Development of a protein food based on texturized wheat proteins, with high protein digestibility and improved lysine content.

The development of plant-based protein foods may facilitate the decrease in animal product consumption in western countries. Wheat proteins, as a starch coproduct, are available in large amounts and are good candidates for this development. We investigated the effect of a new texturing process on wheat protein digestibility and implemented strategies aimed at enhancing the lysine content of the product developed. Protein true ileal digestibility (TID) was determined in minipigs. In a preliminary experiment, the TID of wheat protein (WP), texturized wheat protein (TWP), TWP enriched with free lysine (TWP-L), or with chickpea flour (TWP-CP) was measured and compared to beef meat proteins. In the main experiment, minipigs (n = 6) were fed a dish (blanquette type) containing 40 g of protein in the form of TWP-CP, TWP-CP enriched with free lysine TWP-CP+L, chicken filet, or texturized soy, together with quinoa (18.5 g of protein) in order to improve meal supply of lysine. Wheat protein texturing did not affect total amino acid TID (96.8 % for TWP vs 95.3 % for WP), which was not different from that of beef meat (95.8 %). Chickpea addition did not affect protein TID (96.5 % for TWP-CP vs 96.8 % for TWP). The Digestible Indispensable Amino Acid Score for adults of the dish combining TWP-CP+L with quinoa was 91, whereas it was 110 and 111 for the dishes containing chicken filet or texturized soy. The above results show that, by optimizing lysine content through the formulation of the product, wheat protein texturization can enable the development of protein-rich products of nutritional quality compatible with quality protein intake in the context of a complete meal.

Age-Dependent Serum Volatilomics of Milk and Yogurt Intake: A Randomized Crossover Study in Healthy Young and Older Men.

Nutritional biomarkers of dairy intake can be affected by both food transformation and the metabolic status of the consumer. To assess these effects, this study investigated the serum volatilome of 14 young (YA) and 14 older (OA) adult men undergoing a 3 week restriction of dairy and fermented foods followed by a randomized crossover acute intake of milk and yogurt. 3,5-Dimethyl-octan-2-one was identified as a potential marker of dairy product intake as its response after both milk and yogurt intake was significantly increased during the postprandial phase but significantly decreased in fasting serum samples of the OA group after the restriction phase. The postprandial response of two metabolites was significantly different for the two dairy products while 19 metabolites were modulated by age. Remarkably, the response of all age-dependent metabolites was higher in the OA than in the YA group after milk or yogurt intake, whereas at the end of the restriction phase, their fasting concentrations were lower in the OA than in the YA group. Among these, p-cresol, a specific marker of colonic protein fermentation, had a significant response in the OA but not the YA group, which may suggest impaired intestinal processing of dietary proteins in the OA group.

Targeting the gut to prevent and counteract metabolic disorders and pathologies during aging.

Impairment of gut function is one of the explanatory mechanisms of health status decline in elderly population. These impairments involve a decline in gut digestive physiology, metabolism and immune status, and associated to that, changes in composition and function of the microbiota it harbors. Continuous deteriorations are generally associated with the development of systemic dysregulations and ultimately pathologies that can worsen the initial health status of individuals. All these alterations observed at the gut level can then constitute a wide range of potential targets for development of nutritional strategies that can impact gut tissue or associated microbiota pattern. This can be key, in a preventive manner, to limit gut functionality decline, or in a curative way to help maintaining optimum nutrients bioavailability in a context on increased requirements, as frequently observed in pathological situations. The aim of this review is to give an overview on the alterations that can occur in the gut during aging and lead to the development of altered function in other tissues and organs, ultimately leading to the development of pathologies. Subsequently is discussed how nutritional strategies that target gut tissue and gut microbiota can help to avoid or delay the occurrence of aging-related pathologies.

Anti-inflammatory Streptococcus thermophilus CNRZ160 limits sarcopenia induced by low-grade inflammation in older adult rats.

