p43, a Truncated Form of Thyroid Hormone Receptor α, Regulates Maturation of Pancreatic β Cells

International audienceP43 is a truncated form of thyroid hormone receptor alpha localized in mitochondria, which stimulates mitochondrial respiratory chain activity. Previously, we showed that deletion of p43 led to reduction of pancreatic islet density and a loss of glucose-stimulated insulin secretion in adult mice. The present study was designed to determine whether p43 was involved in the processes of beta cell development and maturation. We used neonatal, juvenile, and adult p43-/- mice, and we analyzed the development of beta cells in the pancreas. Here, we show that p43 deletion affected only slightly beta cell proliferation during the postnatal period. However, we found a dramatic fall in p43-/- mice of MafA expression (V-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog A), a key transcription factor of beta-cell maturation. Analysis of the expression of antioxidant enzymes in pancreatic islet and 4-hydroxynonenal (4-HNE) (a specific marker of lipid peroxidation) staining revealed that oxidative stress occurred in mice lacking p43. Lastly, administration of antioxidants cocktail to p43-/- pregnant mice restored a normal islet density but failed to ensure an insulin secretion in response to glucose. Our findings demonstrated that p43 drives the maturation of beta cells via its induction of transcription factor MafA during the critical postnatal window

New evidence of exercise training benefits in myostatin-deficient mice: Effect on lipidomic abnormalities

Myostatin (Mstn) inactivation or inhibition is considered as a promising treatment for various muscle-wasting disorders because it promotes muscle growth. However, myostatin-deficient hypertrophicmuscles show strong fatigability associated with abnormal mitochondria and lipid metabolism. Here, weinvestigated whether endurance training could improve lipid metabolism and mitochondrial membranelipid composition in mice where theMstngene was genetically ablated (Mstn /-mice). InMstn /-mice, 4weeks of daily running exercise sessions (65e70% of the maximal aerobic speed for 1 h) improvedsignificantly aerobic performance, particularly the endurance capacity (up toþ280% compared withuntrainedMstn /-mice), to levels comparable to those of trained wild type (WT) littermates. Theexpression of oxidative and lipid metabolism markers also was increased, as indicated by the upregu-lation of theCpt1,Ppar-dandFasngenes. Moreover, endurance training also increased, but far less thanWT, citrate synthase level and mitochondrial protein content. Interestingly endurance trainingnormalized the cardiolipin fraction in the mitochondrial membrane ofMstn /-muscle compared withWT. These results suggest that the combination of myostatin inhibition and endurance training couldincrease the muscle mass while preserving the physical performance with specific effects on cardiolipinand lipid-related pathways

Transient Changes of Metabolism at the Pronuclear Stage in Mice Influences Skeletal Muscle Phenotype in Adulthood

International audienceSkeletal muscle has a remarkable plasticity, and its phenotype is strongly influenced by hormones, transcription factors, and physical activity. However, whether skeletal phenotype can be oriented or not during early embryonic stages has never been investigated. Here, we report that pyruvate as the only source of carbohydrate in the culture medium of mouse one cell stage embryo influenced the establishment of the muscular phenotype in adulthood. We found that pyruvate alone induced changes in the contractile phenotype of the skeletal muscle in a sexually dependent manner. For male mice, a switch to a more glycolytic phenotype was recorded, whereas, in females, the pyruvate induced a switch to a more oxidative phenotype. In addition, the influence of pyruvate on the contractile phenotypes was confirmed in two mouse models of muscle hypertrophy: the well-known myostatin deficient mouse (Mstn−/−) and a mouse carrying a specific deletion of p43, a mitochondrial triiodothyronine receptor. Finally, to understand the link between these adult phenotypes and the early embryonic period, we assessed the levels of two histone H3 post-translational modifications in presence of pyruvate alone just after the wave of chromatin reprogramming specific of the first cell cycle. We showed that H3K4 acetylation level was decreased in Mstn−/− 2-cell embryos, whereas no difference was found for H3K27 trimethylation level, whatever the genotype. These findings demonstrate for the first time that changes in the access of energy substrate during the very first embryonic stage can induce a precocious orientation of skeletal muscle phenotype in adulthood

Salidroside supplementation associated with resistance exercise enhances physical performance in old mice

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Muscle regeneration with intermuscular adipose tissue (IMAT) accumulation is modulated by mechanical constraints

