Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy

Arad, Michael; Benson, Donald W.; Perez‐Atayde, Antonio R.; McKenna, William J.; Sparks, Elizabeth; Kanter, Ronald J.; McGarry, K; Seidman, Jonathan G.; Seidman, Christine E.

doi:10.1172/jci200214571

Cited by 69 publications

(64 citation statements)

References 23 publications

(15 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Neither our results nor those of Daniel and Carling (37) support two previous claims (12,36) that WPWS mutations make AMPK complexes constitutively active. When the cells were harvested by rapid lysis (which much better preserves the physiological phosphorylation state of AMPK), none of the mutants exhibited greater activity than the WT (Figure 4c).…”

Section: Figurecontrasting

confidence: 99%

“…It has previously been claimed that mutations that are associated with WPWS cause constitutive activation of AMPK (12,36). To address this, we examined the activation of expressed AMPK in CCL13 cells by slow lysis as opposed to rapid lysis.…”

Section: Resultsmentioning

confidence: 99%

“…One involved making a mutation equivalent to R302Q in the γ1 rather than the γ2 isoform (36), although naturally occurring mutations in γ1 have not been reported. The other involved making mutations equivalent to T400N and N488I in the yeast γ subunit homologue, Snf4, and analyzing two-hybrid interactions with Snf1 (the α homologue) as a surrogate measure of kinase activity (12). In fact, while both mutations did appear to cause small (twofold) increases in the Snf1/Snf4 interaction under basal conditions, removal of glucose from the medium (known to activate the SNF1 complex [ref.…”

Section: Figurementioning

confidence: 99%

See 2 more Smart Citations

CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations

Scott¹,

Hawley²,

Green³

et al. 2004

J. Clin. Invest.

217

337

View full text Add to dashboard Cite

CBS domains were originally identified as sequence motifs of approximately 60 amino acids that occur in CBS and several other proteins, in all organisms from archaea to humans (1). Although their functions were unknown, their importance was emphasized by findings that point mutations within them cause several hereditary diseases in humans. CBS domains are defined as sequence motifs that occur in several different proteins in all kingdoms of life. Although thought to be regulatory, their exact functions have been unknown. However, their importance was underlined by findings that mutations in conserved residues within them cause a variety of human hereditary diseases, including (with the gene mutated in parentheses): Wolff-Parkinson-White syndrome (γ2 subunit of AMP-activated protein kinase); retinitis pigmentosa (IMP dehydrogenase-1); congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members); and homocystinuria (cystathionine β-synthase). AMP-activated protein kinase is a sensor of cellular energy status that is activated by AMP and inhibited by ATP, but the location of the regulatory nucleotide-binding sites (which are prime targets for drugs to treat obesity and diabetes) was not characterized. We now show that tandem pairs of CBS domains from AMP-activated protein kinase, IMP dehydrogenase-2, the chloride channel CLC2, and cystathionine β-synthase bind AMP, ATP, or S-adenosyl methionine,while mutations that cause hereditary diseases impair this binding. This shows that tandem pairs of CBS domains act, in most cases, as sensors of cellular energy status and, as such, represent a newly identified class of binding domain for adenosine derivatives.

show abstract

Section: Figurecontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations

Scott¹,

Hawley²,

Green³

et al. 2004

J. Clin. Invest.

217

337

View full text Add to dashboard Cite

show abstract

“…Although there is some evidence that AMPK inhibits, rather than activates, glycogen synthase (51), the exact role of AMPK in modulating glycogen metabolism remains uncertain. It is interesting that myocardial glycogen content is increased in both human and mouse hearts expressing what is thought to be a constitutively active mutant of the AMPK γ subunit (28,52,53). These hearts have marked accumulation of glycogen, to the extent that it produces pseudohypertrophy with increased ventricular wall thickness.…”

