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- Moilanen, A. M., et al.
(författare)
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WDR12, a Member of Nucleolar PeBoW-Complex, Is Up-Regulated in Failing Hearts and Causes Deterioration of Cardiac Function
- 2015
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Aims In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown. We characterized cardiac expression of WDR12, used adenovirus-mediated WDR12 gene delivery to examine effects of WDR12 on left ventricular (LV) remodeling, and analyzed relationship between MI associated WDR12 allele and cardiac function in human subjects. LV WDR12 protein levels were increased in patients with dilated cardiomyopathy and rats post-infarction. In normal adult rat hearts, WDR12 gene delivery into the anterior wall of the LV decreased interventricular septum diastolic and systolic thickness and increased the diastolic and systolic diameters of the LV. Moreover, LV ejection fraction (9.1%, P<0.05) and fractional shortening (12.2%, P<0.05) were declined. The adverse effects of WDR12 gene delivery on cardiac function were associated with decreased cellular proliferation, activation of p38 mitogen-activated protein kinase (MAPK)/heat shock protein (HSP) 27 pathway, and increased protein levels of Block of proliferation 1 (BOP1), essential for ribosome biogenesis. Post-infarction WDR12 gene delivery decreased E/A ratio (32%, P<0.05) suggesting worsening of diastolic function. In human subjects, MI associated WDR12 allele was associated significantly with diastolic dysfunction and left atrial size. WDR12 triggers distinct deterioration of cardiac function in adult rat heart and the MI associated WDR12 variant is associated with diastolic dysfunction in human subjects.
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- Chaillou, Thomas, 1985-, et al.
(författare)
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NDUFA4L2 : Connecting metabolic signals and mitochondrial function in cardiac and skeletal muscle
- 2016
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Ingår i: Free Radical Biology & Medicine. - : Elsevier. - 0891-5849 .- 1873-4596. ; 100:Suppl., s. S186-S186
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Tidskriftsartikel (refereegranskat)abstract
- The nuclear-encoded mitochondrial protein NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 (NDUFA4L2) was recently identified. NDUFAe4L2 is shown to be induced by hypoxia via HIF1α and is thought to inhibit production of mitochondrial reactive oxygen species in fibroblasts exposed to hypoxia. Here the aim was to characterize the role of NDUFA4L2 in the mitochondria-rich tissues skeletal and cardiac muscle. We show hypoxia induced NDUFA4L2 expression in isolated muscle fibers and in cardiomyocytes with full activation after ~3-6 h in hypoxia. The half-maximal O2 level for NDUFA4L2 expression (~4.6 % of ambient O2) suggests sensitivity to changes in O2 tension that occur under physiological conditions (e.g. exercise, moderate ischemia). We identified that the NDUFA4L2 gene promoter has binding sites for transcription factors other than HIF-1α; repetitive sites for PPARα,γ and one for Nrf2. NDUFA4L2 overexpression resulted in functional effects on skeletal and cardiac muscle; e.g. it alters cellular Ca2+ signaling and the expression of Ca2+ handling genes. Further, NDUFA4L2 overexpression reduces muscle mass (~20%), leading to a decreased force production in skeletal muscle. The NDUFA4L2-induced loss of muscle mass was associated with increases in mRNA levels of e.g. MurF1, Mul1, caspase-3 and Bax. Additionally, femoral artery ligation (FAL) induced NDUFA4L2 expression, which correlates with the decreased force production eight days post-FAL in skeletal muscle. Moreover, NDUFA4L2 upregulates antioxidant gene expression and silencing NDUFA4L2 makes cardiac cells less tolerant to hypoxia/re-oxygenation. Our results suggest that NDUFA4L2 expression affects vital functions in muscle cells and at least part of this effect is mediated by a link between NDUFA4L2 and nuclear gene expression. Thus, NDUFA4L2 might act as an integrator of the nutritional, environmental and functional status in muscle cells.
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- Fauconnier, J, et al.