Background and aims: Aging is characterized, at the systemic level, by the development of low-grade inflammation, which has been identified as determining sarcopenia by blunting postprandial muscle anabolism. The causes of this "inflammageing" is still not clearly defined. An increased intestinal permeability, a microbiota dysbiosis and subsequent generation of intestinal then generalized inflammation have been hypothesized. The objective of this study was to test in vivo during aging if (1) a chronic low-grade intestinal inflammation can lead to anabolic resistance and muscle loss and (2) if a bacterial strain presenting anti-inflammatory properties could prevent these adverse effects. Methods: Young adult (6 m) and elderly rats (18 m) received Dextran Sodium Sulfate (DSS) for 28 days to generate low-grade intestinal inflammation, and received (PB1 or PB2 groups) or not (DSS group) one of the two S. Thermophilus strains (5 × 109 CFU/day) previously shown to present an anti-inflammatory potential in vitro. They were compared to pair fed control (PF). Muscle and colon weights and protein synthesis (using 13C Valine) were measured at slaughter. Muscle proteolysis, gut permeability and inflammatory markers were assessed only in old animals by RT-PCR or proteins quantifications (ELISA). Results: In both adult and old rats, DSS reduced absolute protein synthesis (ASR) in gastrocnemius muscle [-12.4% (PB1) and -9.5% (PB2) vs. PF, P < 0.05] and increased ASR in colon (+86% and +30.5%, respectively vs. PF, P < 0.05). PB1 (CNRZ160 strain) but not PB2 resulted in a higher muscle ASR as compared to DSS in adults (+18%, P < 0.05), a trend also observed for PB1 in old animals (+12%, P = 0.10). This was associated with a blunted increase in colon ASR. In old rats, PB1 also significantly decreased expression of markers of autophagy and ubiquitin-proteasome pathways vs. DSS groups and improved gut permeability (assessed by Occludin, Zonula Occludens 1 and Claudin 1 expression, P < 0.05) and alleviated systemic inflammation (A2M: -48% vs. DSS, P < 0.05). Conclusion: The loss of muscle anabolism associated with low-grade intestinal inflammation can be prevented by supplementation with anti-inflammatory CNRZ160 strain. We propose that the moderated gut inflammation by CNRZ160 may result in curtailed amino acids (AA) utilization by the gut, and subsequent restored AA systemic availability to support muscle protein accretion. Therefore, CNRZ160 could be considered as an efficient probiotic to modulate muscle mass loss and limit sarcopenia during aging.

Approaches to discern if microbiome associations reflect causation in metabolic and immune disorders.

Our understanding of microorganisms residing within our gut and their roles in the host metabolism and immunity advanced greatly over the past 20 years. Currently, microbiome studies are shifting from association and correlation studies to studies demonstrating causality of identified microbiome signatures and identification of molecular mechanisms underlying these interactions. This transformation is crucial for the efficient translation into clinical application and development of targeted strategies to beneficially modulate the intestinal microbiota. As mechanistic studies are still quite challenging to perform in humans, the causal role of microbiota is frequently evaluated in animal models that need to be appropriately selected. Here, we provide a comprehensive overview on approaches that can be applied in addressing causality of host-microbe interactions in five major animal model organisms (Caenorhabditis elegans, Drosophila melanogaster, zebrafish, rodents, and pigs). We particularly focused on discussing methods available for studying the causality ranging from the usage of gut microbiota transfer, diverse models of metabolic and immune perturbations involving nutritional and chemical factors, gene modifications and surgically induced models, metabolite profiling up to culture-based approached. Furthermore, we addressed the impact of the gut morphology, physiology as well as diet on the microbiota composition in various models and resulting species specificities. Finally, we conclude this review with the discussion on models that can be applied to study the causal role of the gut microbiota in the context of metabolic syndrome and host immunity. We hope this review will facilitate important considerations for appropriate animal model selection.

Lacticaseibacillus casei CNCM I-5663 supplementation maintained muscle mass in a model of frail rodents.

