Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice.

International audienceMitochondrial dysfunction in skeletal muscle has been implicated in the development of type 2 diabetes. However, whether these changes are a cause or a consequence of insulin resistance is not clear. We investigated the structure and function of muscle mitochondria during the development of insulin resistance and progression to diabetes in mice fed a high-fat, high-sucrose diet. Although 1 month of high-fat, high-sucrose diet feeding was sufficient to induce glucose intolerance, mice showed no evidence of mitochondrial dysfunction at this stage. However, an extended diet intervention induced a diabetic state in which we observed altered mitochondrial biogenesis, structure, and function in muscle tissue. We assessed the role of oxidative stress in the development of these mitochondrial abnormalities and found that diet-induced diabetic mice had an increase in ROS production in skeletal muscle. In addition, ROS production was associated with mitochondrial alterations in the muscle of hyperglycemic streptozotocin-treated mice, and normalization of glycemia or antioxidant treatment decreased muscle ROS production and restored mitochondrial integrity. Glucose- or lipid-induced ROS production resulted in mitochondrial alterations in muscle cells in vitro, and these effects were blocked by antioxidant treatment. These data suggest that mitochondrial alterations do not precede the onset of insulin resistance and result from increased ROS production in muscle in diet-induced diabetic mice

Muscle-Specific Adaptations, Impaired Oxidative Capacity and Maintenance of Contractile Function Characterize Diet-Induced Obese Mouse Skeletal Muscle

BACKGROUND:The effects of diet-induced obesity on skeletal muscle function are largely unknown, particularly as it relates to changes in oxidative metabolism and morphology. PRINCIPAL FINDINGS:Compared to control fed mice, mice fed a high fat diet (HFD; 60% kcal: fat) for 8 weeks displayed increased body mass and insulin resistance without overt fasting hyperglycemia (i.e. pre-diabetic). Histological analysis revealed a greater oxidative potential in the HFD gastrocnemius/plantaris (increased IIA, reduced IIB fiber-type percentages) and soleus (increased I, IIA cross-sectional areas) muscles, but no change in fiber type percentages in tibialis anterior muscles compared to controls. Intramyocellular lipid levels were significantly increased relative to control in HFD gastrocnemius/plantaris, but were similar to control values in the HFD soleus. Using a novel, single muscle fiber approach, impairments in complete palmitate and glucose oxidation (72.8+/-6.6% and 61.8+/-9.1% of control, respectively; p<0.05) with HFD were detected. These reductions were consistent with measures made using intact extensor digitorum longus and soleus muscles. Compared to controls, no difference in succinate dehydrogenase or citrate synthase enzyme activities were observed between groups in any muscle studied, however, short-chain fatty acyl CoA dehydrogenase (SCHAD) activity was elevated in the HFD soleus, but not tibialis anterior muscles. Despite these morphological and metabolic alterations, no significant difference in peak tetanic force or low-frequency fatigue rates were observed between groups. CONCLUSIONS:These findings indicate that HFD induces early adaptive responses that occur in a muscle-specific pattern, but are insufficient to prevent impairments in oxidative metabolism with continued high-fat feeding. Moreover, the morphological and metabolic changes which occur with 8 weeks of HFD do not significantly impact muscle contractile properties

Differential effects of saturated versus unsaturated dietary fatty acids on weight gain and myocellular lipid profiles in mice

OBJECTIVE: In conditions of continuous high-fat (HF) intake, the degree of saturation of the fatty acids (FAs) in the diet might have a crucial role in the onset of obesity and its metabolic complications. In particular, the FA composition of the diet might influence the storage form of lipids inside skeletal muscle. The aim of the present study was to examine whether the FA composition of HF diets differentially affects weight gain and accumulation of myocellular triacylglycerol (TAG) and diacylglycerol (DAG). Furthermore, we examined whether the FA composition of the diet was reflected in the composition of the myocellular lipid intermediates.DESIGN: C57Bl6 mice were fed HF diets (45% energy) mainly containing palm oil (PO), cocoa butter (CB), olive oil (OO) or safflower oil (SO; n=6 per group) for 8 weeks. A low-fat diet (10% energy, PO) was used as control. Body weight was monitored weekly. At the end of the dietary intervention, myocellular TAG and DAG content and profiles were measured.RESULTS: We here show that HF_CB prevented weight gain after 8 weeks of HF feeding. Furthermore, the HF diet rich in SO prevented the accumulation of both myocellular TAG and DAG. Interestingly, the FA composition of DAG and TAG in skeletal muscle was a reflection of the dietary FA composition.CONCLUSION: Already after a relatively short period, the dietary FA intake relates to the FA composition of the lipid metabolites in the muscle. A diet rich in polyunsaturated FAs seems to prevent myocellular lipid accumulation.<br/

Obesity, diabetes and longevity in the Gulf: is there a Gulf Metabolic Syndrome?

