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Advances in Arrhythmia and Electrophysiology
AMP-Activated Protein Kinase
Potential Role in Cardiac Electrophysiology and Arrhythmias
Masahide Harada, MD, PhD*; Sarah Naomi Nattel, BA*; Stanley Nattel, MD
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A
AMPK phosphorylates a wide range of signaling systems and
effectors, with major functional consequences (Figure 2).
AMPK is a heterotrimeric enzyme with 1 catalytic (α) and
2 regulatory (β and γ) subunits (Figure 1). Thr-172 in the
α-subunit is a crucial phosphorylation site that regulates
AMPK function. The β-subunit has 2 structural components: a
glycogen-binding domain that is sensitive to fuel storage levels and a C-terminal region that anchors α- and γ-subunits.
The γ-subunit has a pair of cystathionine-β-synthase sequence
repeats, called Bateman domains, which bind adenosine
nucleotides.1–5 AMP binding to the γ-subunit facilitates Thr172 phosphorylation by upstream kinases, protects the site
against dephosphorylation by protein phosphatases (PPs),
and allosterically activates the enzyme. The crystal structure of AMPK has recently been resolved, revealing how the
regulatory domain stabilizes the activation loop of the kinase
domain and prevents dephosphorylation.6 Various isoforms of
the AMPK subunits have been identified (α1, α2, β1, β2, γ1,
γ2, γ3), potentially leading to the formation of 12 different
complexes.1–5 The α2, β2, and γ2 subunits predominate in the
heart, which mainly expresses α2/β2/γ2 complexes.1 Activated
AMPK activation is favored by 3 nonexclusive mechanisms
that often occur simultaneously: (1) allosteric activation,
(2) α-subunit phosphorylation by upstream AMPK kinases
(AMPKKs), and (3) inhibition of PP-mediated α-subunit
dephosphorylation.1–6 AMP binding promotes AMPK activation by allosterically activating the enzyme, making it a
poorer substrate for PPs and a better substrate for AMPKK.7
ADP binding also protects AMPK from dephosphorylation.6
Although the AMPK-binding affinity to ATP is high, its affinity for Mg-ATP, the predominant intracellular form, is much
lower, explaining why ADP and AMP (with substantially
lower physiological concentrations than ATP) can compete
with ATP for binding.6 Metabolic dysfunction increases intracellular AMP concentrations, enhancing AMP binding to the
cystathionine-β-synthase motifs in the γ-subunit. AMPK activation occurs with a half-maximally activating AMP concentration (A0.5) of 4 μmol/L and full activation by 10 μmol/L,
within the physiologically attainable range.7,8 ATP antagonizes
activation via AMP by competing with AMP for binding at the
allosteric site, without promoting the active conformation.3
The A0.5 increases ≈20-fold when intracellular ATP concentration increases from 0.2 to 4 mmol/L.1
Phosphorylation of the α-subunit Thr-172 by upstream
AMPKKs crucially regulates AMPK function. Combined
AMPK activation by AMP and AMPK phosphorylation
produces a >1000-fold increase in AMPK activity, whereas
AMP alone elicits only a 5-fold maximum increase.3 Two
major AMPKKs are present in the heart: liver kinase B1
(LKB1), also known as serine/threonine kinase 11,9 and
Ca2+/calmodulin-dependent protein kinase kinase (CaMKK).
LKB1 is much more abundantly expressed in the heart than
CaMKK.2 The amphipathic αG-helix in the AMPK α-subunit
interacts with LKB1.10 LKB1 reacts to myocardial ischemia
by phosphorylating the α2-subunit.1 CaMKK, particularly
the CaMKKβ (CaMKK2) isoform, phosphorylates and activates AMPK on elevation of intracellular Ca2+ concentration.4
MP-activated protein kinase (AMPK), a serine/threonine
kinase, is a highly conserved homeostatic regulatory
enzyme with a plethora of important roles in energy storage
and use. ATP is the primary cellular energy source; in situations of metabolic deficiency, its breakdown product AMP
accumulates. AMPK is sensitive to the cellular energy state:
it is activated by AMP and inactivated by ATP. Under metabolic stress, when the AMP/ATP ratio is elevated, AMPK acts
as an energy sensor and compensates for energy depletion by
upregulating energy sources and downregulating energy-consuming processes that are not immediately essential.1–5 There
is growing recognition that AMPK is particularly important in
the heart, which demands more energy on a continuous basis
than most other organs.1,2 AMPK seems to be a critical regulator of cardiac energy status and may be a potential therapeutic
target. In this article, we will review the literature regarding
cardiac AMPK and discuss evidence for a potentially important and underappreciated role of AMPK in cardiac electrophysiology and arrhythmia generation.
