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Etiopathogenic factors of physical disability in obesity are numerous, underestimated and not sought in the non-geriatric population. Amongst these factors, depression may favor the development of sarcopenic obesity by reducing strength and physical performance even in the absence of overt muscle loss. Objectives and participants: To study the link between depression status and muscle functional disorders (dynapenia) in a population of adult subjects with severe and morbid obesity.Patients were assessed for body composition, grip strength, the Short Physical Performances Battery test (SPPB), for depression according to the Beck II score as well as for metabolic parameters through biological tests.In 373 obese subjects (mean age 44 ± 13y and BMI 43 ± 6 kg/m²), the prevalence of depression was 53% with 18% having mild depression, 18% moderate depression and 16% severe depression. Depression was significantly related to dynapenia: 62% of dynapenic (D) patients suffered from depression compared to 50% of non-dynapenic (ND) patients (p = 0.036). The Beck questionnaire score for D patients was 20 ± 13 and 15 ± 10 for ND patients (p = 0.001). The depression intensity was significantly correlated with dynapenia with D patients having a higher severe depression degree than ND patients (30% versus 11%; p0.0001). Fat-free to fat mass ratio was also significantly correlated with dynapenia (p = 0.01). In multivariate analysis, the presence of depression was twice as likely to be associated with dynapenia.Depression is associated with a reduction of muscle function in severe obesity in relation to its severity and to changes in fat to fat-free mass, suggesting that screening and prevention of sarcopenic obesity should be considered in adult obese patients with depression.

During muscle regeneration, myoblasts engage in cross-talk with immune cells to achieve optimal proliferation and differentiation. In this process, cytokines secreted by immune cells are described to modulate the kinetic of muscle differentiation. Taking into account that immune and muscle cells are both targets of vitamin D, we investigated in vitro the impact of 25-hydroxyvitamin D (25(OH)D) on the transcriptional response of muscle cells in presence of mononuclear cells. To address this objective, an in vitro model of co-culture using L6 myogenic cell line and peripheral blood mononuclear cell (PBMC) isolated from rat was used and compared to L6 cultured alone. Cells were treated with 25(OH)D (125 nM) during the 6 days of differentiation. Gene expression of 25(OH)D metabolism actors, muscle differentiation and metabolism markers, and of Notch signaling pathway effectors were studied in L6 cells by qPCR. In mono-cultured L6 cells, a 25(OH)D treatment induced a 3-fold increase (p VDR mRNA expression at 24 h while no change in mRNA expression of the muscle differentiation markers i.e. Myog, Myh2 and Des was observed. In the presence of PBMCs, the mRNA expression of these markers was enhanced (27.5 times for myogenin, p Dll: 6.8-fold and Hes1: x3.8-fold, p in vitro approach demonstrates the importance of immune cells in stimulating muscle cell differentiation. Taken as a whole, the data show that 25(OH)D attenuates in vitro the Notch pathway-dependent effects of immune cells on muscle cell differentiation and energy metabolism.

Besides its classical biological roles in bone health, extraskeletal effects of vitamin D are currently a subject of extensive research. The expression of the vitamin D receptor in most tissues has strengthened arguments for multiple functions, among which the effect of vitamin D on muscle mass and performance has long been discussed. It is now clear that skeletal muscle is one of the body targets of vitamin D. Studies have demonstrated that vitamin D deficiencies are associated with reduced muscle mass and strength. Vitamin D is also involved in muscle regeneration, i.e., vitamin D modulates the proliferation and differentiation of skeletal muscle cells. Vitamin D is also a significant driver of numerous metabolic pathways of muscle cell metabolism. To explain these multiple actions, research has demonstrated a genetic contribution of vitamin D to muscle function, in addition to its genomic and nongenomic effects. Despite our wide knowledge concerning the action of vitamin D, more studies are still needed to clarify the importance of vitamin D in muscle health and adjust vitamin D treatment more closely to patient characteristics. This would be of direct relevance for older subjects and athletes, and also in situations where muscle mass or function is lost, particularly in chronic illnesses.

Skeletal muscle metabolism is a highly coordinated process involving cross talk between immune and muscle cells. However, the physiological activities of both immune and muscle cells are modified with obesity or high-fat feeding. In this context, skeletal muscle inflammation occurs as a result of immune cell infiltration and activation. The subsequent myocyte metabolic alteration leads to insulino-resistance development. Several studies demonstrate that skeletal muscle repair is reduced during obesity. Interestingly, characteristics of aged muscle contributing to the reduction of muscle repair capacity are observed in obesity such as reduced number and activity of muscle satellite cells, decreased muscle cell differentiation, muscle adipose tissue deposition, modification of macrophage infiltration and phenotype. Obesity likely increases the risk of developing a phenomenon named sarcopenic obesity. This research will highlight new strategies to improve skeletal muscle repair and then limit the adverse effects of obesity on skeletal muscle health.

