Sarcopenia is a disease of muscle wasting primarily seen in older adults. Although this term was first coined over three decades ago, there is a lack of consensus on a definition, screening criteria, and treatment protocol for sarcopenia. The primary purpose of this study is to determine whether registered dietitian nutritionists (RDNs) in the United States (U.S.) screen for sarcopenia. Study participants were recruited through a randomized email list and included RDNs throughout the U.S. Respondents completed a survey questioning knowledge of sarcopenia, screening tools and company protocols in place, and the need and desire for sarcopenia education. Data revealed a lack of pre-existing protocols in place, a dissonance of validated and unvalidated screening tools used in practice, and substantial need for sarcopenia education.

In recent years, the transplant community has explored and adopted tools for quantifying clinical insight into illness severity and frailty. This dissertation work explores the interplay between objective and subjective assessments of physical health status and the implications for liver transplant candidate and recipient outcomes. The first aim characterizes national epidemiologic trends and the impact of Centers for Medicare and Medicaid quality improvement policies on likelihood of waitlist removal based on the patient being too frail to benefit from liver transplant (“too sick to transplant”). This aim includes more than a decade (2002–2012) of comprehensive national transplant waitlist data (Scientific Registry of Transplant Recipients (SRTR)). The second aim will assess and define objective parameters of liver transplant patient frailty by measuring decline in lean core muscle mass (“sarcopenia”) using abdominal CT scans collected retrospectively at a single U.S. transplant center between 2006 and 2015. The relationship between these objective sarcopenia measures and subjective functional status assessed using the Karnofsky Functional Performance (KPS) scale are described and quantified. The third aim quantifies the extent to which poor functional status (KPS) pre-transplant is associated with worse post-transplant survival and includes national data on liver transplantations conducted between 2005 and 2014 (SRTR). The results of this dissertation will help providers in the assessment of frailty and subsequent risk of adverse outcomes and has implications for strategic clinical management in anticipation of surgery. This research will also to serve to inform national policy on the design of transplant center performance measures.

Le vieillissement entraîne plusieurs changements au niveau de la fonction musculaire qui peuvent mener à une perte de la masse musculaire et de sa fonction qu’on appelle sarcopénie. La sarcopénie entraîne une augmentation du risque de chutes et d’hospitalisations qui nuit à la qualité de vie des personnes âgées. Le vieillissement de la population représente un enjeu important au sein de la société en raison de son impact socioéconomique élevé. Plusieurs facteurs contribuent à ce déclin observé au cours du vieillissement, mais un des éléments clés qui y contribue sont des altérations de la jonction neuromusculaire (JNM). La JNM est une synapse tripartite composée de la terminaison nerveuse présynaptique, de la fibre musculaire postsynaptique et des cellules de Schwann périsynaptiques (CSPs), des cellules gliales. Les CSPs jouent un rôle essentiel dans la maintenance, la modulation de la transmission et de la plasticité synaptique et la réparation de la JNM. Plusieurs études effectuées chez le murin ont démontré que la JNM présente des altérations telles que de la dénervation, de la fragmentation du postsynaptique et des signes de modulation et de réparation gliaux au cours du vieillissement. Ces altérations contribuent aux déficits de la fonction neuromusculaire observés lors du vieillissement. La JNM humaine demeure cependant sous-étudiée, particulièrement en considérant sa structure tripartite. Afin de mieux comprendre le vieillissement neuromusculaire chez l’humain, des biopsies du Vastus lateralis ont été effectuées chez 4 jeunes adultes (23-28 ans) et 5 personnes âgées (60-75 ans) sains et actifs. Un marquage immunohistochimique a été effectué sur les biopsies afin d’identifier les trois composantes de base de la JNM et le type de fibre, puis visualiser en microscopie confocale. Des mesures fonctionnelles ont également été prélevées pour chacun des participants âgés. L’analyse des JNMs a permis de démontrer qu’une instabilité de l’innervation de même qu’une relation tripartite divergente se développe avec l’âge. Ces altérations corrèlent également avec un déficit fonctionnel. Dans l’ensemble, notre étude présente des altérations de la JNM humaine au cours du vieillissement ayant un impact sur la fonction neuromusculaire. Elle pourrait permettre de mieux comprendre les mécanismes à la base du vieillissement neuromusculaire pour développer des stratégies d’intervention thérapeutiques efficaces pour limiter l’impact du vieillissement. / Several changes occur in muscular function in aging which can lead to a loss of muscle mass and function called