Mutation analysis of AMP-activated protein kinase subunits in inherited cardiomyopathies: implications for kinase function and disease pathogenesis

Oliveira, Sandra Marisa; Ehtisham, Javed; Redwood, Charles; Östman‐Smith, Ingegerd; Blair, Edward; Watkins, Hugh

doi:10.1016/s0022-2828(03)00237-2

Cited by 48 publications

(31 citation statements)

References 26 publications

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“…87 [PCr] relative to a presumably unchanged [ATP] was lower in 31 HCM patients with known 88,89 broadening the scope of the role of energetics in FHC and perhaps all forms of heart failure.…”

Section: The Effect Of Ischemia On Energetics In the Failing Heartmentioning

confidence: 98%

Is the Failing Heart Energy Starved?

Ingwall

Weiss

2004

Circulation Research

538

281

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Abstract-The requirement of chemical energy in the form of ATP to support systolic and diastolic work of the heart is absolute. Because of its central role in cardiac metabolism and performance, the subject of this review on energetics in the failing heart is ATP. We briefly review the basics of myocardial ATP metabolism and describe how this changes in the failing heart. We present an analysis of what is now known about the causes and consequences of these energetic changes and conclude by commenting on unsolved problems and opportunities for future basic and clinical research. Key Words: adenosine triphosphate Ⅲ phosphocreatine Ⅲ creatine kinase Ⅲ familial hypertrophic cardiomyopathy Ⅲ heart failure T he energy starvation hypothesis suggesting that the failing heart is energy-starved is decades old. 1,2 Because ATP is required for normal systolic and diastolic contractile performance, the idea that the failing heart is unable to meet the hemodynamic requirements of the body because there is not enough chemical energy available is logical. The hypothesis was initially set aside for several reasons. First, it was unclear whether the concentration of ATP ([ATP]) decreased. Second, it was reasoned that even if there were decreases in [ATP] in the failing heart, the remaining ATP should be sufficient to supply the ATP-requiring reactions in the myocyte. Third, our understanding of how ATP synthesis and use are regulated was remarkably incomplete. A good example of our ignorance about cardiac energetics was the use of inotropic agents to increase performance of the failing human heart. While increasing performance, these agents did so at great energetic cost and often resulted in increased, rather than decreased, heart failure mortality.There is now renewed interest in the energy-starvation hypothesis. 3,4 New biophysical tools such as nuclear magnetic resonance (NMR) spectroscopy, positron emission tomography (PET), and transgenesis using the mouse have allowed old questions to be revisited and new ones to be formulated. Combining old and new strategies to address the "energy starvation" hypothesis, we have learned much. We now know when and by how much [ATP] decreases in the hypertrophied and failing heart. We now know that despite increases in some ATP synthesizing pathways such as glycolysis, other pathways such as the creatine kinase (CK)-phosphocreatine (PCr) system decrease. Finally, we now have a better understanding of how the myocyte accomplishes the tasks of maintaining (near) normal ATP supply Original

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Section: The Effect Of Ischemia On Energetics In the Failing Heartmentioning

confidence: 98%

Is the Failing Heart Energy Starved?

Ingwall

Weiss

2004

Circulation Research

538

281

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“…The fusion cDNA/Neo cassette was flanked by loxP sites and was positioned upstream of exons 13-16 of the Raf1 gene itself, with an L613V mutation introduced into exon 16 and an HSV-TK cassette for negative selection. In the absence of Cre recombinase (Cre), Raf1 exon 12 should be spliced to the cDNA (exon [13][14][15][16], leading to the production of WT Raf1. When Cre is present, the floxed cassette should be excised, evoking transcription of the mutant Raf1 allele.…”

Section: Generation Of L613v/+ Mice Expression Of An Activated Raf1 mentioning

confidence: 99%

“…Aberrant activation of hypertrophic signaling pathways can themselves result in hypertrophy. For example, germline mutations in AMPK are a rare cause of HCM (12)(13)(14). Moreover, genetic and cellular models have identified multiple signaling systems that can cause or contribute to pathological hypertrophy, including the calcineurin-NFAT,IGF-I, EGF, and PDGF), cytokines (e.g., IL-6, cardiotrophin, and leukemia inhibitory factor [LIF]), G protein-coupled receptor (GPCR) agonists (e.g., angiotensin II [Ang II] and β-adrenergic agonists), and physical stimuli (e.g., mechanical stretch), in cardiomyocytes as well as other cell types (1,2,16).…”