Activation of AMPK
AMPK Structure
Received April 3, 2012; accepted May 30, 2012.
From the Department of Medicine and Research Centre, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada (M.H., S.N.);
Department of Biology, Stern College for Women, Yeshiva University, New York, NY (S.N.N.); Department of Pharmacology and Therapeutics, McGill
University, Montreal, Quebec, Canada (S.N.).
*These authors contributed equally to this article.
Correspondence to Stanley Nattel, MD, Montreal Heart Institute Research Centre, 5000 Belanger St E, Montreal, Quebec, H1T 1C8, Canada. E-mail
[email protected]
(Circ Arrhythm Electrophysiol. 2012;5:860-867.)
© 2012 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org
860
DOI: 10.1161/CIRCEP.112.972265
Harada et al AMPK and Cardiac Electrophysiology/Arrhythmias 861
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Figure 1. AMP-activated protein kinase
(AMPK) activation. The AMPK complex
consists of 3 different subunits: the
α-subunit has a kinase domain (KD)
that phosphorylates downstream targets,
the β-subunit scaffolds the α and γ subunits, the γ-subunit binds AMP or ATP in
a competitive manner. AMP binding to the
γ-subunit causes a conformational change
of the AMPK complex, which increases
phosphorylation of the α-subunit at
Thr-172, primarily by preventing dephosphorylation by protein phosphatases (PPs)
and by promoting phosphorylation by
AMPK-kinases (AMPKKs), such as liverkinase B1 (LKB1) and Ca2+/calmodulindependent protein kinase kinase (CaMKK).
Thr-172 phosphorylation substantially
increases AMPK enzyme activity. In addition, AMP itself allosterically enhances
enzyme activity.
The transforming growth factor-β–activated kinase, a member
of the mitogen-activated protein kinase kinase family, is also
implicated in AMPK activation.11
PPs, particularly PP2A and PP2C, regulate AMPK activity
by dephosphorylating Thr-172. AMP binding to the γ-subunit
induces a conformational change in the α-subunit that prevents AMPK dephosphorylation by PPs.3
AMPK and Cardiac Metabolism
AMPK phosphorylates a variety of enzymes that play important roles in cardiac metabolism (Figure 2), with a net effect to
increase energy availability.
Fatty Acid Metabolism
Once activated under conditions of metabolic stress, AMPK
enhances cellular energy availability. AMPK stimulates fatty
acid oxidation (a major cardiac energy source) by phosphorylating and inhibiting acetyl-CoA carboxylase, the
rate-limiting enzyme in malonyl-CoA synthesis. Malonyl-CoA
inhibits carnitine palmitoyltransferase-1, a mitochondrial
enzyme that facilitates fatty acid entry into the mitochondria for oxidation. Phosphorylation of acetyl-CoA
carboxylase by AMPK inactivates acetyl-CoA carboxylase,
thereby inhibiting malonyl-CoA production.12 The resulting decrease in malonyl-CoA concentrations disinhibits
Figure 2. Downstream targets and effects of
activated AMP-activated protein kinase (AMPK).