In press; After skeletal muscle injury a regeneration process takes place to repair muscle. Skeletal muscle recovery is a highly coordinated process involving cross-talk between immune and muscle cells. It is well known that the physiological activities of both immune cells and muscle stem cells decline with advancing age, thereby blunting the capacity of skeletal muscle to regenerate. The age-related reduction in muscle repair efficiency contributes to the development of sarcopenia, one of the most important factors of disability in elderly people. Preserving muscle regeneration capacity may slow the development of this syndrome. In this context, nutrition has drawn much attention: studies have demonstrated that nutrients such as amino acids, n-3 polyunsaturated fatty acids, polyphenols and vitamin D can improve skeletal muscle regeneration by targeting key functions of immune cells, muscle cells or both. Here we review the process of skeletal muscle regeneration with a special focus on the cross-talk between immune and muscle cells. We address the effect of aging on immune and skeletal muscle cells involved in muscle regeneration. Finally, the mechanisms of nutrient action on muscle regeneration are described, showing that quality of nutrition may help to preserve the capacity for skeletal muscle regeneration with age.

Introduction et but de l’etude Mammalian Target of rapamycin (mTOR) est un nœud metabolique qui en reponse aux nutriments et facteurs de croissance regule de nombreux processus cellulaires. Bien que cette voie de signalisation soit largement etudiee, les cibles de mTOR et leur importance respective dans le controle du fonctionnement du muscle squelettique est encore peu connu. Les proteines eIF4E-Binding Proteins (4E-BPs) interviennent dans le controle de l’initiation de la traduction par mTOR connectant ainsi l’activite mTOR au metabolisme en general. Chez la souris, la deletion au niveau du corps entier des proteines 4E-BP1 et 4E-BP2 (cibles de mTOR) favorise l’induction de l’obesite, de l’insulinoresistance et l’accumulation ectopique de lipides au niveau musculaire [1] , [2] . A l’inverse, la surexpression de 4E-BP1 protege contre cette obesite [3] , [4] . L’objectif de cette etude etait de determiner l’effet de la deletion de 4E-BP1 et 4E-BP2 sur la fonction musculaire chez des souris âgees. Materiel et methodes La fonction musculaire (grip strength, wire screen holding time) a ete evaluee chez des souris sauvages (WT) et invalidees pour les proteines 4E-BP1 et 2 (4E-BP1/2 Double KO, DKO) âgees de 24 mois. Le poids des muscles des pattes arriere a ete mesure apres sacrifice. La synthese proteique a ete mesuree ex-vivo sur muscle EDL par incorporation de L-[U-14C] Phenylalanine en presence ou absence de leucine/insuline, et la proteolyse par relargage de tyrosine dans le milieu d’incubation. Les resultats ont ete analyses par le test de student (t-test) ou ANOVA a 2 voies, et exprimes en moyenne ± sem. Resultats et analyse statistique la survie des souris WT et DKO est identique. Chez les mâles, la deletion de 4E-BP1 et 4E-BP2 entraine une augmentation de la masse maigre (foie et muscle squelettique, p Conclusion Ces resultats demontrent que la deletion des proteines 4E-BPs au niveau du corps entier a un effet benefique sur le maintien de la force et de la masse musculaire chez des souris âgees. Ils suggerent egalement que les proteines 4E-BPs sont des modulateurs sexe-specifiques de l’homeostasie musculaire.

PURPOSE OF REVIEW: We review recent findings on the involvement of vitamin D in skeletal muscle trophicity. RECENT FINDINGS: Vitamin D deficiencies are associated with reduced muscle mass and strength, and its supplementation seems effective to improve these parameters in vitamin D-deficient study participants. Latest investigations have also evidenced that vitamin D is essential in muscle development and repair. In particular, it modulates skeletal muscle cell proliferation and differentiation. However, discrepancies still exist about an enhancement or a decrease of muscle proliferation and differentiation by the vitamin D. Recently, it has been demonstrated that vitamin D influences skeletal muscle cell metabolism as it seems to regulate protein synthesis and mitochondrial function. Finally, apart from its genomic and nongenomic effects, recent investigations have demonstrated a genetic contribution of vitamin D to muscle functioning. SUMMARY: Recent studies support the importance of vitamin D in muscle health, and the impact of its deficiency in regard to muscle mass and function. These 'trophic' properties are of particular importance for some specific populations such as elderly persons and athletes, and in situations of loss of muscle mass or function, particularly in the context of chronic diseases