The aim of this study was to identify a probiotic-based strategy for maintaining muscle anabolism in the elderly. In previous research, we found that individuals experiencing short bowel syndrome (SBS) after an intestinal resection displayed beneficial metabolic adjustments that were mediated by their gut microbes. Thus, these bacteria could potentially be used to elicit similar positive effects in elderly people, who often have low food intake and thus develop sarcopenia. Gut bacterial strains from an SBS patient were evaluated for their ability to (1) maintain Caenorhabditis elegans survival and muscle structure and (2) promote protein anabolism in a model of frail rodents (18-month-old rats on a food-restricted diet: 75% of ad libitum consumption). We screened a first set of bacteria in C. elegans and selected two Lacticaseibacillus casei strains (62 and 63) for further testing in the rat model. We had four experimental groups: control rats on an ad libitum diet (AL); non-supplemented rats on the food-restricted diet (R); and two sets of food-restricted rats that received a daily supplement of one of the strains (∼109 CFU; R+62 and R+63). We measured lean mass, protein metabolism, insulin resistance, cecal short-chain fatty acids (SCFAs), and SCFA receptor expression in the gut. Food restriction led to decreased muscle mass [-10% vs. AL (p < 0.05)]. Supplementation with strain 63 tempered this effect [-2% vs. AL (p > 0.1)]. The mechanism appeared to be the stimulation of the insulin-sensitive p-S6/S6 and p-eIF2α/eIF2α ratios, which were similar in the R+63 and AL groups (p > 0.1) but lower in the R group (p < 0.05). We hypothesize that greater SCFA receptor sensitivity in the R+63 group promoted gut-muscle cross talk [GPR41: +40% and GPR43: +47% vs. R (p < 0.05)]. Hence, strain 63 could be used in association with other nutritional strategies and exercise regimes to limit sarcopenia in frail elderly people.

Postprandial Responses on Serum Metabolome to Milk and Yogurt Intake in Young and Older Men.

The identification and validation of biomarkers of food intake (BFIs) is a promising approach to develop more objective and complementary tools to the traditional dietary assessment methods. Concerning dairy, their evaluation in terms of intake is not simple, given the variety of existing foods, making it difficult to establish the association between specific dairy products consumption and the effects on human health, which is also dependent on the study population. Here, we aimed at identifying BFI of both milk (M) and yogurt (Y) in 14 healthy young (20-35 years) and 14 older (65-80 years). After a 3-week run-in period of dairy exclusion from the diet, the subjects acutely consumed 600 ml of M or Y. Metabolomics analyses were conducted on serum samples during the following 6 h (LC-MS and GC-MS). Several metabolites showing increased iAUC after milk or yogurt intake were considered as potential BFI, including lactose (M > Y, 2-fold), galactitol (M > Y, 1.5-fold), galactonate (M > Y, 1.2-fold), sphingosine-1-phosphate (M > Y from 2.1-fold), as well as an annotated disaccharide (Y > M, 3.6-fold). Delayed serum kinetics were also observed after Y compared to M intake lysine (+22 min), phenylalanine (+45 min), tyrosine (+30min), threonine (+38 min) 3-phenyllactic acid (+30 min), lactose (+30 min), galactitol (+45min) and galactonate (+30 min). The statistical significance of certain discriminant metabolites, such as sphingosine-1-phosphate and several free fatty acids, was not maintained in the older group. This could be related to the physiological modifications induced by aging, like dysregulated lipid metabolism, including delayed appearance of dodecanoic acid (+60 min) or altered postprandial appearance of myristic acid (+70% Cmax), 3-dehydroxycarnitine (-26% Cmin), decanoylcarnitine (-51% Cmin) and dodecanoylcarnitine (-40% Cmin). In conclusion, candidate BFI of milk or yogurt could be identified based on the modified postprandial response resulting from the fermentation of milk to yogurt. Moreover, population specificities (e.g., aging) should also be considered in future studies to obtain more accurate and specific BFI.

Gut microbes and muscle function: can probiotics make our muscles stronger?

