Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart

Abel, E. Dale; Kaulbach, Helen C.; Tian, Rong; Hopkins, James; Duffy, John; Doetschman, Thomas; Minnemann, T.; Boers, Mary Ellen; Hadro, Ed; Oberste-Berghaus, Corinna; Quist, William C.; Lowell, Bradford B.; Ingwall, Joanne S.; Kahn, Barbara B.

doi:10.1172/jci7605

Cited by 332 publications

(295 citation statements)

References 49 publications

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“…These affects were not simply a function of cardiac overexpression of a transgene, because we have not seen these pathologies with any of the other cardiac-specific transgenes we have described (18,22,(33)(34)(35). Similar hypertrophy has been reported for cardiac selective deletion of GLUT4, which also reduced glycolysis (8).…”

Section: Discussionsupporting

confidence: 72%

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Cardiac Expression of Kinase-deficient 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase Inhibits Glycolysis, Promotes Hypertrophy, Impairs Myocyte Function, and Reduces Insulin Sensitivity

Donthi

et al. 2004

Journal of Biological Chemistry

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Glycolysis is important to cardiac metabolism and reduced glycolysis may contribute to diabetic cardiomyopathy. To understand its role independent of diabetes or hypoxic injury, we modulated glycolysis by cardiacspecific overexpression of kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (kd-PFK-2). PFK-2 controls the level of fructose 2,6-bisphosphate (Fru-2,6-P 2 ), an important regulator of glycolysis. Transgenic mice had over 2-fold reduced levels of Fru-2,6-P 2 . Heart weight/body weight ratio indicated mild hypertrophy. Sirius red staining for collagen was significantly increased. We observed a 2-fold elevation in glucose 6-phosphate and fructose 6-phosphate levels, whereas fructose 1,6-bisphosphate was reduced 2-fold. Pathways branching off of glycolysis above phosphofructokinase were activated as indicated by over 2-fold elevated UDP-N-acetylglucosamine and glycogen. The kd-PFK-2 transgene significantly inhibited glycolysis in perfused hearts. Insulin stimulation of metabolism and Akt phosphorylation were sharply reduced. In addition, contractility of isolated cardiomyocytes was impaired during basal and hypoxic incubations. The present study shows that cardiac overexpression of kinase-deficient PFK-2 reduces cardiac glycolysis that produced negative consequences to the heart including hypertrophy, fibrosis, and reduced cardiomyocyte function. In addition, metabolic and signaling responses to insulin were significantly decreased.

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Section: Discussionsupporting

confidence: 72%

“…Diabetics are prone to heart failure (5) and they suffer more damage following an infarction (6). It has been proposed that reduced cardiac glycolysis contributes to the heart failure and cardiac damage often suffered by diabetics (7,8).…”

mentioning

confidence: 99%

Cardiac Expression of Kinase-deficient 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase Inhibits Glycolysis, Promotes Hypertrophy, Impairs Myocyte Function, and Reduces Insulin Sensitivity

Donthi

et al. 2004

Journal of Biological Chemistry

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“…S6C). Furthermore, prior work by ourselves and others with this specific Cre mouse line has shown no evidence of heart failure (17,(32)(33)(34).…”

