Changes to our environment have led to the emergence of human pathogens such as chikungunya virus. Chikungunya virus infection is today a major public health concern. It is a debilitating chronic disease impeding patients' mobility, affecting millions of people. Disease development relies on skeletal muscle infection. The importance of skeletal muscle in chikungunya virus infection led to the hypothesis that it could serve as a viral reservoir and could participate to virus persistence. Here we questioned the interconnection between skeletal muscle cells metabolism, their differentiation stage and the infectivity of the chikungunya virus. We infected human skeletal muscle stem cells at different stages of differentiation with chikungunya virus to study the impact of their metabolism on virus production and inversely the impact of virus on cell metabolism. We observed that chikungunya virus infectivity is cell differentiation and metabolism-dependent. Chikungunya virus interferes with the cellular metabolism in quiescent undifferentiated and proliferative muscle cells. Moreover, activation of chikungunya infected quiescent muscle stem cells, induces their proliferation, increases glycolysis and amplifies virus production. Therefore, our results showed that Chikungunya virus infectivity and the antiviral response of skeletal muscle cells relies on their energetic metabolism and their differentiation stage. Then, muscle stem cells could serve as viral reservoir producing virus after their activation.

Metabolic skeletal muscle (SM) dysfunction, triggered by increased oxidative stress and mitochondrial impairment, is a pivotal contributor to obesity-associated insulin resistance (IR). Addressing obesity and SM IR demands substantial lifestyle changes including regular exercise and dietary adjustments that are difficult to follow over time. This prompted exploration of alternative approaches. Grape polyphenols (GPPs) have demonstrated a positive impact on metabolism, although few studies have focused on SM. Since grape polyphenolic content and composition depend on tissue and ripening, we explored the antioxidant potential of GPPs from skin (Sk) and seeds (Sd) extracted before veraison (Bv) and at mature (M) stages, on palmitate-induced IR in primary human SM cells. Despite their important difference in polyphenol (PP) content: Sd-BvPP > Sd-MPP/Sk-BvPP > Sk-MPP, all extracts reduced lipid peroxidation by 44–60%, up-regulated the heme-oxygenase 1 protein level by 75–132% and mitochondrial activity by 47–68%. Contrary to the other extracts, which improved insulin response by 50%, Sd-BvPP did not. Our findings suggest that compounds other than stilbenoids or anthocyanin-type molecules, present only in grape Sk, could play an active role in regulating SM oxidative and metabolic stress and insulin sensitivity, paving the way for further exploration of novel bioactive compounds.

L-lactate metabolism was first investigated in exercise physiology since it was considered as a waste product of glycolysis due to oxygen deficiency. Since the 1980s’, several studies showed that lactate is an essential metabolic fuel and signaling molecule (Brooks, 2020). Then, the interest for lactate has extended to a growing number of disciplines, from physiology to pathology and exercise is now viewed as a metabolic trigger for tissues adaptation. Lactate is transported by the monocarboxylate transporters (MCTs) family which present a ubiquitous tissue distribution but lactate can additionally activate the hydroxycarboxylic acid receptor 1 (HCAR1) also known as G protein-coupled receptor 81 (GPR81). In most tissues and cell types, lactate entry is mediated by MCT1 or MCT2 and related to oxidative capacity whereas MCT4 would be mainly involved in lactate output. The basic knowledge on lactate is that it could be a metabolic substrate or exchange molecule for muscle (Brooks), or brain (Pellerin, 2010), that MCTs content vary with training (Dubouchaud et al., 2000), nutritional status (Lambert et al., 2003; Pierre et al., 2007), cellular activity or intracellular signaling (Pérez-Escuredo et al., 2016) and diseases (Py et al., 2001). This Research Topic provides an update about the knowledge of lactate roles and mechanisms of action. Durand et al., focused on blood lactate kinetics in response to exercise. Their findings showed that the longer the recovery period, the better is the quality of models to describe lactate exchange and removal abilities. In the brain, exercise allows to increase lactate release, favoring hippocampal metabolism and especially mitochondrial biogenesis (Park et al.) but also mitochondrial efficiency and brain-derived neurotrophic factor biosynthesis (Hu et al.) (Figure 1). The ability of lactate to increase mitochondrial biogenesis has been previously described in skeletal muscle. The present studies demonstrated that lactate and oxidative metabolism could play an important role in the physiology of other tissues. Indeed, the effects of exercise on hippocampal mitochondria number and function highlight the role of lactate in mediating memory processes and, in turn, physical performance. Lactate is a mediator of neuronastrocyte dialogue since astrocytes provide lactate to neuron as an energetic substrate. Horvat et al. have provided evidence of this relationship with a focus on the lactate-positive feedback mechanism in astrocytes. Astrocytes switch their metabolism to lipid metabolism, enhancing availability of lactate for neuron as a metabolic substrate when ATP needs to be increased. The control and regulation of lactate entry into astrocytes could involve known and unknown transporters. Interestingly, during stressful conditions, such as hypoxia or ischemiareperfusion (I/R), increasing lactate concentration via exogenous lactate perfusion ameliorates the neurological outcome (Roumes et al., 2021). Buscemi et al. have tested the hypothesis that the beneficial effect of lactate in cerebral I/R process could be due to the activation of HCAR1 by Edited and reviewed by: Geoffrey A. Head, Baker Heart and Diabetes Institute, Australia

