Hypercaloric low-carbohydrate high-fat diet protects against the development of nonalcoholic fatty liver disease in obese mice in contrast to isocaloric Western diet

ObjectiveObesity and metabolic complications, such as type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), are one of the greatest public health challenges of the 21st century. The major role of high sugar and carbohydrate consumption rather than caloric intake in obesity and NAFLD pathophysiology remains a subject of debate. A low-carbohydrate but high-fat diet (LCHFD) has shown promising results in obesity management, but its effects in preventing NAFLD need to be detailed. This study aims to compare the effects of a LCHFD with a high-fat high-sugar obesogenic Western diet (WD) on the progression of obesity, type 2 diabetes, and nonalcoholic fatty liver disease.MethodsMale C57BL/6J mice were initially fed a WD for 10 weeks. Subsequently, they were either switched to a LCHFD or maintained on the WD for an additional 6 weeks. Hepatic effects of the diet were explored by histological staining and RT-qPCR.ResultsAfter the initial 10 weeks WD feeding, LCHF diet demonstrated effectiveness in halting weight gain, maintaining a normal glucose tolerance and insulin levels, in comparison to the WD-fed mice, which developed obesity, glucose intolerance, increased insulin levels and induced NAFLD. In the liver, LCHFD mitigated the accumulation of hepatic triglycerides and the increase in Fasn relative gene expression compared to the WD mice. Beneficial effects of the LCHFD occurred despite a similar calorie intake compared to the WD mice.ConclusionOur results emphasize the negative impact of a high sugar/carbohydrate and lipid association for obesity progression and NAFLD development. LCHFD has shown beneficial effects for NAFLD management, notably improving weight management, and maintaining a normal glucose tolerance and liver health

Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a ‘mitohormesis' mechanism involving reactive oxygen species and PGC-1

Aims Statins protect against cardiovascular-related mortality but induce skeletal muscle toxicity. To investigate mechanisms of statins, we tested the hypothesis that statins optimized cardiac mitochondrial function but impaired vulnerable skeletal muscle by inducing different level of reactive oxygen species (ROS). Methods and results In atrium of patients treated with statins, ROS production was decreased and oxidative capacities were enhanced together with an extensive augmentation of mRNAs expression of peroxisome proliferator-activated receptor gamma co-activator (PGC-1) family. However, in deltoid biopsies from patients with statin-induced muscular myopathy, oxidative capacities were decreased together with ROS increase and a collapse of PGC-1 mRNA expression. Several animal and cell culture experiments were conducted and showed by using ROS scavengers that ROS production was the triggering factor responsible of atorvastatin-induced activation of mitochondrial biogenesis pathway and improvement of antioxidant capacities in heart. Conversely, in skeletal muscle, the large augmentation of ROS production following treatment induced mitochondrial impairments, and reduced mitochondrial biogenesis mechanisms. Quercetin, an antioxidant molecule, was able to counteract skeletal muscle deleterious effects of atorvastatin in rat. Conclusion Our findings identify statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities, and suggest the importance of ROS/PGC-1 signalling pathway as a key element in regulation of mitochondrial function in cardiac as well as skeletal muscle

Oxidative stress precedes skeletal muscle mitochondrial dysfunction during experimental aortic cross-clamping but is not associated with early lung, heart, brain, liver, or kidney mitochondrial impairment

