Microtubule Dependent Mechano-Transduction Drives Oxidative Stress and Calcium Dysregulation in Dystrophic Skeletal Muscle

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ω-3 Polyunsaturated fatty acids prevent pressure overload-induced ventricular dilation and decrease in mitochondrial enzymes despite no change in adiponectin

<p>Abstract</p> <p>Background</p> <p>Pathological left ventricular (LV) hypertrophy frequently progresses to dilated heart failure with suppressed mitochondrial oxidative capacity. Dietary marine ω-3 polyunsaturated fatty acids (ω-3 PUFA) up-regulate adiponectin and prevent LV dilation in rats subjected to pressure overload. This study 1) assessed the effects of ω-3 PUFA on LV dilation and down-regulation of mitochondrial enzymes in response to pressure overload; and 2) evaluated the role of adiponectin in mediating the effects of ω-3 PUFA in heart.</p> <p>Methods</p> <p>Wild type (WT) and adiponectin-/- mice underwent transverse aortic constriction (TAC) and were fed standard chow ± ω-3 PUFA for 6 weeks. At 6 weeks, echocardiography was performed to assess LV function, mice were terminated, and mitochondrial enzyme activities were evaluated.</p> <p>Results</p> <p>TAC induced similar pathological LV hypertrophy compared to sham mice in both strains on both diets. In WT mice TAC increased LV systolic and diastolic volumes and reduced mitochondrial enzyme activities, which were attenuated by ω-3 PUFA without increasing adiponectin. In contrast, adiponectin-/- mice displayed no increase in LV end diastolic and systolic volumes or decrease in mitochondrial enzymes with TAC, and did not respond to ω-3 PUFA.</p> <p>Conclusion</p> <p>These findings suggest ω-3 PUFA attenuates cardiac pathology in response to pressure overload independent of an elevation in adiponectin.</p

Improved Mitochondrial Function with Diet-Induced Increase in Either Docosahexaenoic Acid or Arachidonic Acid in Membrane Phospholipids

Mitochondria can depolarize and trigger cell death through the opening of the mitochondrial permeability transition pore (MPTP). We recently showed that an increase in the long chain n3 polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA; 22:6n3) and depletion of the n6 PUFA arachidonic acid (ARA; 20:4n6) in mitochondrial membranes is associated with a greater Ca2+ load required to induce MPTP opening. Here we manipulated mitochondrial phospholipid composition by supplementing the diet with DHA, ARA or combined DHA+ARA in rats for 10 weeks. There were no effects on cardiac function, or respiration of isolated mitochondria. Analysis of mitochondrial phospholipids showed DHA supplementation increased DHA and displaced ARA in mitochondrial membranes, while supplementation with ARA or DHA+ARA increased ARA and depleted linoleic acid (18:2n6). Phospholipid analysis revealed a similar pattern, particularly in cardiolipin. Tetralinoleoyl cardiolipin was depleted by 80% with ARA or DHA+ARA supplementation, with linoleic acid side chains replaced by ARA. Both the DHA and ARA groups had delayed Ca2+-induced MPTP opening, but the DHA+ARA group was similar to the control diet. In conclusion, alterations in mitochondria membrane phospholipid fatty acid composition caused by dietary DHA or ARA was associated with a greater cumulative Ca2+ load required to induced MPTP opening. Further, high levels of tetralinoleoyl cardiolipin were not essential for normal mitochondrial function if replaced with very-long chain n3 or n6 PUFAs

Metabolic phenotyping of murine hearts overexpressing constitutively active soluble guanylate cyclase

