Effect of amino acid supplementation on skeletal muscle during acute immobilization in hospitalized elderly subjects: possible impact on mitochondria

Objective: Older patients are frequently subjected to prolonged hospitalization and extended bed rest, with a negative effect on physical activity and caloric intake. This results in a consistent loss of muscle mass and function, which is associated with functional decline and high mortality. Furthermore, acute muscle disuse can precipitate sarcopenia, defined as the age-dependent loss of muscle mass and function. The aim of this study was to investigate the effect of oral amino acid (AA) supplementation in acute immobilization. We also aimed to characterize the effect and mechanism of the AA mixture in a rodent model of skeletal muscle atrophy, focusing on mitochondrial function. Methods: In the human study, hospitalized older patients (69-87) were included in the control group (n = 50) or were administered 25 g of AA mixture (n = 44) twice daily throughout 7 d of low mobility. We collected data related to length of stay as primary outcome measure. In-hospital mortality, 90-d post-discharge mortality, 90-d post-discharge rehospitalization, and falls also were considered. Moreover, variations of anthropometric measures, body composition and muscle architecture/strength, circulating interleukins, and oxidative stress markers between the beginning and the end of the supplementation period were analyzed as secondary outcomes. In the animal study, C57/Bl6 mice underwent immobilization of one hindlimb by stapling the foot exploiting normal dorsotibial flexion. Age-matched mice that never had their hindlimbs immobilized were used as controls. Sub-groups of mice subjected to the immobilization procedure were administered the AA mixture in drinking water (I+A) and were compared to a placebo group (I+P). After 10 days, muscle function was studied by both endurance running and grip strength tests. Tibialis anterior (TA) muscles were excised and used for mitochondrial isolation. 2 Results: Similar values were reported between the two groups regarding age, body weight, and body mass index. Although no difference in terms of in-hospital, 90-d post-discharge, or overall mortality rate was observed between the two groups, a reduction in length of stay, 90-d post-discharge hospitalization, and falls was observed in the AA supplementation group rather than in controls. Furthermore, the AA mixture limited muscle architecture/strength impairment and circulating oxidative stress, which occurred during hospitalization-related bed rest. The latter data was associated with increased circulating levels of anti-inflammatory cytokines interleukin-4 and -10. In animals, hindlimb immobilization reduced maximal running times and distances, along with limb grip strength; however, the extent of reduction was lower in I+A than I+P mice. Immobilization resulted in TA atrophy, characterized by a reduction in both wet weight and TA/body weight ratio. Interestingly, these alterations were slightly observed in mice treated with the AA mixture. The mitochondrial yield from TA of I+P mice was lower than controls; of note, the mitochondrial yield from TA of I+A animals was similar to controls. AA mixture administration also preserved mitochondrial bioenergetics and oxidative damage in TA muscle, which was disrupted in I+P mice with respect to controls. Conclusions: These results suggest that the AA mixture limits several alterations associated with low mobility in older hospitalized patients, such as length of stay, 90-d post-discharge hospitalization, and falls, preventing the loss of muscle function, as well as the increase of circulating interleukins and oxidative stress markers. Furthermore, this study demonstrates that the AA mixture prevents loss of muscle mass and function in skeletal muscle atrophy by protecting mitochondria. Other than providing a further link between mitochondria and proteostatic maintenance to muscle atrophy, these results encourage further research aimed at targeting mitochondria to treat sarcopenia

Mitochondrial Impairment in Sarcopenia

Sarcopenia is defined by the age-related loss of skeletal muscle quality, which relies on mitochondrial homeostasis. During aging, several mitochondrial features such as bioenergetics, dynamics, biogenesis, and selective autophagy (mitophagy) are altered and impinge on protein homeostasis, resulting in loss of muscle mass and function. Thus, mitochondrial dysfunction contributes significantly to the complex pathogenesis of sarcopenia, and mitochondria are indicated as potential targets to prevent and treat this age-related condition. After a concise presentation of the age-related modifications in skeletal muscle quality and mitochondrial homeostasis, the present review summarizes the most relevant findings related to mitochondrial alterations in sarcopenia