sarcopenia. Sarcopenia can lead to an increased risk of fall and hospitalization and to a poor quality of life. Aging of the population represents an important societal issue due to its high socioeconomic impact. Many factors contribute to the decline of muscular function seen in aging, but alterations of the neuromuscular junctions are a key element leading to sarcopenia. The NMJ is a tripartite synapse composed of the presynaptic nerve terminal, the postsynaptic muscle fiber as well as perisynaptic Schwann cells (PSC), glial cells. PSCs play a key role in maintenance, modulation of synaptic transmission and plasticity as well as repair of the NMJ. Several rodent studies have shown that the NMJ present alterations such as denervation, fragmentation of the postsynaptic and glial-related signs of modulation and repair in aging. These alterations contribute to the neuromuscular deficits observed in aging. However, the NMJ remain widely understudied, particularly when considering its tripartite structure. In order to get a better understanding of neuromuscular aging in humans, biopsies form the Vastus lateralis were performed on 4 young (23-28 years old) and 5 older (60-75 years old) healthy and physically active men. Immunohistochemistry labelling of the NMJ’s main components and type of fibers was performed and then imaged using confocal microscopy. Functional assessment was also measured for each older adult. Analysis of NMJs revealed an instability in the innervation as well as a divergent tripartite relationship in older individuals. These alterations also correlated with neuromuscular deficits. Taken altogether, our study highlights alterations of the NMJ in aging leading to altered neuromuscular function. This could lead to a better understanding of the underlying mechanisms leading to sarcopenia and to develop better therapeutic strategies to limit its impact during aging.

L'encéphalopathie hépatique (EH) est une complication grave de la cirrhose, provoquant des troubles de mémoire, de coordination motrice et de sommeil, avec une progression vers le coma et la mort. Le stress oxydatif dû au foie défaillant et l'ammoniac provenant de la dégradation des protéines alimentaires sont des facteurs pathogènes connus. Simultanément, l'hyperammoniémie et la malnutrition protéino-calorique contribuent à la sarcopénie. Comme les muscles sont le principal mécanisme d'élimination de l'ammoniac pendant la cirrhose, il existe un cercle vicieux où l'hyperammonémie contribue à l'EH et à la sarcopénie, et la sarcopénie contribue à l'hyperammonémie et à l'EH. Notre objectif était de déterminer les effets d’un régime riche en protéines de lactosérum ou de soja administré à long terme, sur la masse musculaire, l'hyperammonémie, et l'EH chez les rats cirrhotiques. Ensuite, nous voulions déterminer les effets d’un gavage aigu de protéines sur l'hyperammonémie et l'EH. Nos résultats montrent qu'un apport élevé en protéines à long terme n'a pas maintenu la masse musculaire ou diminué l'ammoniac, mais que le stress oxydatif a été réduit, ce qui a conduit à la prévention de l'EH, améliorant la mémoire à court et à long terme, l'anxiété, et l'activité locomotrice. Un gavage aigu de protéines chez les rats cirrhotiques n’a pas augmenté l'ammoniac ni précipité l'EH. Cette étude est la première à évaluer l'effet d'un régime élevé en protéines chez des rats cirrhotiques pour observer la masse musculaire, l'ammoniac et l'EH. Nos résultats soutiennent la sécurité et l'efficacité d'une stratégie nutritionnelle riche en protéines dans la cirrhose. / Hepatic encephalopathy (HE) is a serious complication of liver disease, causing impairments in memory, motor coordination, sleep, with progression to coma and death. It affects up to 70% of patients, severely impacting quality of life. Oxidative stress from the failing liver and ammonia from the breakdown of dietary protein are known pathogenic factors. Concurrently, hyperammonemia and protein-calorie malnutrition contribute to muscle wasting, sarcopenia. As muscle is the main clearance mechanism for ammonia during cirrhosis, a vicious cycle exists where elevated ammonia contributes to HE and sarcopenia, and sarcopenia in turn contributes further to hyperammonemia and HE. Our aim was to determine whether long-term high protein whey or soy diets administered from the onset of liver disease in rats could maintain muscle mass, decrease hyperammonemia, and prevent symptoms of HE. Secondly, we wanted to determine the effects an acute load of high protein on hyperammonemia and HE in cirrhotic rodents. Our results show that long-term high protein intake did not maintain muscle mass or decrease ammonia, but oxidative stress was reduced, leading to HE prevention, as shown by the improvement of short- and long-term memory, anxiety, and locomotor activity. An acute load of protein was shown to be safe in cirrhotic rodents, with no increase in ammonia or precipitation of HE. This study is the first of its kind to evaluate the effect of high protein intake in cirrhotic rodents to observe muscle mass, ammonia, and HE. Our results support the safety and efficacy of a high protein nutritional strategy in cirrhosis.

