4E-BP1 and 4E-BP2 double knockout mice are protected from aging-associated sarcopenia

Epub ahead of printBACKGROUND: Sarcopenia is the loss of muscle mass/function that occurs during the aging process. The links between mechanistic target of rapamycin (mTOR) activity and muscle development are largely documented, but the role of its downstream targets in the development of sarcopenia is poorly understood. Eukaryotic initiation factor 4E-binding proteins (4E-BPs) are targets of mTOR that repress mRNA translation initiation and are involved in the control of several physiological processes. However, their role in skeletal muscle is still poorly understood. The goal of this study was to assess how loss of 4E-BP1 and 4E-BP2 expression impacts skeletal muscle function and homeostasis in aged mice and to characterize the associated metabolic changes by metabolomic and lipidomic profiling. METHODS: Twenty-four-month-old wild-type and whole body 4E-BP1/4E-BP2 double knockout (DKO) mice were used to measure muscle mass and function. Protein homeostasis was measured ex vivo in extensor digitorum longus by incorporation of l-[U-(14) C]phenylalanine, and metabolomic and lipidomic profiling of skeletal muscle was performed by Metabolon, Inc. RESULTS: The 4E-BP1/2 DKO mice exhibited an increase in muscle mass that was associated with increased grip strength (P < 0.05). Protein synthesis was higher under both basal (+102%, P < 0.05) and stimulated conditions (+65%, P < 0.05) in DKO skeletal muscle. Metabolomic and complex lipid analysis of skeletal muscle revealed robust differences pertaining to amino acid homeostasis, carbohydrate abundance, and certain aspects of lipid metabolism. In particular, levels of most free amino acids were lower within the 4E-BP1/2 DKO muscle. Interestingly, although glucose levels were unchanged, differences were observed in the isobaric compound maltitol/lactitol (33-fold increase, P < 0.01) and in several additional carbohydrate compounds. 4E-BP1/2 depletion also resulted in accumulation of medium-chain acylcarnitines and a 20% lower C2/C0 acylcarnitine ratio (P < 0.01) indicative of reduced beta-oxidation. CONCLUSIONS: Taken together, these findings demonstrate that deletion of 4E-BPs is associated with perturbed energy metabolism in skeletal muscle and could have beneficial effects on skeletal muscle mass and function in aging mice. They also identify 4E-BPs as potential targets for the treatment of sarcopenia

La supplémentation en leucine stimule la synthèse protéique et les activités enzymatiques mitochondriales chez le rat adulte et agé

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Rôle de la vitamine D sur l'inhibition de la synthèse musculaire par le palmitate : recherche des mécanismes mis en jeu.

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Whole body protein breakdown is less inhibited by insulin, but still responsive to amino acid, in nondiabetic elderly subjects

National audienceResponses of whole body glucose disposal (GDR) and protein breakdown (PB) to physiological insulin levels are altered in nondiabetic elderly subjects. Amino acids enhance inhibition of PB by insulin in young subjects. We hypothesized that addition of amino acid to insulin may improve the defect in PB regulation by insulin in elderly people. Therefore, we investigated the effect of hyperinsulinemia combined to either euaminoacidemia (EuAA) or hyperaminoacidemia (HyperAA) on GDR and PB, using isotopic dilution of D-[6,6-2H2]glucose and L-[1-13C]leucine, in young (mean +/- SEM, 24.4 +/- 0.8 yr) and elderly (70.2 +/- 0.7 yr) subjects. GDR was lower in elderly than in young subjects in all situations (P < 0.05). Despite a greater inhibition with HyperAA, PB was less inhibited in elderly than in young subjects during both clamps (ratio between change over basal PB and change over basal insulinemia, -0.014 +/- 0.002 vs. -0.024 +/- 0.003 in EuAA and -0.022 +/- 0.002 vs. -0.036 +/- 0.003 micromol/ml.microU/kg fat-free mass.min in HyperAA; elderly vs. young, P < 0.05). In conclusion, in nondiabetic elderly subjects, PB is less inhibited by insulin with either basal or high amino acid concentrations. Addition of amino acid potentiates insulin-induced suppression of PB in both groups to the same extent, suggesting a specific dysregulation of PB by insulin with age

