesters glycogen synthase but not other glycogen metabolizing enzymes. We propose that laforin functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen.
MeSH term(s)	Animals ; Disease Models, Animal ; Dual-Specificity Phosphatases/genetics ; Dual-Specificity Phosphatases/physiology ; Ethanol/chemistry ; Glycogen/chemistry ; Humans ; Lafora Disease/genetics ; Lafora Disease/metabolism ; Mice ; Mice, Transgenic ; Models, Biological ; Models, Genetic ; Phosphates/chemistry ; Polymers/chemistry ; Protein Tyrosine Phosphatases, Non-Receptor/genetics ; Protein Tyrosine Phosphatases, Non-Receptor/metabolism ; Time Factors
Chemical Substances	Phosphates ; Polymers ; Ethanol (3K9958V90M) ; Glycogen (9005-79-2) ; Dual-Specificity Phosphatases (EC 3.1.3.48) ; Epm2a protein, mouse (EC 3.1.3.48) ; Protein Tyrosine Phosphatases, Non-Receptor (EC 3.1.3.48)
Language	English
Publishing date	2008-10-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M807428200
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Article ; Online: Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo.

Tagliabracci, Vincent S / Turnbull, Julie / Wang, Wei / Girard, Jean-Marie / Zhao, Xiaochu / Skurat, Alexander V / Delgado-Escueta, Antonio V / Minassian, Berge A / Depaoli-Roach, Anna A / Roach, Peter J

Proceedings of the National Academy of Sciences of the United States of America

2007 Volume 104, Issue 49, Page(s) 19262–19266

Abstract: Lafora disease is a progressive myoclonus epilepsy with onset typically in the second decade of life and death within 10 years. Lafora bodies, deposits of abnormally branched, insoluble glycogen-like polymers, form in neurons, muscle, liver, and other ... ...

Abstract	Lafora disease is a progressive myoclonus epilepsy with onset typically in the second decade of life and death within 10 years. Lafora bodies, deposits of abnormally branched, insoluble glycogen-like polymers, form in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual-specificity protein phosphatase family that additionally contains a glycogen binding domain. The molecular basis for the formation of Lafora bodies is completely unknown. Glycogen, a branched polymer of glucose, contains a small amount of covalently linked phosphate whose origin and function are obscure. We report here that recombinant laforin is able to release this phosphate in vitro, in a time-dependent reaction with an apparent K(m) for glycogen of 4.5 mg/ml. Mutations of laforin that disable the glycogen binding domain also eliminate its ability to dephosphorylate glycogen. We have also analyzed glycogen from a mouse model of Lafora disease, Epm2a(-/-) mice, which develop Lafora bodies in several tissues. Glycogen isolated from these mice had a 40% increase in the covalent phosphate content in liver and a 4-fold elevation in muscle. We propose that excessive phosphorylation of glycogen leads to aberrant branching and Lafora body formation. This study provides a molecular link between an observed biochemical property of laforin and the phenotype of a mouse model of Lafora disease. The results also have important implications for glycogen metabolism generally.
MeSH term(s)	Animals ; Disease Models, Animal ; Dual-Specificity Phosphatases/deficiency ; Dual-Specificity Phosphatases/genetics ; Glycogen/metabolism ; Glycogen Synthase/analysis ; Glycogen Synthase/metabolism ; Lafora Disease/enzymology ; Male ; Mice ; Mice, Knockout ; Mutation ; Phosphorylation ; Protein Tyrosine Phosphatases, Non-Receptor ; Rabbits ; Recombinant Proteins/pharmacology
Chemical Substances	Recombinant Proteins ; Glycogen (9005-79-2) ; Glycogen Synthase (EC 2.4.1.11) ; Dual-Specificity Phosphatases (EC 3.1.3.48) ; Epm2a protein, mouse (EC 3.1.3.48) ; Protein Tyrosine Phosphatases, Non-Receptor (EC 3.1.3.48)
Language	English
Publishing date	2007-11-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0707952104
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Article: Enhanced cardiac function in mice overexpressing protein phosphatase Inhibitor-2.

Kirchhefer, Uwe / Baba, Hideo A / Bokník, Peter / Breeden, Kristine M / Mavila, Nirmala / Brüchert, Nicole / Justus, Isabel / Matus, Marek / Schmitz, Wilhelm / Depaoli-Roach, Anna A / Neumann, Joachim

Cardiovascular research

2005 Volume 68, Issue 1, Page(s) 98–108

Abstract: Objective: Protein phosphatase 1 (PP1) has been implicated in the control of cardiac function. Cardiac specific overexpression of the catalytic subunit, PP1c, results in hypertrophy and depressed contractility.: Methods: To further address the role ... ...