No description available.

INTRODUCTION: Sarcopenia is a loss of muscle function and muscle mass which frequently occurs among the oldest-old adult population (aged 85+ years). The analysis of accelerometer-determined physical behavior volumes and patterns of oldest-old adults might provide novel insights into the associations with sarcopenia and its components. METHODS: A total of 145 participants in the primary sample and 87 participants in the subsample with a mean age of 88.2 (2.5) years from the Health, Aging, and Body Composition study cohort provided cross-sectional data of handgrip strength, appendicular lean mass, gait speed, and accelerometry. Probable, confirmed, and severe sarcopenia were assessed based on the revised definition of the European Working Group on Sarcopenia in Older People 2. Binomial logistic and multivariate linear regression models as well as dose-response analyses were applied and adjusted for demographics, accelerometer wear time, lifestyle factors, and chronic health conditions. RESULTS: Oldest-old adults with higher total volumes of moderate to vigorous physical activity (MVPA) (OR=0.74, 95% CI 0.62 to 0.89) showed a lower likelihood for a probable sarcopenic condition in the primary sample. Likewise, patterns of higher accumulated time spent in MVPA bouts of less than 10 minutes (OR=0.78, 95% CI 0.64 to 0.95) and MVPA bouts of at least 10 minutes (OR=0.78, 95% CI 0.63 to 0.98) were also related with lower odds of probable sarcopenia. A 2.1 times (95% CI 1.01 to 4.35) higher likelihood for confirmed sarcopenia was observed among participants who spent 60 minutes more per day in sedentary behavior (SB). Furthermore, 2.9 times (95% CI 1.05 to 8.02) greater odds of severe sarcopenia were identified following each 0.1 higher active-to-sedentary transition probability (ASTP). Focusing on individual sarcopenic components, higher total activity counts, higher MVPA, higher light intensity physical activity (LIPA), lower SB, and lower ASTP were related with better gait speed. CONCLUSION: The total volume of MVPA, whether accumulated in short sporadic bouts or prolonged bouts, was associated with lower odds of probable sarcopenia. Higher LIPA, lower SB, and a less fragmented activity pattern might also be related with a lower likelihood of sarcopenia status and better physical performance among oldest-old adults.