Arrows indicate proteins whose function is activated as a result of phosphorylation by AMPK;
blunt ends designate inhibited proteins. The
functions around the periphery correspond to
the systems affected by AMPK regulation of
the proteins shown. ACC indicates acetylCoA carboxylase; eEF2, eukaryotic elongation
factor-2; eNOS, endothelial NO synthase; ERRα,
estrogen-related receptor α; FABPpm, fatty acid
binding protein; FAT/CD36, fatty acid transporter; GLUT4, glucose transporter 4; GP, glycogen phosphorylase; GS, glycogen synthase;
HMGR, 3-hydroxy 3-methylglutaryl CoA reductase; mTOR, mammalian target of rapamycin;
PCG-1α, transcriptional coactivator peroxisome
proliferator-activated receptor-γ coactivator
1α; PFK2, phosphofructokinase-2;ULK-1, Unc51–like kinase; ROS, reactive oxygen species;
NADPH, nicotinamide adenine dinucleotide
phosphate.
862 Circ Arrhythm Electrophysiol August 2012
carnitine palmitoyltransferase-1 and promotes fatty acid
oxidation.1,2,4,5,12
AMPK increases the expression of the fatty acid transporter
fatty acid translocase/CD36 and membrane-associated fatty
acid–binding protein, both of which are involved in cellular fatty acid uptake. AMPK also recruits lipoprotein lipase,
which extracts fatty acid molecules from triglycerides and
enhances fatty acid availability.
Glucose Metabolism
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AMPK is involved in carbohydrate metabolism, independently
of insulin-mediated mechanisms. The AMPK-dependent regulation of carbohydrate metabolism is particularly important in
pathological conditions, in which oxygen depletion and anaerobic glycolysis are of primary concern, whereas insulin-dependent regulation predominates at rest or during physiological
stresses, such as exercise. Activated AMPK increases the protein expression of glucose transporters GLUT1 and GLUT4,
increasing cellular glucose uptake. GLUT4 is also trafficked
into the membrane from intracellular stores on AMPK activation.1 AMPK does not directly phosphorylate GLUT4: other
AMPK targets, such as protein kinase C, p38 mitogen–activated
protein kinase, and transforming growth factor-β–activated protein kinase 1–binding protein, may mediate the enhancement
of GLUT4 function.13 Activated AMPK also phosphorylates
phosphofructokinase-2 to convert fructose-6-phosphate to fructose-2,6-bisphosphate.1–5 Fructose-2,6-bisphosphate activates
phosphofructokinase-1, which accelerates glycolysis. Therefore,
AMPK activation promotes both glucose uptake and glycolysis.
AMPK inhibits glycogen synthase (an enzyme that converts glucose to glycogen) and stimulates glycogen phosphorylase (an enzyme that results in the degradation of
glycogen to glucose).1,2 5-Aminoimidazole-4-carboxamide1-β-D-ribofuranoside (a pharmacological AMPK activator)
increases glycogen degradation in perfused rat hearts without
altering glycogen synthase and glycogen phosphorylase activities.14 However, repeated AMPK activation increases glycogen content, and the precise roles of AMPK in the glycogen
storage process are yet to be fully clarified.1
AMPK and Arrhythmia-Promoting
Cardiovascular Disease
A variety of important cardiac disease conditions alter cardiac
ion channel and transporter function and promote arrhythmogenesis.15 Metabolic stress plays a central role in the cellular
dysfunction caused by conditions such as hypertrophy, heart
failure (HF), and myocardial ischemia (Figure 3). By alleviating cellular stress, AMPK plays an important adaptive role and
can mitigate complications, presumably including arrhythmogenesis. Interestingly, although there is a strong body of evidence implicating AMPK as protective against arrhythmogenic
disease conditions (see below), the actual information available about changes in arrhythmogenesis because of activation
or inhibition of AMPK in such conditions is extremely limited.
Cardiac Hypertrophy
Cardiomyocyte hypertrophy is most apparent in response
to pressure loads (eg, hypertension and valvular disease),
although it occurs with any maintained increase in cardiac
load. Cardiac hypertrophy increases metabolic demand, consuming more energy. Relative anoxia results from increased
energy needs, as well as impaired coronary blood flow distribution because of altered diastolic transmural pressure gradients, inducing metabolic perturbations. Several studies have
shown increased AMPK α-subunit phosphorylation in models
of cardiac hypertrophy.16 Upregulated glucose and fatty acid
metabolism with AMPK activation increases the availability of energy sources, which may mitigate metabolic stress.