Today, inactivity and high-calorie diets contribute to the development of obesity and premature aging. In addition, the population of elderly people is growing due to improvements in healthcare management. Obesity and aging are together key risk factors for non-communicable diseases associated with several co-morbidities and increased mortality, with a major impact on skeletal muscle defect and/or poor muscle mass quality. Skeletal muscles contribute to multiple body functions and play a vital role throughout the day, in all our activities. In our society, limiting skeletal muscle deterioration, frailty and dependence is not only a major public health challenge but also a major socio-economic issue. Specific diet supplementation with natural chemical compounds such as grape polyphenols had shown to play a relevant and direct role in regulating metabolic and molecular pathways involved in the prevention and treatment of obesity and aging and their related muscle comorbidities in cell culture and animal studies. However, clinical studies aiming to restore skeletal muscle mass and function with nutritional grape polyphenols supplementation are still very scarce. There is an urgent need for clinical studies to validate the very encouraging results observed in animal models.

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. The 2–5A/RNase L/RNase L Inhibitor (RNI) Pathway Regulates Mitochondrial mRNAs Stability in Interferon α-treated H9 Cells Florence Le Roy, Catherine Bisbal, Michelle Silhol, Camille Martinand, Bernard Lebleu, Tamim Salehzada

Individuellement, la supplémentation en polyphénols de raisin et l’exercice ont démontré des effets bénéfiques sur la prise en charge de l’obésité et les atteintes du métabolisme cardiaque. Le but de cette étude était d’évaluer l’impact de l’association de l’exercice et d’une supplémentation en polyphénols de raisin à dose nutritionnelle (EXOPP) sur l’adaptation cardiaque au niveau moléculaire et au niveau de la réactivité vasculaire. Quarante rats Sprague-Dawley ont reçu pendant 12 semaines un régime riche en lipide (HF). À l’issu du premier mois, où nous avons démontré une obésité et une insulinorésistance, les rats ont été randomisés en 4 groupes pour 8 semaines tout en continuant le régime HF. Dix animaux ont continué le régime HF, 10 rats ont reçu une supplémentation en polyphénols de raisin (50 mg/kg/jour) dans de l’eau de boisson associée à un entraînement quotidien sur tapis roulant pendant une heure à une pente de 32 m/min–10 % de pente, 5 jours/semaine (EXOPP). Enfin 10 rats ont fait uniquement l’entraînement (EXO) et 10 rats ont reçu la supplémentation (PP). La pression artérielle aortique a été mesurée chez les rats anesthésiés. Au moment du sacrifice, le cœur a été retiré et congelé pour des analyses biochimiques et histologiques. La réactivité vasculaire a été réalisée sur des anneaux d’aorte. Grâce à une ANOVA à deux voies (entraînement et supplémentation), nous avons pu mettre en évidence que la supplémentation en polyphénols (PP et EXOPP) induit une diminution de la pression artérielle systolique (p = 0,015) par rapport aux rats non supplémentés (HF et EXO). Individuellement, l’entraînement et la supplémentation en polyphénols induisent une hypertrophie cardiomyocytaire, avec une augmentation de la surface des cardiomyocytes (p < 0,001 et p = 0,022) et du diamètre de Feret (p < 0,008 et p = 0,027), sans qu’il y ait un effet cumulatif. L’expression de la calcineurine cardiaque était diminuée par l’entraînement (p < 0,001) et la supplémentation en polyphénols (p = 0,031), alors que les protéines P-Akt/Akt (p = 0,021), P-AMPK/AMPK (p = 0,032) n’étaient augmentées que par l’entraînement. La supplémentation en polyphénols a diminué la fibrose (p = 0,014) et l’entraînement tend aussi à la diminuer (p = 0,091). Au niveau vasculaire, la relaxation des anneaux d’aorte dépendante de l’endothélium était diminuée dans le groupe EXOPP (p < 0,001). L’entraînement en endurance et la supplémentation en polyphénols induisent des adaptations cardiaques bénéfiques chez les rats obèses via des voies de signalisation différentes. L’association des deux interventions n’apporte aucune amélioration supplémentaire sur les paramètres testés.