ObjectiveLower limb ischemia-reperfusion results in skeletal muscle mitochondrial alterations, production of reactive oxygen species (ROS), and remote organ impairments that are largely involved in patient prognosis. However, whether ischemia without reperfusion increases ROS production and precedes mitochondrial alteration and whether mitochondrial dysfunction occurs early in remote organs is unknown. This study determined muscle mitochondrial function and ROS production after ischemia alone, or followed by two periods of reperfusion, and investigated heart, lung, liver, kidney, and brain mitochondrial functions after lower limb ischemia-reperfusion.MethodsWistar rats were randomized into four groups: sham (aortic exposure but no ischemia, n = 9), I3 (ischemia alone induced by aortic cross-clamping for 3 hours, n = 9), I3R10′ and I3R2 (aortic cross-clamping, followed by reperfusion for 10 minutes [n = 8] or 2 hours [n = 9]). Blood lactate, alanine aminotransferase, aspartate aminotransferase, and creatinine were measured. Mitochondrial respiratory chain complexes I, II, III, and IV activities and mitochondrial coupling (acceptor control ratio) were analyzed using a Clark oxygen electrode in skeletal muscle, lung, heart, brain, liver, and kidney. ROS production was determined using dihydroethidium staining in muscle, heart, liver, and kidney. Inflammation was also investigated in remote organs (heart, liver, and kidney) using monocyte-macrophage-2 antibody staining.ResultsLactate level increased after ischemia in all groups. In muscle, ROS increased significantly after ischemia alone (+324% ± 66%; P = .038), normalized after 10 minutes of reperfusion, and increased again at 2 hours of reperfusion (+349.2 ± 67%; P = .024). Interestingly, mitochondrial function was unaffected by ischemia alone or followed by 10 minutes of reperfusion, but maximal mitochondrial oxidative capacity (6.10 ± 0.51 vs 4.24 ± 0.36 μmol/min/g, −30%; P < .05) and mitochondrial coupling decreased after 2 hours of reperfusion (1.93 ± 0.17 vs 1.33 ± 0.07, −45%; P < .01), in sham and I3R2 rats, respectively. Despite increased serum aspartate aminotransferase (×13; P < .0001), alanine aminotransferase (×6; P = .0019), and creatinine (×3; P = .0004), remote organs did not show mitochondrial alteration, inflammation, or ROS production enhancement after 2 hours of reperfusion.ConclusionsOxidative stress precedes skeletal muscle mitochondrial dysfunction during lower limb ischemia. Such a kinetic explains the efficacy of ischemic preconditioning and supports that therapy should be conducted even during ongoing ischemia, suggesting that ischemic preconditioning might be a successful approach.Clinical RelevanceAortic cross-clamping increases reactive oxygen species (ROS) and impairs skeletal muscle and remote organs, which is involved in patient prognosis. However, the temporal relationship between ROS production and mitochondrial dysfunction during lower limb ischemia reperfusion is unknown. This study demonstrates for the first time that ROS production occurs during ischemia alone, without reperfusion, and precedes skeletal muscle mitochondrial impairments. Although involved in multiorgan failure, lung, heart, brain, liver, and kidney mitochondria are not affected early. These results support a need for muscle protection even during lower limb ischemia and that ischemic preconditioning (conditioning performed during ongoing ischemia) might be a successful approach

PGC-1β modulates statin-associated myotoxicity in mice

Statins inhibit cholesterol biosynthesis and lower serum LDL-cholesterol levels. Statins are generally well tolerated, but can be associated with potentially life-threatening myopathy of unknown mechanism. We have shown previously that statins impair PGC-1β expression in human and rat skeletal muscle, suggesting that PGC-1β may play a role in statininduced myopathy. PGC-1β is a transcriptional co-regulator controlling the expression of important genes in mitochondrial biogenesis, antioxidative capacity and energy metabolism. The principle aim of the current study was to investigate the interaction between atorvastatin and PGC-1β in more detail. We therefore treated wild-type mice and mice with selective skeletal muscle knockout of PGC-1β (PGC-1β(i)skm−/− mice) with oral atorvastatin (5 mg/kg/day) for 2 weeks. At the end of treatment, we determined body parameters, muscle function, structure, and composition as well as the function of muscle mitochondria, mitochondrial biogenesis and activation of apoptotic pathways. In wild-type mice, atorvastatin selectively impaired mitochondrial function in glycolytic muscle and caused a conversion of oxidative type IIA to glycolytic type IIB myofibers. Conversely, in oxidative muscle of wild-type mice, atorvastatin enhanced mitochondrial function via activation of mitochondrial biogenesis pathways and decreased apoptosis. In PGC-1β(i)skm−/− mice, atorvastatin induced a switch towards glycolytic fibers, caused mitochondrial dysfunction, increased mitochondrial ROS production, impaired mitochondrial proliferation and induced apoptosis in both glycolytic and oxidative skeletal muscle. Our work reveals that atorvastatin mainly affects glycolytic muscle in wild-type mice and demonstrates the importance of PGC-1β for oxidative muscle integrity during long-term exposure to a myotoxic agent.Peer reviewe

Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a 'mitohormesis' mechanism involving reactive oxygen species and PGC-1

Aims Statins protect against cardiovascular-related mortality but induce skeletal muscle toxicity. To investigate mechanisms of statins, we tested the hypothesis that statins optimized cardiac mitochondrial function but impaired vulnerable skeletal muscle by inducing different level of reactive oxygen species (ROS). Methods and results In atrium of patients treated with statins, ROS production was decreased and oxidative capacities were enhanced together with an extensive augmentation of mRNAs expression of peroxisome proliferator-activated receptor gamma co-activator (PGC-1) family. However, in deltoid biopsies from patients with statin-induced muscular myopathy, oxidative capacities were decreased together with ROS increase and a collapse of PGC-1 mRNA expression. Several animal and cell culture experiments were conducted and showed by using ROS scavengers that ROS production was the triggering factor responsible of atorvastatin-induced activation of mitochondrial biogenesis pathway and improvement of antioxidant capacities in heart. Conversely, in skeletal muscle, the large augmentation of ROS production following treatment induced mitochondrial impairments, and reduced mitochondrial biogenesis mechanisms. Quercetin, an antioxidant molecule, was able to counteract skeletal muscle deleterious effects of atorvastatin in rat. Conclusion Our findings identify statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities, and suggest the importance of ROS/PGC-1 signalling pathway as a key element in regulation of mitochondrial function in cardiac as well as skeletal muscles