AMPK is also involved in downstream signaling processes
regulating protein synthesis, such as mammalian target of
rapamycin (mTOR), eukaryotic elongation factor-2 (eEF2),
and p70S6 kinase (Figure 2).17 These signaling pathways
increase protein synthesis and promote hypertrophic growth
and proliferation. AMPK inhibits these cascades, countering
cardiac hypertrophy.17 AMPK activation mitigates transverse
aortic constriction–induced cardiac hypertrophy through
inhibition of protein synthetic signaling.18,19 AMPK activation would thus be expected to combat the arrhythmogenic
potential inherent in cardiac hypertrophic conditions,20 both
by limiting metabolic disturbances caused by hypertrophy and
by suppressing hypertrophy itself.
Heart Failure
AMPK prevents the progression from hypertrophy to HF:
AMPK α2-subunit–deficient mice show exacerbated transverse aortic constriction–induced hypertrophy and accelerated
transition to HF.21 Transition to HF is associated with activation of mTOR signaling, which is responsible for protein synthesis and cell proliferation. AMPK also stimulates autophagy
via activation of Unc-51–like kinase that is suppressed by
mTOR (Figure 2).22
Malfunction of mitochondrial biogenesis is an important
component in the development of HF.23 Nuclear receptors and
their coactivators, such as estrogen-related receptor α and peroxisome proliferator–activated receptor-γ coactivator 1α, regulate mitochondrial transcripts and stimulate fatty acid oxidation
and oxidative respiration.24,25 Activation of AMPK increases
expression levels of estrogen-related receptor α: AMPKα2
knockout mice have decreased estrogen-related receptor α
expression, whereas constitutively active AMPK increases
estrogen-related receptor α expression.24 AMPK activation
also stimulates mitochondrial biogenesis via direct phosphorylation of peroxisome proliferator–activated receptor-γ coactivator 1α.25 Both these effects lead to improved mitochondrial
function and could, therefore, protect against HF.
Cardiac angiogenesis concomitant with hypertrophy is
also critical for slowing the transition to HF. AMPK activation increases the expression of proangiogenic factors, such
as endothelial NO synthase and vascular endothelial growth
factor.11 Adiponectin has pleiotropic cardioprotective effects
and activates AMPK. In adiponectin-deficient mice, impaired
AMPK activation accelerates the transition to HF in transverse aortic constriction–induced hypertrophy because of
inadequate angiogenesis.26
AMPK decreases endoplasmic stress in endothelial cells
and prevents cellular apoptosis in cardiomyocytes.27 AMPK
inhibits nicotinamide adenine dinucleotide phosphate-oxidase
activation and thereby reduces reactive oxygen species
Harada et al AMPK and Cardiac Electrophysiology/Arrhythmias 863
Figure 3. AMP-activated protein kinase
(AMPK) in arrhythmia-promoting cardiovascular pathology. Cardiac disease–related
processes (eg, hypertrophy, congestive
heart failure [CHF], and ischemia/reperfusion)
facilitate arrhythmia generation by causing
cellular dysfunction and inducing metabolic
stress. AMPK activation in response to
metabolic stress improves metabolic disturbances and cellular dysfunction. FA indicates
fatty acid.
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generation.9 These effects might also contribute to preventing
transition to HF.
It must be pointed out that actions of AMPK are not necessarily beneficial in all cardiac failure paradigms. For example,
a recent study suggests that AMPK activation may mediate
ethanol-induced myocardial hypocontractility via enhanced
AMPK-mTOR-Unc-51–like kinase–mediated autophagy.28
Myocardial Ischemia and Reperfusion Injury
AMPK is particularly important during ischemia and
ischemia/reperfusion injury. Oxidative metabolism decreases
under ischemic conditions, and anaerobic glycolysis predominates. AMPK accelerates glucose metabolism in response
to an increased AMP/ATP ratio. The metabolic state of the
postischemic myocardium is a critical determinant of myocardial injury and recovery of cardiac function upon reperfusion.
Using transgenic mice overexpressing nonfunctional (kinase
dead) AMPK, Russell et al29 demonstrated that kinase-dead
AMPK hearts fail to augment glucose and fatty acid metabolism during ischemia/reperfusion, manifesting increased myocardial injury.