Abstract	Objective: Protein phosphatase 1 (PP1) has been implicated in the control of cardiac function. Cardiac specific overexpression of the catalytic subunit, PP1c, results in hypertrophy and depressed contractility. Methods: To further address the role of PP1, transgenic mice (TG) were generated that overexpress in heart a functional COOH-terminally truncated form (amino acids 1-140) of the PP1 inhibitor-2 (I-2(140)). Results: The TG hearts show increased levels of I-2(140) mRNA as well as protein and activity. No increase in absolute or relative heart weight was observed, nor any changes in gross pathology or increase in morbidity or mortality in the TG mice. Immunohistochemical and biochemical analyses revealed that expression of the I-2(140) protein is confined to cardiomyocytes where it is mainly localized in the cytosol. The total protein phosphatase (PP) activity was reduced by 80% in TG hearts as compared to wild-type littermates (WT). The PP1c mRNA level was the same in TG and WT, while the protein level was increased by approximately 7-fold in TG animals. The maximal rates of contraction (+dP/dt) and of relaxation (-dP/dt) were increased by 32% and 40%, respectively, in the intact catheterized TG mice compared to WT. However, the maximal contractile response to beta-adrenergic agonists was comparable in hearts from TG and WT mice. In isolated cardiomyocytes of TG mice, Ca2+transient amplitude was increased by 50% under basal conditions and by 60% upon rapid caffeine application. The phospholamban (PLB) protein level was unchanged whereas the basal phosphorylation of PLB at Ser(16) was significantly increased in TG hearts. Conclusion: These results indicate that I-2(140) overexpression results in decreased PP1 activity and enhanced contractility in the heart, underscoring the fundamental role of PP1 in cardiac function.
MeSH term(s)	Animals ; Blotting, Northern/methods ; Calcium/metabolism ; Calcium Channels/metabolism ; Cardiomegaly/enzymology ; Genetic Engineering ; Immunohistochemistry/methods ; Mice ; Mice, Transgenic ; Myocardial Contraction/physiology ; Myocardium/enzymology ; Myocardium/metabolism ; Perfusion ; Phosphoprotein Phosphatases/antagonists & inhibitors ; Phosphoprotein Phosphatases/metabolism ; Protein Phosphatase 1 ; Proteins/genetics ; Proteins/metabolism ; Sarcoplasmic Reticulum/metabolism
Chemical Substances	Calcium Channels ; Proteins ; protein phosphatase inhibitor-2 ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; Protein Phosphatase 1 (EC 3.1.3.16) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2005-10-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1016/j.cardiores.2005.05.019
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Article ; Online: Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator).

Isoda, Takayoshi / Paolocci, Nazareno / Haghighi, Kobra / Wang, Congrong / Wang, Yibin / Georgakopoulos, Dimitrios / Servillo, Giuseppe / Della Fazia, Maria Agnese / Kranias, Evangelia G / Depaoli-Roach, Anna A / Sassone-Corsi, Paolo / Kass, David A

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2003 Volume 17, Issue 2, Page(s) 144–151

Abstract: The cAMP response element modulator (CREM) plays pivotal roles in the hypothalamic-pituitary-gonadal axis. CREM mRNA is robustly expressed in human myocardium, and identified isoforms may suppress cAMP response element-mediated transcription. However, ... ...

Abstract	The cAMP response element modulator (CREM) plays pivotal roles in the hypothalamic-pituitary-gonadal axis. CREM mRNA is robustly expressed in human myocardium, and identified isoforms may suppress cAMP response element-mediated transcription. However, little is known about the physiological importance of CREM in intact hearts remains unknown. We studied CREM-null mice and age-matched control littermates by in vivo pressure-volume loops to analyze basal and reserve cardiac function. Basal systolic and diastolic function, echocardiographic morphology, and myocardial histology were normal in CREM-null animals. However functional reserve with increasing heart rate was markedly depressed, with less contractile augmentation (+22+/-9% CREM-/- vs.+62+/-11% controls, P<0.05) and relaxation shortening (5+/-5% CREM-/- vs. -18+/-3% controls; P<0.05) at faster rates. In contrast, isoproterenol dose-responses were similar, suggesting normal beta-adrenergic receptor-coupled signaling. Gene expression of calcium handling proteins (SERCA, phospholamban) and stress-response genes (e.g., alpha-skeletal actin, beta-myosin heavy chain, natriuretic peptides) were similar between groups. However, total and serine-phosphorylated phospholamban protein declined -38 and -64% respectively, and protein phosphatase-1 (PP1) activity increased 44% without increased protein levels (all P<0.01) in CREM-/- vs. controls. These results demonstrate novel involvement of CREM in regulation of PP1 activity and of PLB, likely resulting in a potent frequency-dependent influence on cardiac function.
MeSH term(s)	Adrenergic beta-Agonists/pharmacology ; Animals ; Blood Pressure/drug effects ; Blood Pressure/physiology ; Calcium-Binding Proteins/metabolism ; Calcium-Transporting ATPases/metabolism ; Cyclic AMP Response Element Modulator ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/physiology ; Dose-Response Relationship, Drug ; Genotype ; Heart/physiology ; Heart Rate/drug effects ; Heart Rate/physiology ; Hemodynamics/drug effects ; Hemodynamics/physiology ; Isoproterenol/pharmacology ; Mice ; Mutation ; Phosphoprotein Phosphatases/metabolism ; Phosphorylation ; Protein Phosphatase 1 ; Repressor Proteins ; Sarcoplasmic Reticulum Calcium-Transporting ATPases
Chemical Substances	Adrenergic beta-Agonists ; Calcium-Binding Proteins ; DNA-Binding Proteins ; Repressor Proteins ; phospholamban ; Cyclic AMP Response Element Modulator (135844-64-3) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; Protein Phosphatase 1 (EC 3.1.3.16) ; Calcium-Transporting ATPases (EC 3.6.3.8) ; Sarcoplasmic Reticulum Calcium-Transporting ATPases (EC 3.6.3.8) ; Isoproterenol (L628TT009W)
Language	English
Publishing date	2003-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.01-0981com
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