Section: Tln2 Deletion Does Not Produce Changes In the Dystrophin-glymentioning

confidence: 87%

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Manso

Okada

Sakamoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Continuous contraction-relaxation cycles of the heart require strong and stable connections of cardiac myocytes (CMs) with the extracellular matrix (ECM) to preserve sarcolemmal integrity. CM attachment to the ECM is mediated by integrin complexes localized at the muscle adhesion sites termed costameres. The ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that links integrins ultimately to the sarcomere. There are two talin genes, Tln1 and Tln2. Here, we tested the function of these two Tln forms in myocardium where Tln2 is the dominant isoform in postnatal CMs. Surprisingly, global deletion of Tln2 in mice caused no structural or functional changes in heart, presumably because CM Tln1 became up-regulated. Tln2 loss increased integrin activation, although levels of the musclespecific β1D-integrin isoform were reduced by 50%. With this result, we produced mice that had simultaneous loss of both CM Tln1 and Tln2 and found that cardiac dysfunction occurred by 4 wk with 100% mortality by 6 mo. β1D integrin and other costameric proteins were lost from the CMs, and membrane integrity was compromised. Given that integrin protein reduction occurred with Tln loss, rescue of the phenotype was attempted through transgenic integrin overexpression, but this could not restore WT CM integrin levels nor improve heart function. Our results show that CM Tln2 is essential for proper β1D-integrin expression and that Tln1 can substitute for Tln2 in preserving heart function, but that loss of all Tln forms from the heart-muscle cell leads to myocyte instability and a dilated cardiomyopathy.T he heart and all of its attendant cells, particularly the contracting cardiac myocytes (CMs), are constantly subjected to high forces. Proper linkage between the cellular cytoskeleton, the cell membrane (termed the sarcolemma in muscle cells), and the extracellular matrix (ECM) is necessary for synchronized force distribution among the cells of the myocardium (1-3). When these linkages are disturbed, forces may be distributed abnormally, cardiac muscle can be injured, and therefore whole-heart function can become abnormal. A number of intracellular proteins and membrane receptors have been found to be crucial for organizing this interactive arrangement between the intracellular CM environment and the surrounding ECM. The integrin family of adhesion receptors are key proteins operative in this response (4). Integrins are a large family of 18 α-subunits and 8 β-subunits, which heterodimerize noncovalently, forming over 24 unique transmembrane receptors on virtually all cells, including CMs. They bind directly to ECM proteins via their proportionally large extracellular domains, and their short cytoplasmic tails assist with organizing a large multiprotein complex that connects integrins to the actin cytoskeleton and may transduce signals to a range of downstream pathways. With these connections, integrins are recognized as key mechanotransducers, converting mechanical perturbations to biochemical signals (...

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“…Mice bearing the targeted Capn4 PZ allele containing loxP sites flanking essential coding exons were generated as described previously (28). Transgenic mice with cardiomyocyte-specific expression of Cre recombinase under the control of ␣-myosin heavy chain (␣-MHC) (TgCre) were generously provided by Dr. Dale E. Abel (University of Utah) (29). Mice with cardiomyocyte-specific disruption of Capn4 (Capn4-ko) were generated by crossing floxed Capn4 PZ mice with transgenic mice overexpressing Cre under the control of the ␣-MHC promoter as we recently described (30).…”

Section: Methodsmentioning

confidence: 99%

Deficiency of Capn4 Gene Inhibits Nuclear Factor-κB (NF-κB) Protein Signaling/Inflammation and Reduces Remodeling after Myocardial Infarction

Wei²,

Wang

et al. 2012

Journal of Biological Chemistry

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Background:The causal role of calpain in myocardial remodeling after infarction has not been addressed. Results: Deficiency of Capn4 inhibited NF-B signaling and inflammation and reduced myocardial remodeling, dysfunction, and mortality after infarction. Conclusion: Calpain contributes to myocardial inflammation and remodeling after infarction. Significance: This study provides a significant insight into the function of calpain in post-myocardial infarction remodeling.

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Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart

Cited by 332 publications

References 49 publications

Cardiac Expression of Kinase-deficient 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase Inhibits Glycolysis, Promotes Hypertrophy, Impairs Myocyte Function, and Reduces Insulin Sensitivity

Cardiac Expression of Kinase-deficient 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase Inhibits Glycolysis, Promotes Hypertrophy, Impairs Myocyte Function, and Reduces Insulin Sensitivity

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Deficiency of Capn4 Gene Inhibits Nuclear Factor-κB (NF-κB) Protein Signaling/Inflammation and Reduces Remodeling after Myocardial Infarction

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