Obesity and exercise lead to structural changes in heart such as cardiac hypertrophy. The underlying signaling pathways vary according to the source of the overload, be it physiological (exercise) or pathologic (obesity). The physiological pathway relies more on PI3K-Akt signaling while the pathologic pathway involves calcineurin-Nuclear factor of activated T-cells activation and fibrosis accumulation. Independently, exercise and polyphenols have demonstrated to prevent pathologic cardiac hypertrophy. Therefore, we investigated the molecular adaptations of the combination of exercise training and grape polyphenols supplementation (EXOPP) in obese high-fat fed rats on heart adaptation in comparison to exercise (EXO), polyphenols supplementation (PP) and high-fat fed rats (HF), alone. Exercised and PP rats presented a higher heart weight/body weight ratio compared to HF rats. EXO and EXOPP depicted an increase in cell-surface area, P-Akt/Akt, P-AMPK/AMPK ratios with a decreased fibrosis and calcineurin expression, illustrating an activation of the physiological pathway, but no additional benefit of the combination. In contrast, neither cell-surface area nor Akt signaling increased in PP rats; but markedly decreased fibrosis, calcineurin expression, systolic blood pressure, higher SERCA and P-Phospholamdan/Phospholamdan levels were observed. These data suggest that PP rats have a shift from pathologic toward physiological hypertrophy. Our study demonstrates that polyphenols supplementation has physical-activity-status-specific effects; it appears to be more protective in sedentary obese insulin-resistant rats than in the exercised ones. Exercise training improved metabolic and cardiac alterations without a synergistic effect of polyphenols supplementation. These data highlight a greater effect of exercise than polyphenols supplementation for the treatment of cardiac alterations in obese insulin-resistant rats.

Mayaro virus (MAYV) is an emerging arthritogenic alphavirus belonging to the Togaviridae family. Infection leads to a dengue-like illness accompanied by severe polyarthralgia. However, the molecular and cellular mechanisms of arthritis as a result of MAYV infection remain poorly understood. In the present study, we assess the susceptibility of human chondrocytes (HC), fibroblast-like synoviocytes and osteoblasts that are the major cell types involved in osteoarthritis, to infection with MAYV. We show that these cells are highly permissive to MAYV infection and that viral RNA copy number and viral titers increase over time in infected cells. Knowing that HC are the primary cells in articular cartilage and are essential for maintaining the cartilaginous matrix, gene expression studies were conducted in MAYV-infected primary HC using polymerase chain reaction (PCR) arrays. The infection of the latter cells resulted in an induction in the expression of several matrix metalloproteinases (MMP) including MMP1, MMP7, MMP8, MMP10, MMP13, MMP14 and MMP15 which could be involved in the destruction of articular cartilage. Infected HC were also found to express significantly increased levels of various IFN-stimulated genes and arthritogenic mediators such as TNF-α and IL-6. In conclusion, MAYV-infected primary HC overexpress arthritis-related genes, which may contribute to joint degradation and pathogenesis.

