SIRT1 may play a crucial role in overload-induced hypertrophy of skeletal muscle

Silent mating type information regulation 2 homologue 1 (SIRT1) activity and content increased significantly in overload-induced hypertrophy. SIRT1-mediated signalling through Akt, the endothelial nitric oxide synthase mediated pathway, regulates anabolic process in the hypertrophy of skeletal muscle. The regulation of catabolic signalling via forkhead box O 1 and protein ubiquitination is SIRT1 dependent. Overload-induced changes in microRNA levels regulate SIRT1 and insulin-like growth factor 1 signalling. Significant skeletal muscle mass guarantees functional wellbeing and is important for high level performance in many sports. Although the molecular mechanism for skeletal muscle hypertrophy has been well studied, it still is not completely understood. In the present study, we used a functional overload model to induce plantaris muscle hypertrophy by surgically removing the soleus and gastrocnemius muscles in rats. Two weeks of muscle ablation resulted in a 40% increase in muscle mass, which was associated with a significant increase in silent mating type information regulation 2 homologue 1 (SIRT1) content and activity (P < 0.001). SIRT1-regulated Akt, endothelial nitric oxide synthase and GLUT4 levels were also induced in hypertrophied muscles, and SIRT1 levels correlated with muscle mass, paired box protein 7 (Pax7), proliferating cell nuclear antigen (PCNA) and nicotinamide phosphoribosyltransferase (Nampt) levels. Alternatively, decreased forkhead box O 1 (FOXO1) and increased K48 polyubiquitination also suggest that SIRT1 could be involved in the catabolic process of hypertrophy. Furthermore, increased levels of K63 and muscle RING finger 2 (MuRF2) protein could also be important enhancers of muscle mass. We report here that the levels of miR1 and miR133a decrease in hypertrophy and negatively correlate with muscle mass, SIRT1 and Nampt levels. Our results reveal a strong correlation between SIRT1 levels and activity, SIRT1-regulated pathways and overload-induced hypertrophy. These findings, along with the well-known regulatory roles that SIRT1 plays in modulating both anabolic and catabolic pathways, allow us to propose the hypothesis that SIRT1 may actually play a crucial causal role in overload-induced hypertrophy of skeletal muscle. This hypothesis will now require rigorous direct and functional testing.National Strength and Conditioning Association OTKA. Grant Number: 112810 Hungarian Academy of Science National Institute of Environmental Health Sciences. Grant Number: ES00359

Contribution à l étude des effets de l activité physique sur le fonctionnement mitochondrial et la production de radicaux libres. Etude sur mitochondries et hépatiques

Ce travail consistait à étudier les effets d'une activité physique modérée aiguë ou chronique sur le fonctionnement mitochondrial musculaire et hépatique. Nous avons étudié la respiration mitochondriale et la production de ROS estimée par mesure de l'HzOz. Nous avons montré que l'exercice était à l'origine d'une augmentation de la production radicalaire et cela de façon persistante après 2h de récupération dans le muscle mais qui était décalée dans le foie. Cette production apparaît comme tolérée par la mitochondrie dont le statut antioxydant n'est pas affecté. L'étude de l'activité physique chronique modérée induit une augmentation de densité mitochondriale à la fois dans le muscle et le foie, associée à des adaptations fonctionnelles. La mitochondrie musculaire semble plus efficace pour extraire des équivalents réduits en provenance des acides gras à travers un processus de s/ipping métabolique. La mitochondrie hépatique présente une amélioration de rendement d'oxydation en état phosphorylant à partir de substrats du complexe I. L'exercice modifie la production d'HzOz à partir du complexe III dans le muscle et du 1 dans le foie. L'utilisation d'oligonucléotides antisens de PGC-Ia, réprimant l'expression protéique, n'a pas d'influence sur l'augmentation de densité mitochondriale induite par l'entraînement au niveau musculaire mais l'inhibe complètement dans le foie. Des adaptations fonctionnelles, de respiration et production de ROS semblent confirmer un rôle majeur de PGC-Ia dans les adaptations mitochondriales à l'exercice. Ces résultats suggèrent que les ROS pourraient contribuer par rétrocontrôle sur PGC-Ia aux adaptations énergétiques induites par l'activité physique.The aim of this work was to study hepatic and muscular mitochondria function in response to chronic or acute exercise. We have studied the mitochondrial oxygen consumption and free radical production based on the HzOz production. We have shown that a single bout of exercise increases free radical production that was persistent for 2 hours in muscle while it was delayed in liver. This free radical production appears to be tolerated by the mitochondria through the antioxidant pool that remained unaffected. We tested the effect of moderate chronic exercise that induced increases in mitochondrial density in muscle and in liver, along with functional adaptations. Muscle mitochondria seems to have a better efficiency to extract reduced equivalents from fatty acids through a process named metabo/ic s/ipping. Liver mitochondria displayed an enhanced oxidation yield in ADP-stimulated respiratory status with complex 1 substrates. Exercise appears to affect mostly the HzOz production from complex III in muscle but complex 1 in liver mitochondria. The use of PGC-I a antisense oligonucleotides, in order to decrease the PGC-I a protein expression, doesn't affect mitochondrial biogenesis induced by endurance training in muscle but totally inhibit the training-induced mitochondrial biogenesis in liver. Functional adaptations (Le. altered respiratory control and ROS production) linked to the absence of this protein seem to confirm the essential role of PGC-l a in tissue-specific mitochondrial adaptations to exercise. These results suggest that free radicals could play a role by feedback control ofPGC-la, on exercise-induced mitochondrial adaptations.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Liver mitochondria and insulin resistance.