Evidence suggests that gut microbiota composition and diversity can be a determinant of skeletal muscle metabolism and functionality. This is true in catabolic (sarcopenia and cachexia) or anabolic (exercise or in athletes) situations. As gut microbiota is known to be causal in the development and worsening of metabolic dysregulation phenotypes such as obesity or insulin resistance, it can regulate, at least partially, skeletal muscle mass and function. Skeletal muscles are physiologically far from the gut. Signals generated by the gut due to its interaction with the gut microbiome (microbial metabolites, gut peptides, lipopolysaccharides, and interleukins) constitute links between gut microbiota activity and skeletal muscle and regulate muscle functionality via modulation of systemic/tissue inflammation as well as insulin sensitivity. The probiotics able to limit sarcopenia and cachexia or promote health performances in rodents are mainly lactic acid bacteria and bifidobacteria. In humans, the same bacteria have been tested, but the scarcity of the studies, the variability of the populations, and the difficulty to measure accurately and with high reproducibility muscle mass and function have not allowed to highlight specific strains able to optimize muscle mass and function. Further studies are required on more defined population, in order to design personalized nutrition. For elderly, testing the efficiency of probiotics according to the degree of frailty, nutritional state, or degree of sarcopenia before supplementation is essential. For exercise, selection of probiotics capable to be efficient in recreational and/or elite athletes, resistance, and/or endurance exercise would also require further attention. Ultimately, a combination of strategies capable to optimize muscle functionality, including bacteria (new microbes, bacterial ecosystems, or mix, more prone to colonize a specific gut ecosystem) associated with prebiotics and other 'traditional' supplements known to stimulate muscle anabolism (e.g. proteins), could be the best way to preserve muscle functionality in healthy individuals at all ages or patients.

Corrigendum: Lacticaseibacillus casei CNCM I-5663 supplementation maintained muscle mass in a model of frail rodents.

[This corrects the article DOI: 10.3389/fnut.2022.928798.].

Peripheral Amino Acid Appearance Is Lower Following Plant Protein Fibre Products, Compared to Whey Protein and Fibre Ingestion, in Healthy Older Adults despite Optimised Amino Acid Profile.

Plant-based proteins are generally characterised by lower Indispensable Amino Acid (IAA) content, digestibility, and anabolic properties, compared to animal-based proteins. However, they are environmentally friendlier, and wider consumption is advocated. Older adults have higher dietary protein needs to prevent sarcopenia, a disease marked by an accelerated loss of muscle mass and function. Given the lower environmental footprint of plant-based proteins and the importance of optimising dietary protein quality among older adults, this paper aims to assess the net peripheral Amino Acid (AA) appearance after ingestion of three different plant protein and fibre (PPF) products, compared to whey protein with added fibre (WPF), in healthy older adults. In a randomised, single-blind, crossover design, nine healthy men and women aged ≥65 years consumed four test meals balanced in AA according to the FAO reference protein for humans, matched for leucine, to optimally stimulate muscle protein synthesis in older adults. A fasted blood sample was drawn at each visit before consuming the test meal, followed by postprandial arterialise blood sampling every 30 min for 3 h. The test meal was composed of a soup containing either WPF or PPF 1-3. The PPF blends comprised pea proteins with varying additional rice, pumpkin, soy, oat, and/or almond protein. PPF product ingestion resulted in a lower maximal increase of postprandial leucine concentration and the sum of branched-chain AA (BCAA) and IAA concentrations, compared to WPF, with no effect on their incremental area under the curve. Plasma methionine and cysteine, and to a lesser extent threonine, appearance were limited after consuming the PPF products, but not WPF. Despite equal leucine doses, the WPF induced greater postprandial insulin concentrations than the PPF products. In conclusion, the postprandial appearance of AA is highly dependent on the protein source in older adults, despite providing equivalent IAA levels and dietary fibre. Coupled with lower insulin concentrations, this could imply less anabolic potential. Further investigation is required to understand the applicability of plant-based proteins in healthy older adults.

A Mix of Dietary Fibres Changes Interorgan Nutrients Exchanges and Muscle-Adipose Energy Handling in Overfed Mini-Pigs.