The Gulf is experiencing a pandemic of lifestyle-induced obesity and type 2 diabetes mellitus (T2DM), with rates exceeding 50 and 30%, respectively. It is likely that T2DM represents the tip of a very large metabolic syndrome iceberg, which precedes T2DM by many years and is associated with abnormal/ectopic fat distribution, pathological systemic oxidative stress and inflammation. However, the definitions are still evolving with the role of different fat depots being critical. Hormetic stimuli, which include exercise, calorie restriction, temperature extremes, dehydration and even some dietary components (such as plant polyphenols), may well modulate fat deposition. All induce physiological levels of oxidative stress, which results in mitochondrial biogenesis and increased anti-oxidant capacity, improving metabolic flexibility and the ability to deal with lipids. We propose that the Gulf Metabolic Syndrome results from an unusually rapid loss of hormetic stimuli within an epigenetically important time frame of 2-3 generations. Epigenetics indicates that thriftiness can be programmed by the environment and passed down through several generations. Thus this loss of hormesis can result in continuation of metabolic inflexibility, with mothers exposing the foetus to a milieu that perpetuates a stressed epigenotype. As the metabolic syndrome increases oxidative stress and reduces life expectancy, a better descriptor may therefore be the Lifestyle-Induced Metabolic Inflexibility and accelerated AGEing syndrome – LIMIT-AGE. As life expectancy in the Gulf begins to fall, with perhaps a third of this life being unhealthy – including premature loss of sexual function, it is vital to detect evidence of this condition as early in life as possible. One effective way to do this is by detecting evidence of metabolic inflexibility by studying body fat content and distribution by magnetic resonance (MR). The Gulf Metabolic Syndrome thus represents an accelerated form of the metabolic syndrome induced by the unprecedented rapidity of lifestyle change in the region, the stress of which is being passed from generation to generation and may be accumulative. The fundamental cause is probably due to a rapid increase in countrywide wealth. This has benefited most socioeconomic groups, resulting in the development of an obesogenic environment as the result of the rapid adoption of Western labour saving and stress relieving devices (e.g. cars and air conditioning), as well as the associated high calorie diet

Liver and Muscle in Morbid Obesity: The Interplay of Fatty Liver and Insulin Resistance

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) can be seen as a manifestation of overnutrition. The muscle is a central player in the adaptation to energy overload, and there is an association between fatty-muscle and -liver. We aimed to correlate muscle morphology, mitochondrial function and insulin signaling with NAFLD severity in morbid obese patients. METHODS: Liver and deltoid muscle biopsies were collected during bariatric surgery in NAFLD patients. NAFLD Activity Score and Younossi's classification for nonalcoholic steatohepatitis (NASH) were applied to liver histology. Muscle evaluation included morphology studies, respiratory chain complex I to IV enzyme assays, and analysis of the insulin signaling cascade. A healthy lean control group was included for muscle morphology and mitochondrial function analyses. RESULTS: Fifty one NAFLD patients were included of whom 43% had NASH. Intramyocellular lipids (IMCL) were associated with the presence of NASH (OR 12.5, p<0.001), progressive hepatic inflammation (p = 0.029) and fibrosis severity (p = 0.010). There was a trend to an association between IMCL and decreased Akt phosphorylation (p = 0.059), despite no association with insulin resistance. In turn, hepatic steatosis (p = 0.015) and inflammation (p = 0.013) were associated with decreased Akt phosphoryation. Citrate synthase activity was lower in obese patients (p = 0.047) whereas complex I (p = 0.040) and III (p = 0.036) activities were higher, compared with controls. Finally, in obese patients, complex I activity increased with progressive steatosis (p = 0.049) and with a trend with fibrosis severity (p = 0.056). CONCLUSIONS: In morbid obese patients, presence of IMCL associates with NASH and advanced fibrosis. Muscle mitochondrial dysfunction does not appear to be a major driving force contributing to muscle fat accumulation, insulin resistance or liver disease. Importantly, insulin resistance in muscle might occur at a late point in the insulin signaling cascade and be associated with IMCL and NAFLD severity

International longitudinal registry of patients with atrial fibrillation and treated with rivaroxaban: RIVaroxaban Evaluation in Real life setting (RIVER)