International audienceWith a steadily increasing prevalence, insulin resistance (IR) is a major public health issue. This syndrome is defined as a set of metabolic dysfunctions associated with, or contributing to, a range of serious health problems. These disorders include type 2 diabetes, metabolic syndrome, obesity, and non-alcoholic steatohepatitis (NASH). According to the literature in the field, several cell types like β-cell, myocyte, hepatocyte and/or adipocyte, as well as related complex signaling environment involved in peripheral insulin sensitivity are believed to be central in this pathology. Because of the central role of the liver in the whole-body energy homeostasis, liver insulin sensitivity and its potential relationship with mitochondrial oxidative phosphorylation appear to be crucial. The following short review highlights how liver mitochondria could be implicated in IR and should therefore be considered as a specific therapeutic target in the future

Citrulline affects skeletal muscle mitochondrial function through a direct inhibition of complex I

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Les effets d'un régime riche en graisse sur la fonction cardiovasculaire étudiée ex vivo

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Les effets d'un régime riche en graisse sur la fonction cardiovasculaire étudiée ex vivo

Session II Cardiométabolisme et fonction cardiovasculaire modérateur Luc DemaisonNational audienc

Non-oxidative Energy Supply Correlates with Lactate Transport and Removal in Trained Rowers

This study aimed to test if the non-oxidative energy supply (estimated by the accumulated oxygen deficit) is associated with an index of muscle lactate accumulation during exercise, muscle monocarboxylate transporter content and the lactate removal ability during recovery in well-trained rowers. Seventeen rowers completed a 3-min all-out exercise on rowing ergometer to estimate the accumulated oxygen deficit. Blood lactate samples were collected during the subsequent passive recovery to assess individual blood lactate curves, which were fitted to the bi-exponential time function: La(t)= [La](0)+A1·(1-e-? 1 t)+A2·(1-e-? 2 t), where the velocity constants ?1 and ?2 (min-1) denote the lactate exchange and removal abilities during recovery, respectively. The accumulated oxygen deficit was correlated with the net amount of lactate released from the previously active muscles (r =0.58,

Na+/H+ exchange inhibition with cariporide prevents alterations of coronary endothelial function in streptozotocin-induced diabetes.

International audienceHyperglycemia encountered during diabetes triggers abnormalities of vascular function associated with cell acidosis and calcium overload. The purpose of this study was to determine, whether Na+/H+ exchanger (NHE-1) inhibition by cariporide protects coronary cells against the deleterious effect of hyperglycemia in the rat. In vivo hyperglycemia was triggered by streptozotocin injection. One week after, the glycemia was checked and the control and diabetic animals were treated or not with cariporide (2.5 mg/kg/day) for two weeks. Glycemia was again estimated and the hearts were perfused according to the Langendorff mode at forced flow. The left ventricle developed pressure (LVDP) and heart rate (HR) were determined with a latex balloon inserted into the left ventricle. Coronary pressure was artificially increased to 130 mmHg by infusing a thromboxane A2 analogue (U46619). This allowed the evaluation of endothelium-dependent (EDD) and endothelium-independent (EID) dilatation through bolus injections of carbamoylcholin and sodium nitroprusside, respectively. Releases of lactate and pyruvate in the coronary effluents were also determined. Diabetes did not modified LVDP, but reduced HR (-15%). This was associated with a marked decrease in EDD (-56%) and EID (-30%), while the cytosolic redox potential (estimated as the lactate/pyruvate ratio) was reduced. NHE-1 inhibition restored EDD and the lactate/pyruvate ratio without improving EID and HR. The present findings indicate that NHE-1 exchanger inhibition by cariporide protects the coronary endothelium against the deleterious effects of hyperglycemia

Combined effects of citrulline supplemntation and physical training in healthy adult rats

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