Separately, polyphenols and exercise are known to prevent insulin resistance (IR) but their combined curative effects on established obesity and IR require further investigation. Therefore, we compared the metabolic effects of a combination of exercise and grape polyphenols supplementation in obese IR rats with high-fat diet (EXOPP) to the effect of high-fat diet alone (HF) or with a nutritional supplementation of grape polyphenols (PP) or with endurance exercise (EXO) during 8 wks. We observed an improvement of systemic and skeletal muscle insulin sensitivity in EXO and EXOPP rats. EXOPP rats compared to HF rats presented a lower insulinemia and HOMA-IR with higher liver and muscle glycogen contents. Interestingly, EXOPP rats had a 68% enhanced endurance capacity compared to EXO rats with also a higher activation of AMPK compared to sedentary and EXO rats with increased lipid oxidation. Together, our results suggest that grape polyphenols supplementation combined with exercise has a synergistic effect by increasing muscle lipid oxidation and sparing glycogen utilization which thus enhances endurance capacity. Our data highlight that in cases of established obesity and IR, the combination of nutritional grape polyphenols supplementation and exercise heighten and intensify their individual metabolic effects.

One of the major insulin resistance instigators is excessive adiposity and visceral fat depots. Individually, exercise training and polyphenol intake are known to exert health benefits as improving insulin sensitivity. However, their combined curative effects on established obesity and insulin resistance need further investigation particularly on white adipose tissue alterations. Therefore, we compared the effects on different white adipose tissue depot alterations of a combination of exercise and grape polyphenol supplementation in obese insulin-resistant rats fed a high-fat diet to the effects of a high-fat diet alone or a nutritional supplementation of grape polyphenols (50 mg/kg/day) or exercise training (1 hr/day to 5 days/wk consisting of treadmill running at 32 m/min for a 10% slope), for a total duration of 8 weeks. Separately, polyphenol supplementation and exercise decreased the quantity of all adipose tissue depots and mesenteric inflammation. Exercise reduced adipocytes' size in all fat stores. Interestingly, combining exercise to polyphenol intake presents no more cumulative benefit on adipose tissue alterations than exercise alone. Insulin sensitivity was improved at systemic, epididymal, and inguinal adipose tissues levels in trained rats thus indicating that despite their effects on adipocyte morphological/metabolic changes, polyphenols at nutritional doses remain less effective than exercise in fighting insulin resistance.

Context: Toll-like receptor 4 (TLR4) activation contributes to obesity-associated insulin resistance in skeletal muscles (SM). TLR4 signaling involves two pathways: the myeloid differentiation primary response gene 88 (MyD88) leading to inflammatory cytokines production and the toll/interleukin-1 receptor domain-containing adapter-inducing interferon (IFN) I (TRIF)-dependent pathways leading to type 1 interferon (IFNI) and interferon stimulated genes (ISG) expression. The E3 ubiquitin ligase RNF41 allows the preferential activation of the TRIF-IFNI pathway; however, its role in insulin response has not been reported. Methods: We measured RNF41 level and IFNI pathway activation (ISG expression) in SM biopsies of obese insulin sensitive (OIS) and obese insulin resistant (OIR) women. Then we isolated and differentiated in myotubes, primary human SM cell progenitors from OIS and OIR SM biopsies. We modulated RNF41 and ISG expression in these myotubes and investigated their effects on insulin response. Results: RNF41 expression is down-regulated in vivo in OIR SM and myotubes compared to OIS SM and myotubes. TLR4 activation with palmitate induces TRIF-IFNI pathway and ISG in OIS myotubes but not in OIR myotubes. Inhibition of RNF41 expression with siRNF41 in OIS myotubes treated with palmitate attenuates insulin response, IFNI pathway activation and ISG induction, mimicking OIR phenotype. Further, overexpression of RNF41 in OIR myotubes increases insulin response and ISG expression. Exposure to IFNI or to its inducer polyinosinicpolycytidylic acid, restores ISG expression and insulin sensitivity in OIR myotubes and OIS myotubes transfected with siRNF41. Conclusion: Our results identify RNF41 as essential to IFNI pathway activation in order to maintain muscle insulin sensitivity during human obesity. (C) 2018 Elsevier Inc. All rights reserved.