Although enhanced cGMP signaling can prevent hypertrophy, mechanisms underlying this cardioprotective effect are not well understood. In this study, we assessed the potential involvement of alterations in myocardial energy substrate metabolism, a parameter known to be determinant in the development of hypertrophy. We used mice overexpressing a constitutively active soluble guanylate cyclase in a cardiomyocyte-specific manner (GC+/0) and ex vivo heart perfusion at physiological workload with 13C-labeled substrates. Compared to controls, hearts from GC+/0 mice displayed a 38±9% lower contribution of exogenous fatty acids to acetyl-CoA formation, while that of carbohydrates remained unchanged despite a two-fold increase in glycolysis. The lower contribution of exogenous fatty acids to energy production was not associated with changes in energy demand or supply (contractile function, oxygen consumption, tissue acetyl-CoA or CoA levels, citric acid cycle flux rate) or the regulation of ?-oxidation (acetyl-CoA carboxylase activity, tissue malonyl-CoA levels). However, GC+/0 hearts showed a two-fold increase in the incorporation of exogenous oleate into triglycerides. Furthermore, a concomitant increase in triglyceride hydrolysis is consistent with our findings of a greater abundance of hormone sensitive lipase (HSL) protein (46±6%) and mRNA (22±4%) as well as a 37±13% decrease in its phosphorylation level at Ser-565. The latter covalent modification inhibits HSL and is regulated by AMP-activated protein kinase (AMPK), whose phosphorylation at its activating site Thr-172 was also reduced by 37±13%. These changes in exogenous fatty acid trafficking in GC+/0 hearts appear to be functionally relevant, as demonstrated by their resistance to fasting-induced myocardial triglyceride accumulation. This raises the possibility that enhanced cGMP signaling in cardiomyocytes may protect the heart from fatty acid-induced toxic effects, either as part of its anti-hypertrophic efUne plus grande utilisation des glucides au dépend des acides gras (AG) pour la production d'énergie a été documentée dans le cœur hypertrophique, mais il n'est toujours pas clair si ces changements métaboliques sont adaptatifs ou maladaptatifs. Étant donné que la voie du cGMP a des propriétés anti-hypertrophiques, nous avons émis l'hypothèse que des changements dans la sélection de substrats énergétiques peuvent être à l'origine de l'effet cardioprotecteur de cette voie. Des cœurs de souris qui surexpriment la guanylate cyclase spécifiquement dans les cardiomyocytes (Tg) ont été perfusés ex vivo au travail avec des substrats marqués au carbone-13. L'activité des voies métaboliques impliquées dans la production d'énergie tel que le cycle de Krebs a été corrélée à des paramètres fonctionnels et physiologiques. Comparativement aux souris témoins, les cœurs Tg maintiennent mieux leur intégrité membranaire, tel qu'indiqué par la baisse de la quantité de lactate déshydrogénase relâché par le cœur, tout en maintenant leur travail cardiaque. Au niveau métabolique, les cœurs Tg ne montrent pas de différence dans la contribution des glucides à la formation de l'acétyl-CoA malgré un flux glycolytique augmenté de 127±21% (p<0.01), alors que l'utilisation des acides gras (AG) est diminuée de 40±4% (p<0.05). Selon les résultats obtenus, cette diminution n'est pas attribuable à des changements: (i) des niveaux tissulaires du malonyl-CoA et de l'acétyl-CoA ou (ii) de l'activité du cycle de Krebs, suggérant que le statut énergétique du cœur n'est pas altéré, ou (iii) de l'expression des gènes métaboliques. Plutôt, il semblerait que les cœurs de souris GC+/0 compensent pour la baisse de la contribution des AG par une utilisation accrue des acides gras endogènes provenant des triglycérides. En effet, la quantité totale de lipase hormone-sensible est augmentée de 46±6% et son ARNm de 22±4%. De plus, sa ph

Levrage financing and the risk-taking behavior of small business managers: What happened after the crisis?

International audienc

Leverage financing and the risk taking behavior of small business managers: what happened after the crisis?

The relationship between leverage and the risk-taking behavior has been largely investigated. However, little attention has been attributed to the link between these two variables for small and medium-sized enterprises (SMEs), especially during and after the global crisis in continental Europe. Consequently, this paper tries to fill this gap by examining the impact of leverage on the risk-taking behavior of small business managers in France. Using a sample of 1403 French listed SME-observations over the period 2008 to 2016, the empirical findings show that corporate leverage is positively and significantly related to the risk-taking behavior of corporate managers. This relationship is more striking and robust after than during the global crisis, especially for low growth firms. Thus, credit institutions seem to favor a high restriction a debt during the crisis and to limit their monitoring scope after the crisis particularly for firms with low conflict of interests in order to limit the related costs