Background Real-world data on non-vitamin K oral anticoagulants (NOACs) are essential in determining whether evidence from randomised controlled clinical trials translate into meaningful clinical benefits for patients in everyday practice. RIVER (RIVaroxaban Evaluation in Real life setting) is an ongoing international, prospective registry of patients with newly diagnosed non-valvular atrial fibrillation (NVAF) and at least one investigator-determined risk factor for stroke who received rivaroxaban as an initial treatment for the prevention of thromboembolic stroke. The aim of this paper is to describe the design of the RIVER registry and baseline characteristics of patients with newly diagnosed NVAF who received rivaroxaban as an initial treatment. Methods and results Between January 2014 and June 2017, RIVER investigators recruited 5072 patients at 309 centres in 17 countries. The aim was to enroll consecutive patients at sites where rivaroxaban was already routinely prescribed for stroke prevention. Each patient is being followed up prospectively for a minimum of 2-years. The registry will capture data on the rate and nature of all thromboembolic events (stroke / systemic embolism), bleeding complications, all-cause mortality and other major cardiovascular events as they occur. Data quality is assured through a combination of remote electronic monitoring and onsite monitoring (including source data verification in 10% of cases). Patients were mostly enrolled by cardiologists (n = 3776, 74.6%), by internal medicine specialists 14.2% (n = 718) and by primary care/general practice physicians 8.2% (n = 417). The mean (SD) age of the population was 69.5 (11.0) years, 44.3% were women. Mean (SD) CHADS2 score was 1.9 (1.2) and CHA2DS2-VASc scores was 3.2 (1.6). Almost all patients (98.5%) were prescribed with once daily dose of rivaroxaban, most commonly 20 mg (76.5%) and 15 mg (20.0%) as their initial treatment; 17.9% of patients received concomitant antiplatelet therapy. Most patients enrolled in RIVER met the recommended threshold for AC therapy (86.6% for 2012 ESC Guidelines, and 79.8% of patients according to 2016 ESC Guidelines). Conclusions The RIVER prospective registry will expand our knowledge of how rivaroxaban is prescribed in everyday practice and whether evidence from clinical trials can be translated to the broader cross-section of patients in the real world

Modulation du métabolisme énergétique du muscle par les nutriments et la nutrition : Rôle potentiel d'un dialogue muscle squelettique-tissu adipeux et implication du métabolisme des lipides

Numéro national de thèse : 2006CLF1MM15 Diplôme : Dr. d'UniversiteObesity is frequently associated with insulin resistance, a feature that precedes by 10 to 20 years the clinical development of type 2 diabetes. These metabolic disturbances are generally combined with mitochondrial dysfunction in skeletal muscle. From these findings has emerged the hypothesis that mitochondria may play a causal role in the aetiology of such pathologies. The aim of this work was 1- to investigate the impact of nutrition on muscle energy metabolism and more particularly on mitochondrial activity and 2- to study the potential role of a cross talk between skeletal muscle and adipose tissue in the induction of mitochondrial dysfunction. A cross study was designed in order to examine the effect of nutrients (quality and quantity) on muscle energy metabolism in Wistar rats. Once our model was validated, a chronological study was used to determine the sequence of events leading to metabolic disorders. This work demonstrates that nutrition, and above all, excess energy intake, influences mitochondrial activity (OXPHOS activity and reactive species production), despite increased synthesis of mitochondrial proteins. These adaptations are muscle-type specific and alter more specifically the oxidative fibers. The decrease in mitochondrial oxidative capacities is not causally related to insulin resistance. However, the results evidence that the enhancement of mitochondrial activity may be involved in the improvement of lipid and glucose homeostasis. On the whole, this work confirms that any strategy to reduce fatty acids availability is a relevant approach to prevent the development of metabolic disorders.L'obésité est fréquemment associée à une insulinorésistance, étape qui précède de 10 à 20 ans l'apparition du diabète de type 2. Ces perturbations métaboliques s'accompagnent généralement d'un dysfonctionnement mitochondrial dans le muscle squelettique. De ces observations a émergé l'hypothèse d'un rôle causal des mitochondries dans l'étiologie de ces pathologies. L'objectif de ce travail était 1- de tester l'impact de la nutrition sur le métabolisme énergétique du muscle et plus particulièrement sur l'activité mitochondriale et 2- d'étudier le rôle potentiel d'un dialogue entre le muscle et le tissu adipeux dans l'induction du dysfonctionnement mitochondrial. Une étude transversale a été mise en place afin d'analyser l'effet des nutriments (qualité et quantité) sur le métabolisme énergétique du muscle du rat Wistar. Après validation du modèle, une approche chronologique a permis d'analyser la séquence d¤installation des perturbations métaboliques. Ce travail démontre que la nutrition, et par-dessus tout, l'excès d'énergie, perturbe l'activité mitochondriale (activité OXPHOS et production de radicaux libres), malgré une stimulation de la synthèse des protéines mitochondriales. Ces adaptations diffèrent selon la typologie du muscle et affectent plus spécifiquement les fibres oxydatives. La diminution des capacités oxydatives mitochondriales dans le muscle n'est pas le facteur causal conduisant au développement de l'insulinorésistance. Cependant, les résultats soulignent le fait qu'une stimulation de l'activité mitochondriale peut participer à l'amélioration de l'homéostasie lipidique et glucidique. Finalement, l'ensemble de ce travail confirme que toute stratégie visant à réduire la disponibilité en acides gras est une approche pertinente de prévention des maladies métaboliques