Approximately 23% of Canadians over the age of 65 are considered frail, with that number predicted to increase up to 40% for the population over the age of 85. Frailty is a geriatric syndrome defined by the natural decline in muscle mass and function caused by the natural aging process. When developing to an excessive degree, frailty may present as a disease state, which is recognized as sarcopenia. The exact definition of sarcopenia relies on the presence of low muscle mass, strength, and/or function, but quantitative cut-off values are still a topic of debate. Understanding how biomarkers measured via diagnostic imaging such as magnetic resonance imaging (MRI) and dual-energy x-ray absorptiometry (DXA) describe skeletal muscle can allow doctors to develop a profile of sarcopenia and define predictors to aide in preventative therapy. 4 male and 9 female (mean age = 78 ± 6.5 years) participants from a frailty study underwent full-body DXA and had their dominant thigh scanned using a 3.0T MRI. DXA-derived appendicular lean mass (ALM) and MRI-derived cross-sectional area (CSA), fat fraction (FF), T2 relaxation (T2), magnetization transfer ratio (MTR), fractional anisotropy (FA) and mean diffusivity (MD) from 4 muscle groups at the mid-thigh were defined as muscle biomarkers. Pearson's correlation was calculated to identify relationships between biomarkers and a Wilcoxon rank-sum test was performed to assess the agreement of low-muscle mass characterization between ALM normalized by height (ALMI), ALM normalized by BMI (ALM/BMI), and the gold standard MRI cross-sectional area. Strong positive correlations between muscle quantity biomarkers such as ALMI and CSA were recognized within the quadriceps (p=0.0095), adductors (p=0.035), and sartorius (p=0.00065) muscles while muscle quality biomarkers such as FF and T2 showed significant positive correlation within the quadriceps (p=3.58*10^-5) and the hamstring (p=0.0042) muscles. Finally, ALM/BMI displayed a much stronger agreement in muscle mass quantification with the gold-standard of MRI-CSA over the more commonly researched ALMI from DXA. The main purpose of this study was to collate a vast array of skeletal muscle biomarkers obtained using DXA and MRI on a frail population, and show that significant correlations can be recognized from a single MRI-slice located at the mid-thigh. Additionally, this study recognized the potential of ALM/BMI as the DXA-derived biomarker of choice in muscle mass assessment of frailty. / Thesis / Master of Applied Science (MASc) / A person is diagnosed with sarcopenia when they present symptoms of low muscle mass, strength, and/or function. Defining these three criteria with objective measures has been long debated by researchers and clinicians alike. By understanding how different properties, or biomarkers, of skeletal muscle relate to one another and change as a person becomes more frail, we hope to better understand sarcopenia and identify the best measures to classify someone as sarcopenic. Being able to accurately diagnose someone as sarcopenic early allows for more effective treatment of this muscle disease. In this study, non-invasive magnetic resonance imaging (MRI) and dual energy x-ray absorptiometry (DXA) were used to measure many different biomarkers of skeletal muscle at the mid-thigh. Through characterizing these measures of muscle quality and quantity between different imaging techniques this study aimed to recognize which imaging techniques, and more specifically biomarkers, can best distinguish between a person who is sarcopenic and one who is non-sarcopenic.

Au cours du vieillissement, l’organisme subit de nombreuses altérations, dont une perte de masse et de fonction musculaire appelée sarcopénie. Ses causes sont multifactorielles. Elle est partiellement liée à une altération de la stimulation de la synthèse protéique musculaire post-prandiale, et certains facteurs tels que le stress oxydant, l’inflammation et la résistance à l’insuline, responsables de nombreux dysfonctionnements métaboliques, accélèrent ce phénomène. Or, ces dérégulations peuvent être induites par une alimentation trop riche en sucres ajoutés, caractéristique des habitudes alimentaires actuelles et qui pourrait donc accélérer le vieillissement. Pourtant, à ce jour, peu d'études ont étudié les effets combinés du vieillissement et d'un régime riche en sucres ajoutés, et à notre connaissance, aucune ne s’est intéressée à la sarcopénie. Ainsi, notre objectif au cours de cette thèse a été de déterminer si un régime riche en sucres ajoutés était