(författare)
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Insulin and inositol 1,4,5-trisphosphate trigger abnormal cytosolic Ca2+ transients and reveal mitochondrial Ca2+ handling defects in cardiomyocytes of ob/ob mice
- 2005
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 54:8, s. 2375-2381
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Tidskriftsartikel (refereegranskat)abstract
- Obesity, insulin resistance, and type 2 diabetes are leading causes of heart failure, and defective cellular Ca2+ handling seems to be a fundamental problem in diabetes. Therefore, we studied the effect of insulin on Ca2+ homeostasis in normal, freshly isolated mouse ventricular cardiomyocytes and whether Ca2+ handling was changed in an animal model of obesity and type 2 diabetes, ob/ob mice. Electrically evoked Ca2+ transients were smaller and slower in ob/ob compared with wild-type cardiomyocytes. Application of insulin (6 or 60 nmol/l) increased the amplitude of Ca2+ transients in wild-type cells by ∼30%, whereas it broadened the transients and triggered extra Ca2+ transients in ob/ob cells. The effects of insulin in ob/ob cells could be reproduced by application of a membrane-permeant inositol trisphosphate (IP3) analog and blocked by a frequently used IP3 receptor inhibitor, 2-aminoethoxydiphenyl borate. In ob/ob cardiomyocytes, insulin increased the IP3 concentration and mitochondrial Ca2+ handling was impaired. In conclusion, we propose a model where insulin increases IP3 in ob/ob cardiomyocytes, which prolongs the electrically evoked Ca2+ release. This, together with an impaired mitochondrial Ca2+ handling, results in insulin-mediated extra Ca2+ transients in ob/ob cardiomyocytes that may predispose for arrhythmias in vivo.
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- Lanner, JT, et al.
(författare)
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The role of Ca2+ influx for insulin-mediated glucose uptake in skeletal muscle
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:7, s. 2077-2083
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Tidskriftsartikel (refereegranskat)abstract
- The involvement of Ca2+ in insulin-mediated glucose uptake is uncertain. We measured Ca2+ influx (as Mn2+ quenching or Ba2+ influx) and 2-deoxyglucose (2-DG) uptake in single muscle fibers isolated from limbs of adult mice; 2-DG uptake was also measured in isolated whole muscles. Exposure to insulin increased the Ca2+ influx in single muscle cells. Ca2+ influx in the presence of insulin was decreased by 2-aminoethoxydiphenyl borate (2-APB) and increased by the membrane-permeable diacylglycerol analog 1-oleyl-2-acetyl-sn-glycerol (OAG), agents frequently used to block and activate, respectively, nonselective cation channels. Maneuvers that decreased Ca2+ influx in the presence of insulin also decreased 2-DG uptake, whereas increased Ca2+ influx was associated with increased insulin-mediated glucose uptake in isolated single cells and whole muscles from both normal and insulin-resistant obese ob/ob mice. 2-APB and OAG affected neither basal nor hypoxia- or contraction-mediated 2-DG uptake. 2-APB did not inhibit the insulin-mediated activation of protein kinase B or extracellular signal–related kinase 1/2 in whole muscles. In conclusion, alterations in Ca2+ influx specifically modulate insulin-mediated glucose uptake in both normal and insulin-resistant skeletal muscle. Moreover, the present results indicate that Ca2+ acts late in the insulin signaling pathway, for instance, in the GLUT4 translocation to the plasma membrane.
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- Tuomainen, T, et al.
(författare)
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PGC-1α4 Interacts with REST to Upregulate Neuronal Genes and Augment Energy Consumption in Developing Cardiomyocytes
- 2022
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 11:19
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Tidskriftsartikel (refereegranskat)abstract
- Transcriptional coactivator PGC-1α is a main regulator of cardiac energy metabolism. In addition to canonical PGC-1α1, other PGC-1α isoforms have been found to exert specific biological functions in a variety of tissues. We investigated the expression patterns and the biological effects of the non-canonical isoforms in the heart. We used RNA sequencing data to identify the expression patterns of PGC-1α isoforms in the heart. To evaluate the biological effects of the alternative isoform expression, we generated a transgenic mouse with cardiac-specific overexpression of PGC-1α4 and analysed the cardiac phenotype with a wide spectrum of physiological and biophysical tools. Our results show that non-canonical isoforms are expressed in the heart, and that the main variant PGC-1α4 is induced by β-adrenergic signalling in adult cardiomyocytes. Cardiomyocyte specific PGC-1α4 overexpression in mice relieves the RE1-Silencing Transcription factor (REST)-mediated suppression of neuronal genes during foetal heart development. The resulting de-repression of REST target genes induces a cardiac phenotype with increased cellular energy consumption, resulting in postnatal dilated cardiomyopathy. These results propose a new concept for actions of the PGC-1α protein family where activation of the Pgc-1α gene, through its isoforms, induces a phenotype with concurrent supply and demand for cellular energy. These data highlight the biological roles of the different PGC-1α isoforms, which should be considered when future therapies are developed.
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