This study evaluates the capacity of a bread enriched with fermentable dietary fibres to modulate the metabolism and nutrients handling between tissues, gut and peripheral, in a context of overfeeding. Net fluxes of glucose, lactate, urea, short chain fatty acids (SCFA), and amino acids were recorded in control and overfed female mini-pigs supplemented or not with fibre-enriched bread. SCFA in fecal water and gene expressions, but not protein levels or metabolic fluxes, were measured in muscle, adipose tissue, and intestine. Fibre supplementation increased the potential for fatty acid oxidation and mitochondrial activity in muscle (acox, ucp2, sdha and cpt1-m, p < 0.05) as well as main regulatory transcription factors of metabolic activity such as pparα, pgc-1α and nrf2. All these features were associated with a reduced muscle fibre cross sectional area, resembling to controls (i.e., lean phenotype). SCFA may be direct inducers of these cross-talk alterations, as their feces content (+52%, p = 0.05) was increased in fibre-supplemented mini-pigs. The SCFA effects could be mediated at the gut level by an increased production of incretins (increased gcg mRNA, p < 0.05) and an up-regulation of SCFA receptors (increased gpr41 mRNA, p < 0.01). Hence, consumption of supplemented bread with fermentable fibres can be an appropriate strategy to activate muscle energy catabolism and limit the establishment of an obese phenotype.

Microbiota and Metabolite Modifications after Dietary Exclusion of Dairy Products and Reduced Consumption of Fermented Food in Young and Older Men.

The gut microbiota adapts to age-related changes in host physiology but is also affected by environmental stimuli, like diet. As a source of both pre- and probiotics, dairy and fermented foods modulate the gut microbiota composition, which makes them interesting food groups to use for the investigation of interactions between diet and ageing. Here we present the effects of excluding dairy products and limiting fermented food consumption for 19 days on gut microbiota composition and circulating metabolites of 28 healthy, young (YA) and older (OA) adult men. The intervention affected gut microbial composition in both groups, with significant increases in Akkermansia muciniphila and decreases in bacteria of the Clostridiales order. Lower fasting levels of glucose and insulin, as well as dairy-associated metabolites like lactose and pentadecanoic acid, were observed after the intervention, with no effect of age. The intervention also decreased HDL and LDL cholesterol levels. Dairy fat intake was positively associated with the HDL cholesterol changes but not with the LDL/HDL ratio. In conclusion, restricting the intake of dairy and fermented foods in men modified their gut microbiota and blood metabolites, while the impact of the dietary restrictions on these outcomes was more marked than the effect of age.

Important determinants to take into account to optimize protein nutrition in the elderly: solutions to a complex equation.

During ageing, skeletal muscle develops anabolic resistance towards the stimulation of protein synthesis induced by dietary amino acids. The stimulation of muscle protein synthesis after food intake remains insufficient, even with a protein intake recommended for healthy adults. This alteration is one of the mechanisms known to be responsible for the decrease of muscle mass and function during ageing, namely sarcopenia. Increasing dietary protein intake above the current RDA(0⋅83 g/kg/d) has been strongly suggested to overcome the anabolic resistance observed. It is also specified that the dietary protein ingested should be of good quality. A protein of good quality is a protein whose amino acid (AA) composition covers the requirement of each AA when ingested at the RDA. However, the biological value of proteins may vary among dietary sources in which AA composition could be unbalanced. In the present review, we suggest that the quality of a dietary protein is also related to several other determinants. These determinants include the speed of digestion of dietary proteins, the presence of specific AA, the food matrix in which the dietary proteins are included, the processes involved in the production of food products (milk gelation and cooking temperature), the energy supply and its nature, and the interaction between nutrients before ingestion. Particular attention is given to plant proteins for nutrition of the elderly. Finally, the timing of protein intake and its association with the desynchronized intake of energetic nutrients are discussed.

Postprandial NMR-Based Metabolic Exchanges Reflect Impaired Phenotypic Flexibility across Splanchnic Organs in the Obese Yucatan Mini-Pig.