Modulation du métabolisme énergétique du muscle par les nutriments et la nutrition (rôle potentiel d'un dialogue muscle squelettique-tissu adipeux et implication du métabolisme des lipides)

L'obésité est fréquemment associée à une insulinorésistance, étape qui précède de 10 à 20 ans l'apparition du diabète de type 2. Ces perturbations métaboliques s'accompagnent généralement d'un dysfonctionnement mitochondrial dans le muscle squelettique. De ces observations a émergé l'hypothèse d'un rôle causal des mitochondries dans l'étiologie de ces pathologies. L'objectif de ce travail était 1- de tester l'impact de la nutrition sur le métabolisme énergétique du muscle et plus particulièrement sur l'activité mitochondriale et 2- d'étudier le rôle potentiel d'un dialogue entre le muscle et le tissu adipeux dans l'induction du dysfonctionnement mitochondrial. Une étude transversale a été mise en place afin d'analyser l'effet des nutriments (qualité et quantité) sur le métabolisme énergétique du muscle du rat Wistar. Après validation du modèle, une approche chronologique a permis d'analyser la séquence d installation des perturbations métaboliques. Ce travail démontre que la nutrition, et par-dessus tout, l'excès d'énergie, perturbe l'activité mitochondriale (activité OXPHOS et production de radicaux libres), malgré une stimulation de la synthèse des protéines mitochondriales. Ces adaptations diffèrent selon la typologie du muscle et affectent plus spécifiquement les fibres oxydatives. La diminution des capacités oxydatives mitochondriales dans le muscle n'est pas le facteur causal conduisant au développement de l'insulinorésistance. Cependant, les résultats soulignent le fait qu'une stimulation de l'activité mitochondriale peut participer à l'amélioration de l'homéostasie lipidique et glucidique. Finalement, l'ensemble de ce travail confirme que toute stratégie visant à réduire la disponibilité en acides gras est une approche pertinente de prévention des maladies métaboliques.Obesity is frequently associated with insulin resistance, a feature that precedes by 10 to 20 years the clinical development of type 2 diabetes. These metabolic disturbances are generally combined with mitochondrial dysfunction in skeletal muscle. From these findings has emerged the hypothesis that mitochondria may play a causal role in the aetiology of such pathologies. The aim of this work was 1- to investigate the impact of nutrition on muscle energy metabolism and more particularly on mitochondrial activity and 2- to study the potential role of a cross talk between skeletal muscle and adipose tissue in the induction of mitochondrial dysfunction. A cross study was designed in order to examine the effect of nutrients (quality and quantity) on muscle energy metabolism in Wistar rats. Once our model was validated, a chronological study was used to determine the sequence of events leading to metabolic disorders. This work demonstrates that nutrition, and above all, excess energy intake, influences mitochondrial activity (OXPHOS activity and reactive species production), despite increased synthesis of mitochondrial proteins. These adaptations are muscle-type specific and alter more specifically the oxidative fibers. The decrease in mitochondrial oxidative capacities is not causally related to insulin resistance. However, the results evidence that the enhancement of mitochondrial activity may be involved in the improvement of lipid and glucose homeostasis. On the whole, this work confirms that any strategy to reduce fatty acids availability is a relevant approach to prevent the development of metabolic disorders.CLERMONT FD-BCIU-Santé (631132104) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Caractérisation du métabolisme protéino-énergétique musculaire au cours de la cachexie cardiaque

CLERMONT FD-BCIU-Santé (631132104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Dietary-induced alterations in mitochondrial oxidative phosphorylation (OXPHOS) functions in muscle rats. Association with induction of glucose intolerance

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