Redox Homeostasis and Immune Alterations in Coronavirus Disease-19

The global Coronavirus Disease 2019 (COVID-19) pandemic is characterized by a wide variety of clinical features, from no or moderate symptoms to severe illness. COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that first affects the respiratory tract. Other than being limited to lungs, SARS-CoV-2 may lead to a multisystem disease that can even be durable (long COVID). The clinical spectrum of COVID-19 depends on variability in the immune regulation. Indeed, disease progression is consequent to failure in the immune regulation, characterized by an intensification of the pro-inflammatory response. Disturbance of systemic and organ-related redox balance may be a further mechanism underlying variability in COVID-19 severity. Other than being determinant for SARS-CoV-2 entry and fusion to the host cell, reactive species and redox signaling are deeply involved in the immune response. This review sums up the present knowledge on the role of redox balance in the regulation of susceptibility to SARS-CoV-2 infection and related immune response, debating the effectiveness of antioxidant compounds in the management of COVID-19

Mitochondrial Impairment in Sarcopenia

Sarcopenia is defined by the age-related loss of skeletal muscle quality, which relies on mitochondrial homeostasis. During aging, several mitochondrial features such as bioenergetics, dynamics, biogenesis, and selective autophagy (mitophagy) are altered and impinge on protein homeostasis, resulting in loss of muscle mass and function. Thus, mitochondrial dysfunction contributes significantly to the complex pathogenesis of sarcopenia, and mitochondria are indicated as potential targets to prevent and treat this age-related condition. After a concise presentation of the age-related modifications in skeletal muscle quality and mitochondrial homeostasis, the present review summarizes the most relevant findings related to mitochondrial alterations in sarcopenia

Muscle Delivery of Mitochondria-Targeted Drugs for the Treatment of Sarcopenia: Rationale and Perspectives

An impairment in mitochondrial homeostasis plays a crucial role in the process of aging and contributes to the incidence of age-related diseases, including sarcopenia, which is defined as an age-dependent loss of muscle mass and strength. Mitochondrial dysfunction exerts a negative impact on several cellular activities, including bioenergetics, metabolism, and apoptosis. In sarcopenia, mitochondria homeostasis is disrupted because of reduced oxidative phosphorylation and ATP generation, the enhanced production of reactive species, and impaired antioxidant defense. This review re-establishes the most recent evidence on mitochondrial defects that are thought to be relevant in the pathogenesis of sarcopenia and that may represent promising therapeutic targets for its prevention/treatment. Furthermore, we describe mechanisms of action and translational potential of promising mitochondria-targeted drug delivery systems, including molecules able to boost the metabolism and bioenergetics, counteract apoptosis, antioxidants to scavenge reactive species and decrease oxidative stress, and target mitophagy. Even though these mitochondria-delivered strategies demonstrate to be promising in preclinical models, their use needs to be promoted for clinical studies. Therefore, there is a compelling demand to further understand the mechanisms modulating mitochondrial homeostasis, to characterize powerful compounds that target muscle mitochondria to prevent sarcopenia in aged people

Controlling Nutritional Status (CONUT) Score as a Predictive Marker in Hospitalized Frail Elderly Patients

: The Controlling Nutritional Status (CONUT) score is a simple screening tool able to detect altered nutritional status as well as to predict clinical adverse outcomes in specific populations. No data are available in frail patients. This study aims to investigate the predictive role of the CONUT score on mortality and length of stay (LOS) in frail patients admitted to an Internal Medicine Department. We consecutively enrolled 246 patients aged 65 years or older, divided into two groups based on frailty status. The two groups were further divided according to low (<5) or high (≥5) CONUT score. Length of stay (LOS) was higher in frail patients than not-frail patients, as well as in the frail group with high CONUT scores compared to the frail group with low CONUT scores. Multiple linear regression showed an increase of 2.1 days for each additional point to the CONUT score. In-hospital mortality was higher in frail compared to not-frail patients, but it did not differ between frail patients with high CONUT scores and frail patients with low CONUT scores. An analysis of the survival curve for 30-day mortality showed a higher mortality rate for frail/high-CONUT-score patients as compared to the not-frail/low-CONUT-score group. The CONUT score shows high prognostic value for higher LOS-but not mortality-in the clinical setting of internal medicine departments for old frail patients

Cardioprotective Effects of Resveratrol in the Mediterranean Diet: A Short Narrative Review