Enhanced muscle mixed and mitochondrial protein synthesis rates after a high-fat or high-sucrose diet

International audienceOBJECTIVE: Obesity and insulin resistance are associated with muscle mitochondrial dysfunction, which might be related to impairment of mitochondrial protein synthesis. This study aimed at investigating mixed and mitochondrial protein synthesis in skeletal muscle in response to dietary manipulations. RESEARCH METHODS AND PROCEDURES: High-sucrose (SU) and high-fat, high-sucrose (F) diets were provided for 6 weeks to Wistar rats at standard (N) and high (H) energy intakes and compared with controls. Fractional synthesis rates of mixed (FSRPT) and mitochondrial (FSRm) proteins within the oxidative (soleus) and glycolytic (tibialis) muscles were measured using stable isotope flooding dose technique using L-[13C]-valine. Carbonyl content, citrate synthase, and cytochrome c oxidase activities were assayed spectrophotometrically on isolated mitochondria. RESULTS: In the soleus, FSRPT was increased by 40% in the NSU and NF groups and by 65% in the HSU and HF groups (p<0.001 vs. control). FSRm was increased with high-fat diets (NF, +16%; HF, +32%; p<0.01). In the tibialis, FSR(PT) was enhanced in all experimental groups (+31% to 37%, p<0.05 vs. control). FSRm was augmented in the NSU, NF, and HF groups (+28% to 32%, p<0.01). Cytochrome c oxidase activity was significantly decreased in all experimental groups in the soleus (p<0.001). DISCUSSION: Muscle mixed and mitochondrial protein FSR are enhanced after short-term dietary intervention known to induce insulin resistance and obesity. Adaptations are muscle type specific and may not explain alterations in mitochondrial oxidative capacity but might contribute to maintain mitochondrial functioning

Wetting and adhesion of a polymer melt on porous self‐assembled polymer substrates by breath figure templating

International audienceThis study addresses the wetting and adhesion of a low molecular mass poly( n ‐butyl acrylate) homopolymer melt, used as a weak acrylic adhesive, on two types of textured polymer films prepared by the breath figure templating method. The first film is a polystyrene homopolymer honeycomb‐like structure with well‐defined porous structure and long‐range ordering. The second is a disordered poly( n ‐butyl acrylate)‐ block ‐polystyrene diblock copolymer film featuring a broad distribution of pore diameters. Static contact angle measurements show that porous films repel better the polymer melt than the corresponding nontextured films. Contact angles and spreading of polymer melt droplets on these textured surfaces reveals a Cassie‐Baxter state on the ordered porous film and a partial Wenzel state on the disordered porous films. In addition, probe tack results show that the textured surfaces tend to induce cavitation. The correlation between the wetting and adhesion highlights the major role of melt insertion into the pores, which is primarily controlled by the pores’ dimensions

Mechanisms of body weight gain in patients with Parkinson's disease after subthalamic stimulation