capable d'accélérer la sarcopénie. Il était également intéressant d'étudier les effets combinés du vieillissement et de ce régime sur d'autres tissus qui semblent particulièrement exposés, le foie, et le cerveau. Enfin, nous avons également voulu analyser les effets préventifs d'un mélange de micronutriments à la fois in vivo et in vitro. Pour cela, des rats âgés de 16 mois ont été nourris durant 5 mois avec un régime contrôle ou un régime composé à 62% de saccharose, supplémenté ou non en rutine, vitamine A, vitamine E, vitamine D, zinc, et sélénium. En outre, nous avons également inclut un groupe de témoins adultes (8 mois), nourris avec un régime contrôle. Par ailleurs, les effets anti-inflammatoires des micronutriments ont été testés in vitro.Nous avons pu constater que le régime riche en saccharose a accéléré la perte de masse musculaire liée à l’âge en altérant la synthèse protéique musculaire post prandiale, vraisemblablement via l’altération de la sensibilité à l’insuline plutôt que par une augmentation du stress oxydant et de l'inflammation, qui ont été peu affectés par le régime. Il a également entraîné un gain de masse grasse et une augmentation marquée des triglycérides hépatiques et plasmatiques, qui pourraient en partie s’expliquer par une modification de l’activité des enzymes du métabolisme lipidique dans le foie. Au niveau cérébral, la surconsommation de fructose a entraîné une diminution de la concentration protéique qui ne semble pas due à un défaut de synthèse protéique. La supplémentation en micronutriments n’a que partiellement contrecarré les effets du saccharose puisqu’elle n’a pas eu d’effet sur la masse maigre mais a permis de limiter la prise de masse grasse, notamment en inhibant la lipogenèse hépatique. Elle a également restauré la synthèse protéique diminuée au cours du vieillissement dans le cerveau. In vitro, elle a permis de réduire l'inflammation induite expérimentalement.Ainsi, cette thèse a permis de montrer qu’un régime riche en sucres ajoutés accélère la sarcopénie chez le rat âgé mais entraîne également des altérations au niveau hépatique et cérébral. La prévention par les micronutriments testés reste malgré tout limitée. / With aging, several alterations occur, including a loss of muscle mass and function, called sarcopenia. Many factors are responsible for the development of sarcopenia, but some factors as inflammation, oxidative stress and insulin resistance, which have many deleterious effects during aging, can reduce meal-induced stimulation of muscle protein synthesis which was shown to partly explain age-related muscle mass loss. Those factors can be induced by a diet rich in added sugar, characteristic of current dietary habits. Although this kind of diet could accelerate aging features, little is known about combined effect of aging and high sugar diet, particularly on sarcopenia. Thus, the purpose of this work was to determine whether high chronic intake of added sugars could accelerate sarcopenia. We also interested in the combined effect of added sugars and aging on other exposed tissues: liver and brain. Finally, we assessed the preventive effects of a micronutrient supplementation both in vivo and in vitro.In order to do that, for 5 months, 16 month old rats were starch fed or sucrose fed (62% sucrose), with or without micronutrients supplementation (rutin, vitamin A, vitamin E, vitamin D, selenium and zinc). Additionally, an adult control group of 8 month old rats was included. Besides, anti-inflammatory effects of micronutrients were tested in vitro.We showed that high sucrose diet accelerated age-related muscle mass loss by impairing postprandial protein synthesis, likely through decreased insulin sensitivity since inflammation and oxidative stress were only slightly affected by high sucrose diet. This diet also resulted in fat mass gain and increased plasma and liver triglycerides, by modulating the activity of enzymes involved in liver lipid metabolism. In the brain, high sucrose consumption led to decreased protein concentration independently of protein synthesis alteration. Micronutrients supplementation only partially reversed high sucrose diet effects: it did not act on lean body mass but prevented fat mass gain, by inhibiting hepatic lipogenesis. It also restored brain protein synthesis, which was reduced by aging. In vitro, it reduced experimentally induced inflammation.Thus, this work showed that a high sucrose diet accelerates sarcopenia in old rats but also induces liver and brain alterations. Prevention by micronutrients remained limited.