Substantial energy resources are consumed to incorporate
amino acids into protein. AMPK activation limits energy
consumption by suppressing protein synthetic signaling pathways, such as eEF-2 and mTOR.30
Although myocardial necrosis is primarily responsible for
cell death during ischemia/reperfusion, apoptosis also contributes. The increased myocardial damage in kinase-dead AMPK
hearts subjected to ischemia/reperfusion is also because of
increased apoptosis.29 The antiapoptotic effect of adiponectin
is also mediated by the activation of AMPK.31
AMPK and Cardiac
Electrophysiology/Arrhythmias
PRKAG2 Mutation Cardiomyopathy
The most striking example of arrhythmogenesis related to
AMPK dysfunction is protein kinase, AMP-activated, γ2
noncatalytic subunit (PRKAG2) mutation cardiomyopathy.
Humans with missense mutations in the γ2 regulatory subunit
of AMPK (PRKAG2) have hypertrophic cardiomyopathies
and frequently manifest arrhythmogenic electrophysiological abnormalities.1,32,33 The pathology caused by the diseaseproducing PRKAG2 mutations Arg302Gln, Thr400Asn, and
Asn488Ile is characterized by preexcitation, atrial fibrillation
(AF), progressive conduction system disease, and cardiac
hypertrophy.32,33 Mice overexpressing PRKAG2 genes with
disease-causing mutations R302Q, N488I, or R531G in the
heart recapitulate the phenotype of human PRKAG2 cardiomyopathy.34–36 The effects of these mutations on AMPK
function is complex: they seem to enhance basal activity but
impair activation because of AMP accumulation.1 Histological findings include an abundance of vacuoles and increased
periodic acid-Schiff-positive materials, indicating increased
glycogen deposition. Myofiber disarray, typical of hypertrophic cardiomyopathy, is not detected, and interstitial fibrosis is
minimal, although the myocytes are enlarged. Ventricular preexcitation and supraventricular tachyarrhythmia are observed
in most of the transgenic animals. Patel et al34 demonstrated
that the annulus fibrosis, which limits electrical connection
between the atria and ventricles, is thinned, stretched, and
disrupted in N488I-expressing transgenic mice and that this
region contains many vacuolated, glycogen-loaded myocytes.
These data suggest that PRKAG2 cardiomyopathy and the
associated preexcitation are attributable to a glycogen storage abnormality distinct from hypertrophic cardiomyopathy.
Developmental abnormalities lead to failure of formation of a
complete annulus fibrosis, preserving atrioventricular muscle
bundle connections. The effect of N4881 PRKAG2 mutations
is specific for AMPK containing α2-subunits; AMPK containing α1-subunits is unaffected.37
Ion Channel Regulation and Other Determinants
of Arrhythmia
Figure 4 shows the potential effects of AMPK on a variety of
arrhythmia determinants, including ion channels, transporters,
and structural factors. The open-state inactivation of cardiac
voltage-gated Na+ channels is slowed in mice overexpressing a
864 Circ Arrhythm Electrophysiol August 2012
Figure 4. AMP-activated protein kinase
(AMPK)–dependent modification of factors
governing cardiac arrhythmogenesis. Activated AMPK can directly regulate ion
channel/transporter function, altering cardiac
electrophysiological function and thereby
modifying cardiac arrhythmogenesis. In
addition, effects on cell proliferation and
hypertrophy can modify cardiac structure
to alter arrhythmogenic substrates. Most
of the effects shown are directly induced
by AMPK; however, changes in SERCA
and PLB have been observed in models
of AMPK knockdown and may be secondary to a cardiomyopathic phenotype.
NCX indicates Na+/Ca2+-exchanger; PLB,
phospholamban; RyR2, ryanodine receptor
type-2 (cardiac form); SERCA, sarcoplasmic reticulum Ca2+-ATPase; DADs, delayed
afterdepolarizations.