EMBO Mol Med

Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease in adults. Numerous studies indicate that ALS is a systemic disease that affects whole body physiology and metabolic homeostasis. Using a mouse model of the disease (SOD1(G86R)), we investigated muscle physiology and motor behavior with respect to muscle metabolic capacity. We found that at 65 days of age, an age described as asymptomatic, SOD1(G86R) mice presented with improved endurance capacity associated with an early inhibition in the capacity for glycolytic muscle to use glucose as a source of energy and a switch in fuel preference toward lipids. Indeed, in glycolytic muscles we showed progressive induction of pyruvate dehydrogenase kinase 4 expression. Phosphofructokinase 1 was inhibited, and the expression of lipid handling molecules was increased. This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression. Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation. In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology.The following values have no corresponding Zotero field:alt-title: EMBO Mol Mednumber: 5remote-database-provider: PubMe

Étude de la plasticité mitochondriale musculaire dans différentes situations physiologiques (exercice physique) et physiopathologiques (maladie cardiovasculaire) : rôle de l'hormèse mitochondriale

Sciences de la vie et de la sant

Capacités d'adaptation de la fonction mitochondriale et des transports d'énergie dans le muscle squelettique normal et pathologique

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Le régime cétogène : une stratégie alimentaire efficace en complément des traitements contre le cancer ?

Le cancer est une pathologie qui touche tout type de tissu et qui tue chaque année en France plus de 150 000 personnes. Les cellules cancéreuses présentent des modifications dans leur métabolisme par rapport aux cellules saines, puisqu’elles tirent leur énergie très majoritairement de la glycolyse anaérobie et non de la phosphorylation oxydative mitochondriale : on parle de l’effet Warburg. À l’heure actuelle, les traitements les plus utilisés pour soigner le cancer en routine sont des traitements dits non spécifiques qui présentent de nombreux effets secondaires, altérant la vie des patients. Il semble de plus en plus crucial de trouver de nouvelles stratégies pour lutter contre la progression des cellules cancéreuses. Le régime cétogène, pauvre en sucres et riche en lipides, est un candidat intéressant, puisqu’il affaiblit la machinerie énergétique de la cellule cancéreuse. Ce régime est déjà utilisé dans le cadre de la prise en charge de l’épilepsie réfractaire aux traitements classiques, et commence à être étudié en cancérologie également. Cet article, qui fait le point sur les preuves scientifiques des effets bénéfiques du régime cétogène, souligne son intérêt thérapeutique potentiel comme traitement complémentaire pour lutter contre certains cancers

Obésité, inflammation et COVID-19 : intérêt préventif de l’alimentation cétogène ?

L’obésité est considérée comme une pandémie responsable de plusieurs millions de morts dans le monde depuis de nombreuses années. Fin 2019 est apparue la maladie à Coronavirus 2019 (COVID-19) qui a provoqué la mort de plus d’un million de personnes en moins d’un an. De nombreuses études suggèrent que l’obésité pourrait être un paramètre clé dans l’apparition des formes graves de cette maladie émergente. En effet, le SARS-CoV2 infecte l’hôte en se fixant aux récepteurs ACE2 présents à la surface des cellules et entraîne une sécrétion excessive de cytokines pro-inflammatoires notamment l’IL-1, l’IL-6 et le TNF-α qui conduisent au développement d’un syndrome de détresse respiratoire aigu (SDRA). Il paraît essentiel d’élaborer des stratégies préventives efficaces pour protéger cette partie de la population du risque de développer une forme grave de COVID-19. L’alimentation cétogène, pauvre en sucres et riche en lipides, présente d’intéressantes propriétés, à la fois pour la lutte contre l’obésité mais également contre les infections sévères. Cet article fait le point sur les dernières avancées scientifiques qui permettent d’envisager l’alimentation cétogène comme une stratégie préventive visant à diminuer le développement de l’obésité et à renforcer le système immunitaire, deux actions clés dans la lutte contre l’infection au SARS-CoV2 et le développement de formes graves de COVID-19