In this thesis the primary focus is on the evaluation of biomedical microwave sensor to be used in the muscle analyzer system. Lower muscle quality is one indicator that a patient can have sarcopenia. Therefore the muscle analyzer system can be a tool used in screening for sarcopenia. Sarcopenia is a progressive skeletal muscle disorder that typically affects elderly people. It is characterized by several different things, one of them is that there is an infiltration of fat into the muscle. At microwave frequencies the dielectric properties of fat are vastly different than the muscles. So, this fat infiltration creates a dielectric contrast compared to muscle without this fat infiltration that the sensors aim to detect. The muscle analyzer system is proposed to be a portable device that can be employed in clinics to assess muscle quality. The sensors are evaluated on their ability to distinguish between normal muscle tissue and muscle of lower quality. This is achieved via electromagnetic simulations, clinical trials, where the system is compared against established techniques, and phantom experiments, where artificial tissue emulating materials is used in a laboratory setting to mimick the properties of human tissues. In a initial clinical pilot study the split ring resonator sensor was used, but the results raised concerns over the penetration depth of the sensor. Therefore, three new alternative sensors were designed and evaluated via simulations. Two of the new sensors showed encouraging results, one of which has been fabricated. This sensor was used in a another clinical study.This study only had data from 4 patients, 8 measurements in total, meaning it was hard to draw any conclusions from it. The sensors used in the clinical setting as well as another were evaluated in the phantom experiments. Those experiments were exploratory because a wider frequency range was used, although some problems in the experiments were found. A secondary approach in this thesis is devoted to a data-driven approach, where a microwave sensor is simulated. The data from it is simulated and used to train a neural network to predict the dielectric properties of materials. The network predicts these properties with relatively high accuracy. However, this approach is currently limited to simulations only. Several ideas on how to improve this approach and extend it to measurements is given.

Contexte et objectifs : L'encéphalopathie hépatique (EH) est un trouble neuropsychiatrique, une complication majeure de la maladie hépatique chronique (MHC). L'EH se manifeste par un large éventail de symptômes, allant d'un léger manque d'attention et de troubles de la mémoire à une léthargie sévère et un coma. L'hyperammoniémie est centrale dans la pathogenèse de l'EH puisque l'ammoniac est neurotoxique et que l'ammoniac dérivé du sang traverse facilement la barrière hémato-encéphalique (BHE). Cependant, d'autres facteurs pathogènes sont également impliqués dans l'EH, notamment le stress oxydatif. Au cours de la MHC, le muscle joue un rôle compensatoire essentiel dans l'élimination de l'ammoniac par l'action de l'enzyme glutamine synthétase (GS), qui transforme le glutamate en glutamine. Étant donné que les cellules endothéliales de la BHE sont l'interface entre le sang et le cerveau, il est plausible qu'elles métabolisent l'ammoniac pour protéger le cerveau de la neurotoxicité induite par l'ammoniac. Cependant, cela n'a jamais fait l'objet d'études. Les thérapies de réduction de l'ammoniac sont les traitements courants de l'EH. Cependant, les réponses des patients aux traitements sont hétérogènes, et les différences de sexe pourraient en être la cause. Par conséquent, nos objectifs étaient 1) d'explorer le métabolisme de l'ammoniac dans les cellules endothéliales de la BHE par la présence de GS et 2) d'évaluer l'impact du sexe sur la MHC et ses complications, y compris la sarcopénie et l'EH. Méthodes : Pour le premier objectif, nous avons évalué l'expression et l'activité de la protéine GS in vitro et ex vivo chez des rats naïfs. Nous avons également évalué l'impact de l'ornithine, du glutamate et du α-kétoglutarate sur l'activité de la GS dans les cellules endothéliales de la BHE via la génération de glutamine 5-13C marquée. Pour le deuxième objectif, nous avons évalué l'impact du sexe sur le neurophénotype (anxiété, mémoire, coordination motrice et activité) chez des rats ligaturés des voies biliaires (BDL) (et contrôles respectifs) ainsi que sur le développement d'une EH sévère (léthargie/perte du réflexe de redressement). Nous avons également évalué les marqueurs des lésions hépatiques, l'hyperammoniémie, le stress oxydatif systémique, la masse et la fonction musculaire et la clairance de l'ammoniac musculaire. Résultats : Nous avons trouvé l'activité et l'expression de la GS in