The beneficial effects of a Mediterranean diet are due to the numerous active compounds in the food and, particularly, the high concentration of compounds with synergistically acting antioxidant properties. Resveratrol, a stilbenoid nonflavonoid phenol, is an antioxidant that is naturally produced by numerous plants as a defensive agent in response to attacks from pathogens, such as bacteria and fungi. Resveratrol has several effects on human health, including on the lipid profile, where it primarily downregulates the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, reducing the synthesis of cholesterol. Resveratrol also increases the expression of LDL receptors in the liver, contributing to the reduction in the LDL-cholesterol levels. This short narrative review, based on relevant articles written in English from a PubMed search, using the keywords “resveratrol”, “atherosclerosis”, “cardiovascular disease”, and “Mediterranean Diet“, focuses on the possible effects of this molecule on cardiovascular disease, lipid metabolism, and atherosclerosis

Malnutrition in Hospitalized Old Patients: Screening and Diagnosis, Clinical Outcomes, and Management

Malnutrition in hospitalized patients heavily affects several clinical outcomes. The prevalence of malnutrition increases with age, comorbidities, and intensity of care in up to 90% of old populations. However, malnutrition frequently remains underdiagnosed and undertreated in the hospital. Thus, an accurate screening to identify patients at risk of malnutrition or malnourishment is determinant to elaborate a personal nutritional intervention. Several definitions of malnutrition were proposed in the last years, affecting the real frequency of nutritional disorders and the timing of intervention. Diagnosis of malnutrition needs a complete nutritional assessment, which is often challenging to perform during a hospital stay. For this purpose, various screening tools were proposed, allowing patients to be stratified according to the risk of malnutrition. The present review aims to summarize the actual evidence in terms of diagnosis, association with clinical outcomes, and management of malnutrition in a hospital setting

Adherence to Mediterranean Diet, Malnutrition, Length of Stay and Mortality in Elderly Patients Hospitalized in Internal Medicine Wards

This investigation aimed to explore the adherence to a Mediterranean Diet and its relationship with length of stay and in-hospital mortality, circulating interleukins, body composition, and frailty, in elderly patients hospitalized in internal medicine wards. Thus, a cross-sectional study in 194 acute hospitalized, community-dwelling elderly patients was performed. Adherence to a Mediterranean Diet was evaluated by the Italian Mediterranean Index (IMI). Length of stay, but not in-hospital mortality rate, was higher in patients with a low IMI score, as compared to subjects with high IMI score. Markers of systemic inflammation, as well as circulating interleukin-6 and tumor necrosis factor alpha, were higher in patients with a low IMI score, with respect to patients with high IMI score. Furthermore, patients with low IMI score had increased fat mass and reduced lean mass, together with a higher prevalence of frailty, as compared to those presenting with high IMI score. In a multivariate logistic regression model, an IMI score < 3 resulted as an independent predictor of longer length of stay. In conclusion, low adherence to a Mediterranean Diet in elderly patients hospitalized in internal medicine wards is associated with higher length of stay and related to unfavorable changes in circulating pro-inflammatory markers and body composition

Association between Controlling Nutritional Status (CONUT) Score and Body Composition, Inflammation and Frailty in Hospitalized Elderly Patients

The Controlling Nutritional Status (CONUT) score has demonstrated its ability to identify patients with poor nutritional status and predict various clinical outcomes. Our objective was to assess the association between the CONUT score, inflammatory status, and body composition, as well as its ability to identify patients at risk of frailty in hospitalized elderly patients. Methods: a total of 361 patients were retrospectively recruited and divided into three groups based on the CONUT score. Results: patients with a score ≥5 exhibited significantly higher levels of inflammatory markers, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Neutrophil/Lymphocytes ratio (NLR), main platelet volume (MPV), and ferritin, compared to those with a lower score. Furthermore, these patients showed unfavorable changes in body composition, including a lower percentage of skeletal muscle mass (MM) and fat-free mass (FFM) and a higher percentage of fatty mass (FM). A positive correlation was found between the CONUT score and inflammatory markers, Geriatric Depression Scale Short Form (GDS-SF), and FM. Conversely, the Mini Nutritional Assessment (MNA), Mini-Mental Status Examination, activity daily living (ADL), instrumental activity daily living (IADL), Barthel index, FFM, and MM showed a negative correlation. Frailty was highly prevalent among patients with a higher CONUT score. The receiver operating characteristic (ROC) curve demonstrated high accuracy in identifying frail patients (sensitivity). Conclusions: a high CONUT score is associated with a pro-inflammatory status as well as with unfavorable body composition. Additionally, it is a good tool to identify frailty among hospitalized elderly patients