Context Obesity is associated with insulin-resistance (IR), the key feature of type 2 diabetes. Although chronic low-grade inflammation has been identified as a central effector of IR development, it has never been investigated simultaneously at systemic level and locally in skeletal muscle and adipose tissue in obese humans characterized for their insulin sensitivity. Objectives We compared metabolic parameters and inflammation at systemic and tissue levels in normal-weight and obese subjects with different insulin sensitivity to better understand the mechanisms involved in IR development. Methods 30 post-menopausal women were classified as normal-weight insulin-sensitive (controls, CT) and obese (grade I) insulin-sensitive (OIS) or insulin-resistant (OIR) according to their body mass index and homeostasis model assessment of IR index. They underwent a hyperinsulinemic-euglycemic clamp, blood sampling, skeletal muscle and subcutaneous adipose tissue biopsies, an activity questionnaire and a self-administrated dietary recall. We analyzed insulin sensitivity, inflammation and IR-related parameters at the systemic level. In tissues, insulin response was assessed by P-Akt/Akt expression and inflammation by macrophage infiltration as well as cytokines and IκBα expression. Results Systemic levels of lipids, adipokines, inflammatory cytokines, and lipopolysaccharides were equivalent between OIS and OIR subjects. In subcutaneous adipose tissue, the number of anti-inflammatory macrophages was higher in OIR than in CT and OIS and was associated with higher IL-6 level. Insulin induced Akt phosphorylation to the same extent in CT, OIS and OIR. In skeletal muscle, we could not detect any inflammation even though IκBα expression was lower in OIR compared to CT. However, while P-Akt/Akt level increased following insulin stimulation in CT and OIS, it remained unchanged in OIR. Conclusion Our results show that systemic IR occurs without any change in systemic and tissues inflammation. We identified a muscle defect in insulin response as an early mechanism of IR development in grade I obese post-menopausal women.

La micro-inflammation chronique, l’activation de l’immunité innée, le stress oxydant sont des mécanismes impliqués dans le développement de l’insulinorésistance (IR), au cours de l’obésité. L’IR affecte notamment le tissu musculaire (TM) et le tissu adipeux (TA). Cependant, les mécanismes initiateurs du développement de l’IR ne sont pas entièrement identifiés. Chez l’homme, la sensibilité à l’insuline et l’inflammation n’ont jamais été analysées au niveau systémique et tissulaire chez un même sujet. Notre objectif est de caractériser la sensibilité à l’insuline, le profil inflammatoire/immunitaire au niveau systémique/tissulaire, chez des sujets obèses. Mesure systémique et tissulaire (TA, TM) de la sensibilité à l’insuline, du profil inflammatoire/immunitaire chez 30 femmes ménopausées (10 sujets contrôles CT, IMC: 18,5-25 kg/m² et 20 sujets obèses IMC > 30 kg/m²) sans antécédent familiaux de diabète de type 2. Les volontaires obèses ont été classées comme obèses insulinosensibles (OIS) ou insulinorésistantes (OIR) selon leur HOMAIR et leur GIR (glucose infusion rate). Nos résultats montrent que: 1/ la production d’adipokines/ cytokines est identique entre les OIS et les OIR, au niveau systémique et tissulaire, 2/ la sensibilité à l’insuline dans le TA est identique entre les CT, OIS et OIR, 3/ la sensibilité à l’insuline dans le TM est significativement diminuée chez les OIR par rapport aux CT et OIS. Elle est associée à une activation de la voie TLR4/Myd88/NFκB et une inactivation de la voie TLR4/TLR3/TRIFF/ IRF3, conduisant à une diminution de l’expression de MnSOD. Dans notre cohorte de sujets obèses, seul le TM est touché par l’IR. Cette IR musculaire se développe sans inflammation systémique ni tissulaire, mais est associée à une modification de la balance des voies de l’immunité innée Myd88/TRIF. Ces résultats mettent en exergue l’importance de l’immunité innée dans la régulation de la sensibilité à l’insuline. Les auteurs déclarent ne pas avoir d’intérêt direct ou indirect (financier ou en nature) avec un organisme privé, industriel ou commercial en relation avec le sujet présenté.