vivo et ex vivo dans les cellules endothéliales de la BHE. L'analyse au microscope confocal a montré que la GS dans les cellules endothéliales est moins abondante que dans les astrocytes. L'exposition de cellules endothéliales cultivées à des substrats marqués a révélé que l'ornithine est la plus efficace pour générer de la glutamine. Chez les femmes, la chirurgie BDL a provoqué une MHC (augmentation des enzymes hépatiques circulantes et de la bilirubine) et de l'EH (altération de la coordination motrice et de l'activité nocturne) par rapport aux rats contrôles respectifs. De plus, le degré d'hyperammoniémie et la clairance musculaire de l'ammoniac étaient similaires entre les sexes. Contrairement aux mâles, les rats femelles n'ont pas développé de perte musculaire, d'œdème cérébral et de perte de mémoire à court terme. De plus, les femelles présentaient un stress oxydatif plus faible et étaient complètement protégées contre les EH sévères précipitées par l'ammoniac par rapport aux mâles BDL. Conclusions : Nous concluons que la GS est exprimée dans les cellules endothéliales de la BHE, jouant peut-être un rôle dans l'atténuation ou le retard de l'entrée de l'ammoniac dans le cerveau et que la supplémentation en ornithine améliore l'activité de la GS en fournissant du glutamate pour la détoxification de l'ammoniac. De plus, nous concluons que le sexe a un impact sur les complications des maladies du foie, y compris la sarcopénie et l'EH, le stress oxydatif systémique jouant un rôle vital dans la susceptibilité à l'EH sévère induite par l'ammoniac. / Background and aims: Hepatic encephalopathy (HE) is a neuropsychiatric disorder and a major complication of chronic liver disease (CLD). HE manifests with a wide range of symptoms, from mild lack of attention and memory impairments to severe lethargy and coma. Hyperammonemia is central in the pathogenesis of HE since ammonia is neurotoxic, and blood-derived ammonia easily crosses the blood-brain barrier (BBB). However, other pathogenic factors are also implicated in HE, including oxidative stress. During CLD, muscle plays an essential compensatory role in removing ammonia by the action of the enzyme glutamine synthetase (GS), which amidates glutamate into glutamine. Since the endothelial cells of the BBB are the interface between the blood and the brain, it is plausible that they metabolize ammonia to protect the brain from ammonia-induced neurotoxicity. However, this has never been investigated. Ammonia lowering therapies are the mainstream treatments for HE. However, patients' response to treatments are heterogeneous, and sex differences might be the cause. Therefore, our aims were 1) To explore ammonia metabolism in BBB’s endothelial cells through the presence of GS and 2) to assess the impact of sex on CLD and its complications, including sarcopenia and HE. Methods: For the first aim, we assessed GS protein expression and activity in vitro and ex vivo in naïve rats. We also evaluated the impact of ornithine, glutamate, and α-ketoglutarate on GS activity in endothelial cells of the BBB via the generation of labeled 5-13C glutamine. For the second aim, we assessed the impact of sex on the neurophenotype (anxiety, memory, motor coordination, and activity) in bile-duct ligated (BDL) rats (and respective SHAMs) as well as on the development of an ammonia-precipitated severe HE (lethargy/loss of righting reflex). We also assessed liver injury markers, hyperammonemia, systemic oxidative stress, muscle mass and function, and muscle ammonia clearance. Results: We found GS activity and expression in vivo and ex vivo in endothelial BBB cells. The confocal microscope analysis showed that GS in endothelial cells is less abundant than astrocytes. Exposing cultured endothelial cells to labeled substrates revealed that ornithine is the most efficient in generating glutamine. In females, BDL surgery caused CLD (increased hepatic enzymes and bilirubin) and HE (impaired motor coordination and night activity) vs. respective SHAMs. Furthermore, the degree of hyperammonemia and muscle ammonia clearance was similar between sexes. Contrary to males, female rats did not develop muscle loss, brain edema, and short-term memory loss. In addition, females had lower oxidative stress and were completely protected against ammonia-precipitated severe HE compared to male BDLs. Conclusions: We conclude that GS is expressed in endothelial cells of the BBB, possibly playing a role in attenuating or delaying ammonia entry into the brain and, ornithine supplementation enhances GS activity by providing glutamate for ammonia detoxification. In addition, we conclude that sex impacts the complications of liver disease, including sarcopenia and HE, with systemic oxidative stress playing a vital role in the susceptibility to ammonia-induced overt HE.