The postprandial period represents one of the most challenging phenomena in whole-body metabolism, and it can be used as a unique window to evaluate the phenotypic flexibility of an individual in response to a given meal, which can be done by measuring the resilience of the metabolome. However, this exploration of the metabolism has never been applied to the arteriovenous (AV) exploration of organs metabolism. Here, we applied an AV metabolomics strategy to evaluate the postprandial flexibility across the liver and the intestine of mini-pigs subjected to a high fat-high sucrose (HFHS) diet for 2 months. We identified for the first time a postprandial signature associated to the insulin resistance and obesity outcomes, and we showed that the splanchnic postprandial metabolome was considerably affected by the meal and the obesity condition. Most of the changes induced by obesity were observed in the exchanges across the liver, where the metabolism was reorganized to maintain whole body glucose homeostasis by routing glucose formed de novo from a large variety of substrates into glycogen. Furthermore, metabolites related to lipid handling and energy metabolism showed a blunted postprandial response in the obese animals across organs. Finally, some of our results reflect a loss of flexibility in response to the HFHS meal challenge in unsuspected metabolic pathways that must be further explored as potential new events involved in early obesity and the onset of insulin resistance.

Arterio-venous metabolomics exploration reveals major changes across liver and intestine in the obese Yucatan minipig.

Blood circulation mainly aims at distributing the nutrients required for tissue metabolism and collecting safely the by-products of all tissues to be further metabolized or eliminated. The simultaneous study of arterial (A) and venous (V) specific metabolites therefore has appeared to be a more relevant approach to understand and study the metabolism of a given organ. We propose to implement this approach by applying a metabolomics (NMR) strategy on paired AV blood across the intestine and liver on high fat/high sugar (HFHS)-fed minipigs. Our objective was to unravel kinetically and sequentially the metabolic adaptations to early obesity/insulin resistance onset specifically on these two tissues. After two months of HFHS feeding our study of AV ratios of the metabolome highlighted three major features. First, the hepatic metabolism switched from carbohydrate to lipid utilization. Second, the energy demand of the intestine increased, resulting in an enhanced uptake of glutamine, glutamate, and the recruitment of novel energy substrates (choline and creatine). Third, the uptake of methionine and threonine was considered to be driven by an increased intestine turnover to cope with the new high-density diet. Finally, the unique combination of experimental data and modelling predictions suggested that HFHS feeding was associated with changes in tryptophan metabolism and fatty acid ß-oxidation, which may play an important role in lipid hepatic accumulation and insulin sensitivity.

Post Meal Energy Boluses Do Not Increase the Duration of Muscle Protein Synthesis Stimulation in Two Anabolic Resistant Situations.

BACKGROUND: When given in the long term, whey proteins alone do not appear to be an optimal nutritional strategy to prevent or slow down muscle wasting during aging or catabolic states. It has been hypothesized that the digestion of whey may be too rapid during a catabolic situation to sustain the anabolic postprandial amino acid requirement necessary to elicit an optimal anabolic response. Interestingly, it has been shown recently that the duration of the postprandial stimulation of muscle protein synthesis in healthy conditions can be prolonged by the supplementary ingestion of a desynchronized carbohydrate load after food intake. We verified this hypothesis in the present study in two different cases of muscle wasting associated with anabolic resistance, i.e., glucocorticoid treatment and aging. METHODS: Multi-catheterized minipigs were treated or not with glucocorticoids for 8 days. Muscle protein synthesis was measured sequentially over time after the infusion of a 13C phenylalanine tracer using the arterio-venous method before and after whey protein meal ingestion. The energy bolus was given 150 min after the meal. For the aging study, aged rats were fed the whey meal and muscle protein synthesis was measured sequentially over time with the flooding dose method using 13C Valine. The energy bolus was given 210 min after the meal. RESULTS: Glucocorticoid treatment resulted in a decrease in the duration of the stimulation of muscle protein synthesis. The energy bolus given after food intake was unable to prolong this stimulation despite a simultaneous increase of insulin and glucose following its absorption. In old rats, a similar observation was made with no effect of the energy bolus on the duration of the muscle anabolic response following whey protein meal intake. CONCLUSIONS: Despite very promising observations in healthy situations, the strategy aimed at increasing muscle protein synthesis stimulation by giving an energy bolus during the postprandial period remained inefficient in our two anabolic resistance models.

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

BACKGROUND: 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 ß-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.

Impaired Skeletal Muscle Branched-Chain Amino Acids Catabolism Contributes to Their Increased Circulating Levels in a Non-Obese Insulin-Resistant Fructose-Fed Rat Model.