Section: Figurementioning

confidence: 99%

AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury

et al. 2004

View full text Add to dashboard Cite

AMP-activated protein kinase (AMPK)is an important regulator of diverse cellular pathways in the setting of energetic stress. Whether AMPK plays a critical role in the metabolic and functional responses to myocardial ischemia and reperfusion remains uncertain. We examined the cardiac consequences of long-term inhibition of AMPK activity in transgenic mice expressing a kinase dead (KD) form of the enzyme. The KD mice had normal fractional shortening and no heart failure, cardiac hypertrophy, or fibrosis, although the in vivo left ventricular (LV) dP/dt was lower than that in WT hearts. During low-flow ischemia and postischemic reperfusion in vitro, KD hearts failed to augment glucose uptake and glycolysis, although glucose transporter content and insulin-stimulated glucose uptake were normal. KD hearts also failed to increase fatty acid oxidation during reperfusion. Furthermore, KD hearts demonstrated significantly impaired recovery of LV contractile function during postischemic reperfusion that was associated with a lower ATP content and increased injury compared with WT hearts. Caspase-3 activity and TUNEL-staining were increased in KD hearts after ischemia and reperfusion. Thus, AMPK is responsible for activation of glucose uptake and glycolysis during low-flow ischemia and plays an important protective role in limiting damage and apoptotic activity associated with ischemia and reperfusion in the heart.

show abstract

“…Each subunit has 2-3 isoforms; all except γ3 are expressed in the heart. Mutations in the γ2 subunit (encoded by the PRKAG2 gene) cause human cardiomyopathy characterized by substantial myocardial glycogen accumulation, preexcitation syndrome, and cardiac hypertrophy (4)(5)(6). These characteristics closely resemble the cardiac manifestation of glycogen storage disease (7), which prompted us to focus on the mechanisms of glycogen accumulation in the cardiomyopathy caused by mutation of PRKAG2.…”

mentioning

confidence: 99%

Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage

Luptak¹,

Shen²,

He³

et al. 2007

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

AMP-activated protein kinase (AMPK) responds to impaired cellular energy status by stimulating substrate metabolism for ATP generation. Mutation of the γ2 regulatory subunit of AMPK in humans renders the kinase insensitive to energy status and causes glycogen storage cardiomyopathy via unknown mechanisms. Using transgenic mice expressing one of the mutant γ2 subunits (N488I) in the heart, we found that aberrant high activity of AMPK in the absence of energy deficit caused extensive remodeling of the substrate metabolism pathways to accommodate increases in both glucose uptake and fatty acid oxidation in the hearts of γ2 mutant mice via distinct, yet synergistic mechanisms resulting in selective fuel storage as glycogen. Increased glucose entry in the γ2 mutant mouse hearts was directed through the remodeled metabolic network toward glycogen synthesis and, at a substantially higher glycogen level, recycled through the glycogen pool to enter glycolysis. Thus, the metabolic consequences of chronic activation of AMPK in the absence of energy deficiency is distinct from those previously reported during stress conditions. These findings are of particular importance in considering AMPK as a target for the treatment of metabolic diseases.Introduction AMP-activated protein kinase (AMPK) is a serine/threonine kinase that acts as a cellular energy sensor and a master regulator of metabolism in a variety of cell types including cardiac myocytes (1). AMPK responds to increases in the cellular AMP/ATP ratio, an ultrasensitive indicator of impaired energy status, and triggers multiple signaling cascades to restore energy balance by stimulating ATP-generating pathways while inhibiting ATP-consuming pathways (1-3). AMPK is a heterotrimeric protein consisting of a catalytic subunit (α) and 2 regulatory subunits (β and γ). Each subunit has 2-3 isoforms; all except γ3 are expressed in the heart. Mutations in the γ2 subunit (encoded by the PRKAG2 gene) cause human cardiomyopathy characterized by substantial myocardial glycogen accumulation, preexcitation syndrome, and cardiac hypertrophy (4-6). These characteristics closely resemble the cardiac manifestation of glycogen storage disease (7), which prompted us to focus on the mechanisms of glycogen accumulation in the cardiomyopathy caused by mutation of PRKAG2. Interestingly, mutations in the corresponding sites on the γ3 subunits of AMPK in skeletal muscle such as R200Q in pigs and R225Q in mice have also been shown to cause glycogen accumulation (8-10), suggesting an important role of altered glycogen metabolism in the phenotype caused by mutations of γ-AMPK.

show abstract

Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy

Cited by 69 publications

References 23 publications

CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations

CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations

AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury

Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage

Contact Info

Product

Resources

About