International audienceChronic bilateral subthalamic stimulation leads to a spectacular clinical improvement in patients with motor complications. However, the post-operative body weight gain involved may limit the benefits of surgery and induce critical metabolic disorders. Twenty-four Parkinsonians (61.1 +/- 1.4 years) were examined 1 month before (M - 1) and 3 months after (M + 3) surgery. Body composition and energy expenditure (EE) were measured (1) over 36 h in calorimetric chambers (CC) with rigorous control of food intakes and activities [sleep metabolic rate, resting activities, meals, 3 or 4 sessions of 20 min on a training bicycle at 13 km/h and daily EE] and (2) in resting conditions (basal metabolic rate) during an acute L-dopa challenge (M - 1) or according to acute 'off' and 'on' stimulation (M + 3). Before surgery, EE was compared between the Parkinsonian patients and healthy subjects matched for height and body composition (metabolic rate during sleep, daily EE) or matched to predicted values (basal metabolic rate). Before surgery, in Parkinsonian men but not women, (1) daily EE was higher while sleep metabolic rate was lower compared to healthy matched men (+9.2 +/- 3.9 and -8.2 +/- 2.3%, respectively, P < 0.05) and (2) basal metabolic rate (L-dopa 'on') was higher than predicted basal metabolic rate (+11.5 +/- 4.0%, P < 0.05) but was further increased without L-dopa (+8.4 +/- 3.2% vs L-dopa 'on', P < 0.05). EE during daily activities was higher during 'off' periods compared to 'on' periods for both men (+19.3 +/- 3.3%, P < 0.0001) and women (+16.1 +/- 4.7%, P < 0.01). After surgery, there was a 3.4 +/- 0.6 kg (P < 0.0001) body weight increase together with fat mass (P < 0.0001) and fat-free mass (P < 0.05) in Parkinsonian men and a 2.6 +/- 0.8 kg (P < 0.05) body weight increase together with fat mass (P < 0.05) in Parkinsonian women. Sleep metabolic rate increased in men (+7.5 +/- 2.0%, P < 0.01) to reach control values but remained unchanged in women. Daily EE decreased significantly in both men and women (-7.3 +/- 2.2% and -13.1 +/- 1.7%, respectively, P < 0.01) but there was no correlation between daily EE changes and body weight gain. Parkinson's disease is associated with profound alterations in the central control of energy metabolism. Normalization of energy metabolism after DBS-STN implantation may favour body weight gain, of which quality was gender specific. As men gained primarily fat-free mass, a reasonable weight gain may be tolerated, in contrast with women who gained only fat. Other factors such as changes in free-living physical activity may help to limit body weight gain in some patients

Characterization of the Skeletal Muscle Proteome in Undernourished Old Rats

International audienceAging is associated with a progressive loss of skeletal muscle mass and function termed sarcopenia. Various metabolic alterations that occur with aging also increase the risk of undernutrition,which can worsen age-related sarcopenia. However, the impact of undernutrition on aged skeletal muscle remains largely under-researched. To build a deeper understanding of the cellular andmolecular mechanisms underlying age-related sarcopenia, we characterized the undernutritioninduced changes in the skeletal muscle proteome in old rats. For this study, 20-month-old male ratswere fed 50% or 100% of their spontaneous intake for 12 weeks, and proteomic analysis was performed on both slow- and fast-twitch muscles. Proteomic profiling of undernourished aged skeletal musclerevealed that undernutrition has profound effects on muscle proteome independently of its effect on muscle mass. Undernutrition-induced changes in muscle proteome appear to be muscle-type-specific:slow-twitch muscle showed a broad pattern of differential expression in proteins important for energy metabolism, whereas fast-twitch muscle mainly showed changes in protein turnover betweenundernourished and control rats. This first proteomic analysis of undernourished aged skeletal muscle provides new molecular-level insight to explain phenotypic changes in undernourishedaged muscle. We anticipate this work as a starting point to define new biomarkers associated with undernutrition-induced muscle loss in the elderl

Photocurrent persistence reduction in ZnO nanowire photodetectors (Conference Presentation)

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Mitigating the photocurrent persistence of single ZnO nanowires for low noise photodetection applications

International audienceIn this work, we investigate the optoelectronic properties of zinc oxide (ZnO) nanowires, which are good candidates for applications based on integrated optics. Single ZnO nanowire photodetectors were fabricated with ohmic contacts. By taking current transient measurements in different atmospheres (oxygen, air, vacuum and argon), and at various temperatures, we point out the importance of surface effects on the electrical behaviour. Results confirm that oxygen chemisorption is responsible for the existence of a high photoconductive gain in these devices, and for the first time a two step process in the photocurrent rise transient is reported. A maximum gain of G = 7.8 × 107 is achieved. However, under certain conditions, the persistence of the photocurrent can last up to several hours and as such may prevent the device from operating at useful rates. From a knowledge of the photocurrent response mechanisms, we establish a method to restore the photodetector to its initial state, with very low dark current, by applying an appropriate gate voltage sequence. This advances the state of the art for these detectors towards commercial applications