Mechanisms for Increased Glycolysis in the Hypertrophied Rat Heart

Nascimben, Luigino; Ingwall, Joanne S.; Lorell, Beverly H.; Pinz, Ilka; Schultz, Vera; Tornheim, Keith; Tian, Rong

doi:10.1161/01.hyp.0000144292.69599.0c

Cited by 209 publications

(171 citation statements)

References 35 publications

(48 reference statements)

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“…A number of key glycolytic enzymes in the pathway leading to either glucose oxidation or lactate production have been identified as direct Myc target genes. These include ENO-1α, HK-2, LDHA, and glucose transporter I, as well as PFK, defined as the rate-limiting enzyme for glycolysis in the hypertrophied heart (15,27,44,45). Consistent with these findings our data demonstrated increased expression of ENO-1α, PFK-1, LDHA, and MCT-1 after Myc activation.…”

Section: Figuresupporting

confidence: 88%

Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice

et al. 2010

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In the adult heart, regulation of fatty acid oxidation and mitochondrial genes is controlled by the PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators. However, in response to pathological stressors such as hemodynamic load or ischemia, cardiac myocytes downregulate PGC-1 activity and fatty acid oxidation genes in preference for glucose metabolism pathways. Interestingly, despite the reduced PGC-1 activity, these pathological stressors are associated with mitochondrial biogenesis, at least initially. The transcription factors that regulate these changes in the setting of reduced PGC-1 are unknown, but Myc can regulate glucose metabolism and mitochondrial biogenesis during cell proliferation and tumorigenesis in cancer cells. Here we have demonstrated that Myc activation in the myocardium of adult mice increases glucose uptake and utilization, downregulates fatty acid oxidation by reducing PGC-1α levels, and induces mitochondrial biogenesis. Inactivation of Myc in the adult myocardium attenuated hypertrophic growth and decreased the expression of glycolytic and mitochondrial biogenesis genes in response to hemodynamic load. Surprisingly, the Myc-orchestrated metabolic alterations were associated with preserved cardiac function and improved recovery from ischemia. Our data suggest that Myc directly regulates glucose metabolism and mitochondrial biogenesis in cardiac myocytes and is an important regulator of energy metabolism in the heart in response to pathologic stress.

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Section: Figuresupporting

confidence: 88%

Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice

et al. 2010

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“…we found that the cardiac function in triheptanoin-treated VLCAD / mice did not differ in any parameter compared with the cardiac function of VLCAD / mice on control diet. The analysis of genes typically expressed in adult hearts during functional impairment and metabolic derangement (44), and responsible for the substrate switch toward enhanced glucose oxidation, showed a marked upregulation that correlated with the increased specific activity of PDH and PK. A similar effect on glucose metabolism has been described in rats with pressure overload treated over 6 weeks with a triheptanoin-based diet (45).…”

Section: Discussionmentioning

confidence: 99%

Triheptanoin: long-term effects in the very long-chain acyl-CoA dehydrogenase-deficient mouse

Tucci

Floegel

Beermann

et al. 2017

Journal of Lipid Research

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This article is available online at http://www.jlr.org symptoms include i) severe energy deficiency due to a deficient fatty acid oxidation and subsequent impairment of ketone body biosynthesis and ii) accumulation of toxic long-chain acylcarnitines. Therefore, catabolic situations in which the organism mainly relies on fatty acid oxidation induce symptoms and severe metabolic derangement. The clinical phenotype is very heterogeneous and presents with different severity and age of onset (3), involving organs and tissues that mostly rely on fatty acid -oxidation for energy production. To date, treatment recommendations (5) include a long-chain fat-restricted and fat-modified diet in which long-chain fatty acids are fully or in part replaced by medium-chain triglycerides (MCTs) (1, 5) and the avoidance of prolonged fasting. In contrast to long-chain fatty acids, medium-chain fatty acids (MCFAs) are oxidized by medium-chain acyl-CoA dehydrogenase, bypassing VLCAD; therefore, MCTs may be fully metabolized, supplying the organism with the required energy. Many reports confirm the effectiveness of MCT application in the treatment of cardiomyopathy in long-chain fatty acid oxidation disorders (FAODs) (6-9). In patients with exercise-induced muscle pain, the application of an MCT bolus immediately prior to physical exercise has been proven effective (1, 5). Our own studies on the VLCAD-deficient (VLCAD / ) mouse showed the beneficial effects of MCTs when applied during increased demand (10). Although an MCT diet is considered to be a safe dietary intervention and is applied in different FAODs for longer periods of time, recent reports highlight the adverse effects of an MCT diet in the murine model of VLCAD deficiency (11)(12)(13)(14). A rather new therapeutic approach for the treatment of FAODs is represented by the application of MCTs in the form of Mitochondrial -oxidation is essential for energy production from fat. Deficiency of one of the enzymes involved is associated with life-threatening events and death. Verylong chain acyl-CoA dehydrogenase (VLCAD) deficiency (OMIM 609575) is the second most common disorder of fatty acid oxidation in Europe and the USA, with an incidence of 1:25,000-1:100,000 newborns (1-4). Pathophysiological mechanisms responsible for the development of

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“…(PFK-2), leading to increased synthesis of fructose-2,6-bisphosphate, a potent stimulator of the rate-limiting enzyme for the glycolytic pathway, PFK-1 (18,31). However, PFK-1 activity is also regulated by other stimulators (e.g., ADP, AMP, and inorganic phosphate) and inhibitors (e.g., ATP, H + , and citrate).…”

Section: Figurementioning

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.

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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.

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Mechanisms for Increased Glycolysis in the Hypertrophied Rat Heart

Cited by 209 publications

References 35 publications

Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice

Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice

Triheptanoin: long-term effects in the very long-chain acyl-CoA dehydrogenase-deficient mouse

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

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