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constitutively active mutant (T172D) of the AMPK α1-subunit.38
This induces a gain in late Na+-channel function, increasing
action potential duration (APD) and causing early afterdepolarizations, similar to long-QT syndromes caused by SCN5Aa
mutations.38 Thus, basal AMPK activation due to PRKAG2
mutations may be arrhythmogenic by altering Na+-channel
function. Delayed repolarization is a well-recognized consequence of HF that contributes to arrhythmogenesis15; one of
the causes may be incomplete Na+-channel inactivation due to
AMPK activation secondary to HF-induced metabolic stress.
AMPK has potentially significant effects on cardiac K+
channels. Ischemic preconditioning involves myocardial ATPdependent K+ (KATP) channels. Mice expressing dominantnegative AMPK α2-subunits (functional AMPK-knockdown)
lack preconditioning-induced activation of KATP channels,
APD shortening, and cardioprotection.39 The authors provided
evidence suggesting that AMPK may be needed to enhance
trafficking of KATP channels to the sarcolemma on preconditioning. Phenylephrine-induced cardiac preconditioning also
seems to require AMPK-related sarcolemmal KATP-channel
activation.40 Although in the case of preconditioning AMPKrelated APD abbreviation may contribute to cardioprotection,
the same effect could promote the risk of malignant reentrant
arrhythmias during acute myocardial ischemia/infarction.
An important recent study showed that AMPK binds
directly to KATP channels and AMPK activation enhances
KATP open probability during metabolic inhibition.41 This
observation raises the possibility that low-micromolar AMP
concentrations, as seen in early ischemia and possibly intense
exercise, open KATP channels by activating AMPK. This
action could be an important contributor to cardioprotection
but could also contribute to arrhythmogenesis by reducing
APD and promoting reentry.
AMPK has been shown to affect a variety of cardiac-expressed
ion channels in noncardiac systems. AMPK phosphorylation of
specific sites on Kv2.1 channels causes hyperpolarizing voltage
shifts in activation and inactivation gating of neuronal Kv2.1
channels.42 AMPK inhibits KCa3.1 (SK1) Ca2+-activated K+ channels in human embryonic kidney cells.43 The Kir2.1 subunit
that underlies inward-rectifier IK1 background outward currents
maintaining the cardiomyocyte resting potential is regulated by
AMPK when expressed in Xenopus oocytes.44 AMPK reduces
Kir2.1 membrane expression and current, apparently by phosphorylating the ubuiquitin ligase Nedd4-2.44 A similar type
of regulation occurs for the potassium voltage-gated channel,
KCNQ1 (KQT-like subfamily, member 1)/potassium voltagegated channel, KCNE1 (Isk-related family, member 1 channel) that underlies cardiac IKs. If cardiac IK1 and IKs channels
are similarly controlled by AMPK in situ, AMPK activation
might downregulate their expression, causing eventual APD
prolongation as seen with myocardial ischemia or HF.15 In the
case of ischemia, this might lead to a biphasic response as has
been observed experimentally,15 with initial APD reduction due
to KATP activation, followed by normalization and then APD
prolongation due to IK1/IKs downregulation.
Ca2+ is a central regulator of a wide range of cellular functions, including important cardiac electrophysiological determinants.46 Although relatively little is known about AMPK
regulation of cardiac Ca2+ handling, there are suggestions that
it might be significant. Turdi et al47 examined interactions
between aging and AMPK in the control of Ca2+ handling and
contractility in mice. AMPK kinase-dead young mice showed
almost no functional abnormalities other than reduced contractility at rapid rates. Aging reduced AMPK function, expression
of the sarcoplasmic reticulum Ca2+-uptake pump, sarcoplasmic reticulum Ca2+-ATPase-2A (SERCA2A) and contractility,
while increasing reactive oxygen species levels and causing
cardiomyocyte hypertrophy. Elderly kinase-dead mice demonstrated enhancement of the aging-dependent changes, as well
as reduced systolic [Ca2+]-transients and downregulation of the
sarcoplasmic reticulum Ca2+-ATPase-2A–inhibiting protein
phospholamban. Treatment with an AMPK activator, metformin, attenuated physiological aging-induced cardiomyocyte
contractile defects. Thus, AMPK contributes to the regulation
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of Ca2+ handling and contractile function, and a decrease in
AMPK function with aging reduces cardiac contractility.