Elevated plasma branched-chain amino acids (BCAA) levels are often observed in obese insulin-resistant (IR) subjects and laboratory animals. A reduced capacity of the adipose tissues (AT) to catabolize BCAA has been proposed as an explanation, but it seems restricted to obesity models of genetically modified or high fat⁻fed rodents. We aimed to determine if plasma BCAA levels were increased in a model of IR without obesity and to explore the underlying mechanisms. Rats were fed with a standard diet, containing either starch or fructose. BCAA levels, body weight and composition were recorded before and after 5, 12, 30, or 45 days of feeding. Elevated blood BCAA levels were observed in our IR model with unaltered body weight and composition. No changes were observed in the liver or the AT, but instead an impaired capacity of the skeletal muscle to catabolize BCAA was observed, including reduced capacity for transamination and oxidative deamination. Although the elevated blood BCAA levels in the fructose-fed rat seem to be a common feature of the IR phenotype observed in obese subjects and high fat⁻fed animals, the mechanisms involved in such a metabolic phenomenon are different, likely involving the skeletal muscle BCAA metabolism.

A mix of dietary fermentable fibers improves lipids handling by the liver of overfed minipigs.

Obesity induced by overfeeding ultimately can lead to nonalcoholic fatty liver disease, whereas dietary fiber consumption is known to have a beneficial effect. We aimed to determine if a supplementation of a mix of fibers (inulin, resistant starch and pectin) could limit or alleviate overfeeding-induced metabolic perturbations. Twenty female minipigs were fed with a control diet (C) or an enriched fat/sucrose diet supplemented (O + F) or not (O) with fibers. Between 0 and 56 days of overfeeding, insulin (+88%), HOMA (+102%), cholesterol (+45%) and lactate (+63%) were increased, without any beneficial effect of fibers supplementation. However, fibers supplementation limited body weight gain (vs. O, -15% at D56) and the accumulation of hepatic lipids droplets induced by overfeeding. This could be explained by a decreased lipids transport potential (-50% FABP1 mRNA, O + F vs. O) inducing a down-regulation of regulatory elements of lipids metabolism / lipogenesis (-36% SREBP1c mRNA, O + F vs. O) but not to an increased oxidation (O + F not different from O and C for proteins and mRNA measured). Glucose metabolism was also differentially regulated by fibers supplementation, with an increased net hepatic release of glucose in the fasted state (diet × time effect, P<.05 at D56) that can be explained partially by a possible increased glycogen synthesis in the fed state (+82% GYS2 protein, O + F vs. O, P=.09). The direct role of short chain fatty acids on gluconeogenesis stimulation is questioned, with probably a short-term impact (D14) but no effect on a long-term (D56) basis.

Efficacy of non-pharmacological interventions to treat malnutrition in older persons: A systematic review and meta-analysis. The SENATOR project ONTOP series and MaNuEL knowledge hub project.

INTRODUCTION: We aimed to perform a review of SRs of non-pharmacological interventions in older patients with well-defined malnutrition using relevant outcomes agreed by a broad panel of experts. METHODS: PubMed, Cochrane, EMBASE, and CINHAL databases were searched for SRs. Primary studies from those SRs were included. Quality assessment was undertaken using Cochrane and GRADE criteria. RESULTS: Eighteen primary studies from seventeen SRs were included. Eleven RCTs compared oral nutritional supplementation (ONS) with usual care. No beneficial effects of ONS treatment, after performing two meta-analysis in body weight changes (six studies), mean difference: 0.59 (95%CI -0.08, 1.96) kg, and in body mass index changes (two studies), mean difference: 0.31 (95%CI -0.17, 0.79) kg/m2 were found. Neither in MNA scores, muscle strength, activities of daily living, timed Up&Go, quality of life and mortality. Results of other intervention studies (dietary counselling and ONS, ONS combined with exercise, nutrition delivery systems) were inconsistent. The overall quality of the evidence was very low due to risk of bias and small sample size. CONCLUSIONS: This review has highlighted the lack of high quality evidence to indicate which interventions are effective in treating malnutrition in older people. High quality research studies are urgently needed in this area.