Background: Hypovitaminosis D is very prevalent, especially in the obese population. However, the degree of severity and the parameters involved in vitamin D deficiency in this population are still unclear. The present study aimed to identify, from among the factors known to influence vitamin D status in a healthy population, those impacting the same parameter in obese population. Methods: Serum 25-OH-D concentration was measured in 564 patients with class III obesity [i.e. severe and morbid obesity; mean (SD) body mass index (BMI) 42.04 (6.92) kg m–2] and their demographic, clinical, biologi- cal, anthropometric, dietary and socio-economic data were collected. Results: We observed that 96% of the obese patients had serum 25-OH-D lower than 30 ng mL 1. Severe vitamin D deficiency (serum 25-OH-D con-centration

cope In recent years, several studies reported the role of eIF4E-binding proteins (4E-BPs) on the development of diet-induced obesity and insulin resistance. Our aim was to investigate the effect of 4E-BP protein deletion on lipid accumulation and metabolism in skeletal muscle in response to a high fat diet-induced obesity in 4E-BP1/2 DKO mice. Methods and results Diet-induced obesity engendered increased ectopic accumulation of lipotoxic species in skeletal muscle of 4E-BP1 and 4E-BP2 double-knockout mice (4E-BP1/2 DKO), namely diacylglycerols and ceramides. Increased lipid accumulation was associated with alterations in the expression of genes involved in fatty acid transport (FATP, CD36), diacylglycerol/triacylglycerol biosynthesis (GPAT1, AGPAT1, DGAT1) and β-oxidation (CPT1b, MCAD). Diet-induced obesity resulted in increased lean mass and muscle in 4E-BP1/2 DKO mice despite the development of a more severe systemic insulin resistance. Since increased expression of genes of several proteolytic systems (MuRF1, Atrogin/MAFbx and Cathepsin-L) in 4EBP1/2 DKO skeletal muscle was reported, the increased of skeletal muscle mass in 4E-BP1/2 DKO mice suggests that ablation of 4E-BPs compensate with activation of muscle anabolism. Conclusions These findings indicate that 4E-BP proteins may prevent excess lipid accumulation in skeletal muscle and suggest that 4E-BPs are key regulators of muscle homeostasis regardless of insulin sensitivity. This article is protected by copyright. All rights reserved

The authors gratefully acknowledge all members of the animal facilities from Theix's INRA center for their valuable assistance in conducting this study; We investigated the impact of vitamin D deficiency and repletion on muscle anabolism in old rats. Animals were fed a control (1 IU vitamin D3/g, ctrl, n=20) or a vitamin D-depleted diet (VDD; 0 IU, n=30) for 6 months. A subset was thereafter sacrificed in the control (ctrl6) and depleted groups (VDD6). Remaining control animals were kept for 3 additional months on the same diet (ctrl9), while a part of VDD rats continued on a depleted diet (VDD9) and another part was supplemented with vitamin D (5 IU, VDS9). The ctr16 and VDD6 rats and the ctr19, VDD9 and VDS9 rats were 21 and 24 months old, respectively. Vitamin D status, body weight and composition, muscle strength, weight and lipid content were evaluated. Muscle protein synthesis rate (fractional synthesis rate; FSR) and the activation of controlling pathways were measured. VDD reduced plasma 25(OH)-vitamin D, reaching deficiency (

in press; SCOPE: One strategy to manage malnutrition in older patients is to increase protein and energy intake. Here we evaluate the influence of protein quality during refeeding on improvement in muscle protein and energy metabolism.METHODS AND RESULTS: Twenty-month-old male rats (n = 40) were fed 50% of their spontaneous intake for 12 weeks to induce malnutrition, then refed ad libitum with a standard diet enriched with casein or soluble milk proteins (22%) for 4 weeks. 13C-valine was infused to measure muscle protein synthesis and expression of MuRF1, and MAFbx was measured to evaluate muscle proteolysis. mTOR pathway activation and mitochondrial function were assessed in muscle. Malnutrition was associated with a decrease in body weight, fat mass and lean mass, particularly muscle mass. Malnutrition decreased muscle mTOR pathway activation and protein FSR associated with increased MuRF1 mRNA levels, and decreased mitochondrial function. The refeeding period partially restored fat mass and lean mass. Unlike the casein diet, the soluble milk protein diet improved muscle protein metabolism and mitochondrial function in old malnourished rats.CONCLUSIONS: These results suggest that providing better-quality proteins during refeeding may improve efficacy of renutrition in malnourished older patients. This article is protected by copyright. All rights reserved.