Sports trauma are able to induce muscle injury with fibrosis and accumulation of intermuscular adipose tissue (IMAT), which affect muscle function. This study was designed to investigate whether hypoactivity would influence IMAT accumulation in regenerating mouse skeletal muscle using the glycerol model of muscle regeneration. The animals were immediately hindlimb unloaded for 21 days after glycerol injection into the tibialis anterior (TA) muscle. Muscle fiber and adipocyte cross-sectional area (CSA) and IMAT accumulation weredetermined by histomorphometric analysis. Adipogenesis during regenerative processes was examined using RT-qPCR and Western blot quantification. Twenty-one days of hindlimb unloading resulted in decreases of 38% and 50.6% in the muscle weight/body weight ratio and CSA, respectively, in soleus muscle. Glycerol injection into TA induced IMAT accumulation, reaching 3% of control normal-loading muscle area. This IMAT accumulationwas largely inhibited in unloading conditions (0.09%) and concomitant with a marked reduction in perilipin and FABP4 protein content, two key markers of mature adipocytes. Induction of PPARγ and C/EBPα mRNA, two markers of adipogenesis, was also decreased. Furthermore, the protein expression of PDGFRα, a cell surface marker of fibro/adipogenic progenitors, was much lower in regenerating TA from the unloaded group. Exposure ofregenerating muscle to hypoactivity severely reduces IMAT development and accumulation. These results provide new insight into the mechanisms regulating IMAT development in skeletal muscle and highlight the importance of taking into account the level of mechanical constraint imposed on skeletal muscle during the regeneration processes

Furan fatty acid extracted from Hevea brasiliensis latex increases muscle mass in mice

Skeletal muscle is essential for locomotion and plays a crucial role in energy homeostasis. It is regulated by nutrition, genetic factors, physical activity and hormones. Furan fatty acids (FuFAs) are minor fatty acids present in small quantities in food from plants and animals origin. Recently, we showed that a preventive nutritional supplementation with furan fatty acid in a DIO mouse model reduces metabolic disorders. The present study was designed to determine the influence of FuFA-F2 extracted from Hevea brasiliensis latex on skeletal muscle phenotype. In C2C12 myotubes we found that FuFA-F2 whatever the concentration used increased protein content. We revealed that in C2C12 myotubes FuFA-F2 (10 µM) increases protein synthesis as shown by the stimulation of mTOR phosphorylation. Next, to confirm in vivo our results C57Bl6 mice were supplemented by oral gavage with vehicle or FuFA-F2 (20 mg/kg) for 3 and a half weeks. We found that mice supplemented with FuFA-F2 had a greater lean mass than the control mice. In line with this observation, we revealed that FuFA-F2 increased muscle mass and promoted more oxidative muscle metabolism in mice as attested by cytochrome c oxidase activity. In conclusion, we demonstrated that FuFA-F2 stimulates muscle anabolism in mice in vitro and in vivo, mimicking in part physical activity. This study highlights that in vivo FuFA-F2 may have health benefits by increasing muscle mass and oxidative metabolism

L'inactivation du gène de la myostatine augmente la protéolyse musculaire post-mortem dépendante de la calpaïne chez la souris

International audienceLe déficit en myostatine entraîne une hypertrophie étendue des muscles squelettiques, mais ses conséquences sur la protéolyse musculaire post-mortem sont inconnues. Ici, nous avons comparé la dégradation des protéines myofibrillaires musculaires et l'autophagie, l'ubiquitine-protéasome et le Ca 2+-protéolyse dépendante par rapport au statut énergétique et redox chez les souris de type sauvage (WT) et les souris knock-out pour la myostatine (KO) au cours du stockage post-mortem précoce. Les muscles KO ont montré une dégradation plus élevée des protéines myofibrillaires dans les 24 premières heures après la mort, associée à un statut antioxydant préservé, par rapport aux muscles WT. L'analyse des principaux marqueurs de l'autophagie et du système ubiquitine-protéasome a indiqué que ces deux voies n'étaient pas régulées à la hausse dans le muscle post-mortem (les deux génotypes), mais que le flux autophagique basal et la teneur en ATP étaient inférieurs dans les muscles KO. Les activités du protéasome et de la caspase n'étaient pas différentes entre les souris WT et KO. À l'inverse, l'activité de la calpaïne était plus élevée dans les muscles KO, en même temps qu'une dégradation plus élevée de la troponine T et de la desmine. Au total, ces résultats suggèrent que les calpaïnes, mais pas les systèmes d'autophagie, de protéasome et de caspase