Erythropoietin (EPO) ameliorates glucose metabolism through mechanisms not fully understood. In this study, we investigated the effect of EPO on glucose metabolism and insulin signaling in skeletal muscle. A 2-week EPO treatment of rats fed with a high-fat diet (HFD) improved fasting glucose levels and glucose tolerance, without altering total body weight or retroperitoneal fat mass. Concomitantly, EPO partially rescued insulin-stimulated AKT activation, reduced markers of oxidative stress, and restored heat-shock protein 72 expression in soleus muscles from HFD-fed rats. Incubation of skeletal muscle cell cultures with EPO failed to induce AKT phosphorylation and had no effect on glucose uptake or glycogen synthesis. We found that the EPO receptor gene was expressed in myotubes, but was undetectable in soleus. Together, our results indicate that EPO treatment improves glucose tolerance but does not directly activate the phosphorylation of AKT in muscle cells. We propose that the reduced systemic inflammation or oxidative stress that we observed after treatment with EPO could contribute to the improvement of whole-body glucose metabolism.

OBJECTIVES:Polyphenols (PP) have demonstrated beneficial effects on low-grade inflammation and oxidative stress; however, little is known about their effect on highly inflamed muscle. The purposes of this study were (i) to evaluate muscle alteration induced by high-grade inflammation, and (ii) to test the effects of red grape PP supplementation on these alterations.METHODS:We used a transgenic mice model (transforming growth factor [TGF] mice) to develop a high T cell-dependent inflammation and C57 BL/6 control (CTL) mice model. Skeletal muscles of TGF and CTL mice were investigated for inflammation, atrophy and oxidative stress markers. Isolated mitochondria from hindlimb muscles were used for respiration with pyruvate as substrate and oxidative damages were measured by Western blot. TGF mice were supplemented with a mixture of red grape polyphenols (50 mg/kg/d) for 4 wk. Data were analyzed by one-way analysis of variance (ANOVA) and post hoc Bonferroni's multiple comparison tests.RESULTS:TGF mice presented skeletal muscle inflammation, oxidative stress, mitochondrial alteration and muscle atrophy. Atrophy was associated with two distinct pathways: (i) one linked to inflammation, NF-κB activation and increased ubiquitin ligase expression, and (ii) one dependent on reactive oxygen species (ROS) production leading to damaged mitochondria accumulation and activation of caspase-9 and 3. Supplementation of TGF mice with a mixture of red grape polyphenols (50 mg/kg/d) for 4 wk improved mitochondrial function and highly decreased caspases activation, which allowed muscle atrophy mitigation.CONCLUSIONS:These observations suggest that nutritional dosages of red grape polyphenols might be beneficial for reducing skeletal muscle atrophy, even in a high-grade inflammation environment.

Obesity is associated with chronic low-grade inflammation and oxidative stress that blunt insulin response in its target tissues, leading to insulin resistance (IR). IR is a characteristic feature of type 2 diabetes. Skeletal muscle is responsible for 75% of total insulin-dependent glucose uptake; consequently, skeletal muscle IR is considered to be the primary defect of systemic IR development. Interestingly, some obese people stay insulin-sensitive and metabolically healthy. With the aim of understanding this difference and identifying the mechanisms responsible for insulin sensitivity maintenance/IR development during obesity, we explored the role of the latent endoribonuclease (RNase L) in skeletal muscle cells. RNase L is a regulator of innate immunity, of double-stranded RNA sensors and of toll-like receptor (TLR) 4 signaling. It is regulated during inflammation by interferons and its activity is dependent on its binding to 2-5A, an oligoadenylate synthesized by oligoadenylate synthetases (OAS). Increased expression of RNase L or downregulation of its inhibitor (RLI) improved insulin response in mouse myogenic C2C12 cells and in primary human myotubes from normal-weight subjects treated with palmitate, a saturated free fatty acid (FFA) known to induce inflammation and oxidative stress via TLR4 activation. While RNase L and RLI levels remained unchanged, OAS level was decreased in primary myotubes from insulin-resistant obese subjects (OB-IR) compared with myotubes from insulin-sensitive obese subjects (OB-IS). TLR3 and mitochondrial manganese superoxide dismutase (MnSOD) were also underexpressed in OB-IR myotubes. Activation of RNase L by 2-5A transfection allowed to restore insulin response, OAS, MnSOD and TLR3 expression in OB-IR myotubes. Due to low expression of OAS, OB-IR myotubes present a defect in RNase L activation and TLR3 regulation. Consequently, MnSOD level is low and insulin sensitivity is reduced. These results support that RNase L activity limits FFA/obesity-induced impairment of insulin response in muscle cells via TLR3 and MnSOD expression.