Lipids and their derivatives accumulate in skeletal muscle with obesity. Hence, dysfunctions in glucose utilization, in mitochondrial capacity and in fiber type occur, especially in older obese individuals. Intramyocellular lipids promote insulin resistance, and blunt protein turnover through altered signaling pathways involved in stress response. Adiposity, particularly ectopic lipid deposition, affects the metabolic response of proteins to insulin and amino acids at whole body and muscle level, suggesting that muscle protein turnover might be impaired during obesity. These changes may be related to metabolic disorders like lipotoxicity, inflammation, or other adipokines. These obesity-related modifications may affect mobility, morbidity, and quality of life leading to sarcopenic obesity. To better phenotype, the skeletal muscle mass and function in obese patients is of importance in order to detect early potential causes of sarcopenia and propose an integrated approach considering muscle protein metabolism as a therapeutical target to improve their quality of life.

Background The diminished ability of aged muscle to self-repair is a factor behind sarcopenia and contributes to muscle atrophy. Muscle repair depends on satellite cells whose pool size is diminished with aging. A reduction in Notch pathway activity may explain the age-related decrease in satellite cell proliferation, as this pathway has been implicated in satellite cell self-renewal. Skeletal muscle is a target of vitamin D which modulates muscle cell proliferation and differentiation in vitro and stimulates muscle regeneration in vivo. Vitamin D status is positively correlated to muscle strength/function, and elderly populations develop a vitamin D deficiency. The aim of this study was to evaluate how vitamin D deficiency induces skeletal muscle atrophy in old rats through a reduction in Notch pathway activity and proliferation potential in muscle. Methods 15-month-old male rats were vitamin D-depleted or not (control) for 9 months (n = 10 per group). Rats were 24-month-old at the end of the experiment. Gene and/or protein expression of markers of proliferation, or modulating proliferation, and of Notch signalling pathway were studied in the tibialis anterior muscle by qPCR and western blot. An unpaired student’s t-test was performed to test the effect of the experimental conditions. Results Vitamin D depletion led to a drop in concentrations of plasma 25-hydroxyvitamin D in depleted rats compared to controls (-74%, p

Introduction et but de l’etude La sarcopenie associee a une obesite represente un facteur de risque pour l’etat de sante des personnes âgees. Ce phenotype defini sous le terme d’obesite sarcopenique a ete reproduit dans un modele de rats âges soumis durant 10 semaines a un regime hyperlipidique–hypercalorique. Une resistance de l’anabolisme proteique musculaire est observee, associee a une alteration des capacites oxydatives mitochondriales, et cela de maniere plus prononcee que chez des rats âges nourris avec un regime standard [1] . Les apports nutritionnels peuvent moduler ce phenotype puisque les niveaux d’apports proteiques influencent l’anabolisme proteique. Le but de cette etude etait de determiner si des apports proteiques eleves au sein d’un regime inducteur d’obesite pourraient prevenir les alterations musculaires induites par le regime hyperlipidique. Materiel et methodes Des rats âges de 19 mois ont ete soumis durant 10 semaines a un regime hyperlipidique–hypercalorique (HFD) ou standard (STD) associe a des apports proteiques moderes (12 % de l’apport energetique total [AET ; STD12, HFD12] ou eleves (25 % de l’AET ; STD25, HFD25). La composition corporelle des animaux a ete analysee par echoMRI au debut et a la fin du regime. Des evaluations de force et de puissance musculaire ont ete realisees in vivo avec un dynamometre isocinetique en meme temps. Les activites enzymatiques mitochondriales (hydroxyacyl-CoA-deshydrogenase [HAD], citrate synthase [CS] et cytochrome C oxydase [COX]) ont ete mesurees par spectrophotometrie. Resultats et analyse statistique Au bout de 10 semaines de regime, la variation de masse grasse etait significativement plus elevee dans les groupes HFD (HFD25 : + 103,5 ± 33,0 g ; HFD12 : + 113,5 ± 31,6 g) que dans les groupes STD (STD25 : + 41,2 ± 20,8 g ; STD12 : + 60,5 ± 32,4 g ; p Tableau 1 ). Conclusion Chez le rat âge, l’effet benefique des proteines alimentaires sur l’anabolisme et le metabolisme musculaire n’est pas retrouve en situation de surnutrition lipidique, suggerant un etat de resistance anabolique induit par l’obesite.