Ikeda et al48 developed cardiomyocyte-specific LKB1
knockout mice and demonstrated a crucial role of the LKB1/
AMPK axis in maintaining cardiac function. LKB1 knockout
mice had attenuated AMPK α2-subunit activation, enhanced
protein synthetic signaling (via mTOR and eEF-2), and cardiomyocyte hypertrophy. They also showed impaired contractility
in association with decreased phospholamban and sarcoplasmic reticulum Ca2+-ATPase-2 mRNA/protein expression and
had significant atrial dilation along with spontaneous AF.
In addition to direct electrophysiological effects mediated
by altered ion channel and transporter function, AMPK might
affect arrhythmogenesis indirectly by altering cellular processes that impact indirectly on arrhythmia risk. For example,
AMPK-induced reductions in cell proliferation could decrease
the likelihood of cardiac tissue fibrosis, an important arrhythmia-promoting change.49 Similarly, antihypertrophic effects
of AMPK could reduce the likelihood of reentrant arrhythmia
by preventing increases in cardiac mass.50
Evidence for a Role in Arrhythmias
Despite important AMPK regulation of many arrhythmia-­
controlling factors and conditions (Figure 4), data regarding
the involvement of AMPK in arrhythmias per se are quite limited. The only 2 clear-cut demonstrations of arrhythmogenesis
resulting from primary disturbances in AMPK function are
the mouse models of PRKAG2 ­cardiomyopathy associated
with inducible orthodromic AV-reentrant tachycardia36 and
of LKB1 deletion with spontaneous AF.48 With LKB1 deletion, AF occurs in a context of substantial structural remodeling and is not necessarily directly attributable to AMPK
dysfunction.
Other observations suggest a role of AMPK in controlling
arrhythmogenesis but are not definitive. Barth et al51,52 found a
relationship between metabolic alterations and permanent AF
in human cardiomyocytes; transcripts involved in carbohydrate
metabolism were significantly upregulated in atrial tissues from
AF patients, whereas transcripts involved in fatty acid metabolism were downregulated. Recent metabolomic and proteomic
analyses in human AF also demonstrate significant changes in
the atrial enzymes and metabolites responsible for glycolysis
and fatty acid oxidation, consistent with metabolic stress.53 A
lower ratio of glycolytic/lipid metabolism end products was
associated with early onset of postoperative AF, suggesting
that metabolic disturbances increase AF vulnerability. This
notion is supported by experiments showing that the inhibition
of glycolysis promotes the occurrence of spontaneous AF in
Langendorff-perfused rat hearts.54 In an electrically maintained
AF model in goats, phosphocreatine decreased by 60% in atrial
myocytes within 1 week, suggesting increased energy demand
and expenditure during the early phases of AF.55
It is well known that HF promotes atrial and ventricular
arrhythmogenesis.15 Cha et al56 demonstrated that dogs with
Figure 5. Metabolic stress–related mechanisms in atrial fibrillation (AF) and possible role of AMP-activated protein kinase (AMPK).
Increased cellular workload during the rapid atrial activation in AF increases energy demand and expenditure. The consequent metabolic
stress limits the availability of ATP that controls cellular integrity and channel/transporter protein function. AF-induced dysregulation of
ion channels, such as ICa-L and INa, causes action potential duration (APD)/wavelength (WL) shortening and conduction velocity (CV) slowing, which stabilizes reentrant mechanisms maintaining AF. Abnormal Ca2+ handling causes hypocontractility and atrial dilation that contributes to the AF substrate, as well as triggered arrhythmia mechanisms. In addition, enhanced production of reactive oxygen species
(ROS) because of metabolic stress damages cellular macromolecules to cause AF-promoting dysfunction. AF-induced metabolic stress
reduces the ratios of AMP/ATP and ADP/ATP, activating AMPK. AMPK activation should increase energy production (fatty acid/glucose
metabolism) and limits energy consumption (protein synthesis), thereby counteracting the AF-induced metabolic stress. AMPK might also
regulate ion channel function via direct phosphorylation. Changes in black have been observed experimentally; those in gray have not
yet been examined but would be expected to occur. RyR2 indicates ryanodine receptor type-2; NCX, Na+/Ca2+-exchanger; SERCA2, sarcoplasmic reticulum Ca2+-ATPase; PLB, phospholamban; Tn-I, troponin-I; MyBP-C, myosin binding protein C; mTOR, mammalian target
of rapamycin.