Preventive nutritional supplementation with furan fatty acid in a DIO mouse model increases muscle mass and reduces metabolic disorders

International audienceThe increase in obesity has become a major global health problem and is associated with numerous metabolic dysfunctions. Furan fatty acids (FuFAs) are minor lipids present in our diet. Recently we showed that FuFA-F2 extracted from Hevea brasiliensis latex stimulates muscle anabolism in mice in vitro and in vivo, mimicking in part physical activity. While skeletal muscle is essential for energy metabolism and is the predominant site of insulin-mediated glucose uptake in the post prandial state, our results suggested that FuFA-F2 could have favorable effects against obesity. The aim of this work was therefore to study whether a preventive nutritional supplementation with FuFA-F2 (40 mg or 110 mg/day/kg of body weight) in a diet-induced obesity (DIO) mouse model may have beneficial effects against obesity and liver and skeletal muscle metabolic dysfunction. We showed that 12 weeks of FuFA-F2 supplementation in DIO mice decreased fat mass, increased lean mass and restored normal energy expenditure. In addition, we found that FuFA-F2 improved insulin sensitivity. We revealed that FuFA-F2 increased muscle mass but had no effect on mitochondrial function and oxidative stress in skeletal muscle. Furthermore, we observed that FuFA-F2 supplementation reduced liver steatosis without impact on mitochondrial function and oxidative stress in liver. Our findings demonstrated for the first time that a preventive nutritional supplementation with a furan fatty acid in DIO mice reduced metabolic disorders and was able to mimic partly the positive effects of physical activity. This study highlights that nutritional FuFA-F2 supplementation could be an effective approach to treat obesity and metabolic syndrome

Acute and chronic effects of Rhaponticum carthamoides and Rhodiola rosea extracts supplementation coupled to resistance exercise on muscle protein synthesis and mechanical power in rats

International audienceBackground: Owing to its strength-building and adaptogenic properties, Rhaponticum carthamoides (Rha) has been commonly used by elite Soviet and Russian athletes. Rhodiola rosea (Rho) is known to reduce physical and mental fatigue and improve endurance performance. However, the association of these two nutritional supplements with resistance exercise performance has never been tested. Resistance exercise is still the best way to stimulate protein synthesis and induce chronic muscle adaptations. The aim of this study was to investigate the acute and chronic effects of resistance exercise coupled with Rha and Rho supplementation on protein synthesis, muscle phenotype, and physical performance. Methods: For the acute study, fifty-six rats were assigned to either a trained control group or one of the groups treated with specific doses of Rha and/or Rho. Each rats performed a single bout of climbing resistance exercise. The supplements were administered immediately after exercise by oral gavage. Protein synthesis was measured via puromycin incorporation. For the chronic study, forty rats were assigned to either the control group or one of the groups treated with doses adjusted from the acute study results. The rats were trained five times per week for 4 weeks with the same bout of climbing resistance exercise with additionals loads. Rha + Rho supplement was administered immediately after each training by oral gavage. Results: The findings of the acute study indicated that Rha and Rha + Rho supplementation after resistance exercise stimulated protein synthesis more than resistance exercise alone (p < 0.05). After 4 weeks of training, the mean power performance was increased in the Rha + Rho and Rha-alone groups (p < 0.05) without any significant supplementation effect on muscle weight or fiber cross-sectional area. A tendency towards an increase in type I/ type II fiber ratio was observed in Rha/Rho-treated groups compared to that in the trained control group. Conclusion: Rhodiola and Rhaponticum supplementation after resistance exercise could synergistically improve protein synthesis, muscle phenotype and physical performance

Changes in mRNA induction of adipogenesis markers.

<p>C/EBPβ <b>(a)</b>, PPARγ <b>(b)</b> and C/EBPα <b>(c)</b> mRNA levels of saline-injected (TA) and glycerol-injected (TAg) tibialis anterior from control (CTL) and hindlimb unloading (HU) mice. * <i>p</i><0.05 <i>vs</i> control group (unloading effect). ## <i>p</i><0.01 <i>vs</i> TA-CTL (glycerol-injection effect).</p