Section: Introductionmentioning

confidence: 99%

MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1L613V mutation

Simpson²,

Hong³

et al. 2011

J. Clin. Invest.

187

182

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Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden death in children and young adults. Abnormalities in several signaling pathways are implicated in the pathogenesis of HCM, but the role of the RAS-RAF-MEK-ERK MAPK pathway has been controversial. Noonan syndrome (NS) is one of several autosomal-dominant conditions known as RASopathies, which are caused by mutations in different components of this pathway. Germline mutations in RAF1 (which encodes the serine-threonine kinase RAF1) account for approximately 3%-5% of cases of NS. Unlike other NS alleles, RAF1 mutations that confer increased kinase activity are highly associated with HCM. To explore the pathogenesis of such mutations, we generated knockin mice expressing the NS-associated Raf1 L613V mutation. Like NS patients, mice heterozygous for this mutation (referred to herein as L613V/+ mice) had short stature, craniofacial dysmorphia, and hematologic abnormalities. Valvuloseptal development was normal, but L613V/+ mice exhibited eccentric cardiac hypertrophy and aberrant cardiac fetal gene expression, and decompensated following pressure overload. Agonist-evoked MEK-ERK activation was enhanced in multiple cell types, and postnatal MEK inhibition normalized the growth, facial, and cardiac defects in L613V/+ mice. These data show that different NS genes have intrinsically distinct pathological effects, demonstrate that enhanced MEK-ERK activity is critical for causing HCM and other RAF1-mutant NS phenotypes, and suggest a mutation-specific approach to the treatment of RASopathies.

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“…14 -17 Mutations in the genes encoding the other subunit isoforms of AMPK do not appear to cause this phenotype, suggesting that alteration of the function of heterotrimers containing the ␥2 subunit specifically cause this disease. 18 Because ␥2 is a minority isoform and is ubiquitously expressed, this phenotype suggests a specific role for this subunit in the heart. We hypothesized that the unique N-terminal region of the ␥2 subunit may play a role in determining substrate specificity in the heart or intracellular localization.…”

mentioning

confidence: 99%

AMP-Activated Protein Kinase Phosphorylates Cardiac Troponin I and Alters Contractility of Murine Ventricular Myocytes

Oliveira

Zhang²,

Solis

et al. 2012

Circulation Research

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Rationale: AMP-activated protein kinase (AMPK) is an important regulator of energy balance and signaling in the heart. Mutations affecting the regulatory ␥2 subunit have been shown to cause an essentially cardiacrestricted phenotype of hypertrophy and conduction disease, suggesting a specific role for this subunit in the heart.Objective: The ␥ isoforms are highly conserved at their C-termini but have unique N-terminal sequences, and we hypothesized that the N-terminus of ␥2 may be involved in conferring substrate specificity or in determining intracellular localization. Methods and Results:A yeast 2-hybrid screen of a human heart cDNA library using the N-terminal 273 residues of ␥2 as bait identified cardiac troponin I (cTnI) as a putative interactor. In vitro studies showed that cTnI is a good AMPK substrate and that Ser150 is the principal residue phosphorylated. Furthermore, on AMPK activation during ischemia, Ser150 is phosphorylated in whole hearts. Using phosphomimics, measurements of actomyosin ATPase in vitro and force generation in demembraneated trabeculae showed that modification at Ser150 resulted in increased Ca 2؉ Key Words: familial hypertrophic cardiomyopathy Ⅲ myocardial contractility Ⅲ phosphorylation A MP-activated protein kinase (AMPK) is a crucial component of a highly conserved serine/threonine protein kinase cascade central to the control of energy balance at the cellular and whole-body levels. 1,2 AMPK exists as a ␣␤␥ heterotrimer, with ␣ being the catalytic subunit, and the ␤ and ␥ subunits performing structural and regulatory functions. Isoforms of all subunits have been identified (␣1, ␣2, ␤1, ␤2, ␥1, ␥2, and ␥3), each being encoded by a different gene (PRKAA1, PRKAA2, PRKAB1, PRKAB2, PRKAG1, PRKAG2, and PRKAG3, respectively). The ␣ subunits consist of a typical serine/threonine protein kinase domain at the N-terminus (which also contains the critical phosphorylation site for AMPK activation, Thr172 3 ) and a C-terminal domain involved in the binding of the ␤ and ␥ subunits. 1,2 The ␤ subunits are myristoylated at their N-terminus, contain a conserved C-terminal domain that is involved in binding of the ␣ and ␥ subunits, and a carbohydrate binding domain. The carbohydrate binding domain may allow AMPK to sense the status of cellular energy reserves in the form of glycogen in addition to responding to AMP/ATP levels. 4 The ␥ subunits have a high degree of homology in their C-terminal Original received October 31, 2011; revision received March 14, 2012; accepted March 19, 2012. In February 2012 sequences, all containing 2 pairs of highly conserved cystathionine ␤-synthase domains, which have been shown to be directly involved in the binding of adenine nucleotides. [5][6][7] In contrast, their N-terminal regions are highly variable, with ␥2 and ␥3 possessing different long N-terminal extensions compared with the shorter ␥1 isoform (Figure 1). The ␥2 and ␥3 N-terminal sequences appear to be unique in that they do not share sequence identity with each other nor with any known protein. ...

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Mutation analysis of AMP-activated protein kinase subunits in inherited cardiomyopathies: implications for kinase function and disease pathogenesis

Cited by 48 publications

References 26 publications

Is the Failing Heart Energy Starved?

Is the Failing Heart Energy Starved?

MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1L613V mutation

AMP-Activated Protein Kinase Phosphorylates Cardiac Troponin I and Alters Contractility of Murine Ventricular Myocytes

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