866 Circ Arrhythm Electrophysiol August 2012
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dilated cardiomyopathic phenotypes caused by ventricular
tachypacing have important defects in atrial bioenergetics,
with depletion of ATP and creatine kinase, and that the propensity for AF is inversely related to atrial cellular ATP concentration. Another study in the same model showed profound
changes in the expression of metabolic proteins and metabolites, with increased ADP/ATP ratio and a shift from glycolysis to α-ketoacid metabolism after 2 weeks of ventricular
tachypacing.57 The glycolytic system was upregulated at 24
hours of ventricular tachypacing, suggesting an early response
to increase energy output in the face of increased demands,
with longer-term energy-preserving adaptations.57
There is thus extensive evidence for a role of metabolic
stress in AF. Figure 5 shows a schema illustrating the potential involvement of metabolic abnormalities and AMPK in
AF. AF induces metabolic stress by virtue of an increased
workload due to a much increased atrial rate. Biochemical
derangements resulting from metabolic stress alter ion channel function in ways that promote arrhythmia induction and
maintenance, creating a positive feedback circuit. AMPK
activation would be expected, based on the observed increase
in ADP/ATP ratio57 and a likely concomitant rise in the
AMP/ATP ratio. AMPK-induced phosphorylation would be
expected to increase energy availability and reduce demands.
If so, modulation of the AMPK system might provide a useful therapeutic target, and failed or deficient AMPK activation
could promote AF in some cases.
AMPK may also be a mediator of antiarrhythmic drug properties. Resveratrol has important AMPK-activating properties19,58 and is antiarrhythmic.59 Although the compound may
have direct ion channel effects, it is conceivable that AMPK
activation contributes to its beneficial effects on arrhythmias.59
Conclusions
Emerging evidence demonstrates a close relationship between
metabolic disturbances and cardiac electrophysiology and
suggests the ability of AMPK to regulate a wide range of
determinants of electrophysiological function and arrhythmogenesis. However, relatively little work has been done to
address directly the participation of AMPK in cardiac electrical function and arrhythmias. Much more research is required
to complete our understanding of the susceptibility of cardiac
ion channels and transporters to modulation by AMPK activation, as well as to understand the involvement of AMPK in
controlling arrhythmogenesis in pathological states. AMPK
activation may play a protective role in some contexts and a
proarrhythmic role in others—clarification of its consequences
in specific contexts will be important. Present antiarrhythmic drug therapy is limited by poor efficacy and significant
adverse effect risk: improved mechanistic understanding of
arrhythmias may hold the key to ameliorating therapeutic
potential.60,61 A better appreciation of the role of this important
enzyme in controlling electrical activity in the normal and diseased heart might lead to important new mechanistic insights
and potentially to new therapeutic opportunities.
Acknowledgment
We thank France Thériault for expert secretarial assistance with the
manuscript.
Sources of Funding
This work was funded by Canadian Institutes of Health Research
(MGP 6957 and MOP 68929), European-North American Atrial
Fibrillation Research Alliance (ENAFRA; 07CVD03) of Fondation
Leducq, and Quebec Heart and Stroke Foundation.
Disclosures
None.
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KEY WORDS: atrial fibrillation ◼ cardiomyopathy ◼ cardiac remodeling
◼ myocardial ischemia ◼ potassium channels
AMP-Activated Protein Kinase: Potential Role in Cardiac Electrophysiology and
Arrhythmias
Masahide Harada, Sarah Naomi Nattel and Stanley Nattel
Downloaded from http://circep.ahajournals.org/ by guest on May 2, 2017
Circ Arrhythm Electrophysiol. 2012;5:860-867
doi: 10.1161/CIRCEP.112.972265
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