Inhibitory regulation of FoxO1 in PPARδ expression drives mitochondria dysfunction and insulin resistance.

Forkhead box protein O1 (FoxO1) regulates muscle growth, but the metabolic role of FoxO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FoxO1 in skeletal muscle, we generated skeletal muscle-specific FoxO1 inducible knockout (mFoxO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFoxO1 iKO mice, and assessed the correlation between FoxO1 and mitochondrial-related protein in the skeletal muscle of diabetic patients. Obese mFoxO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FoxO1 in peroxisome proliferator-activated receptor δ (PPARδ) expression was confirmed in skeletal muscle and deletion of PPARδ abolished the beneficial effects of FoxO1 deficiency. FoxO1 protein levels were higher in the skeletal muscle of diabetic patients and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FoxO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FoxO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ.

Stimulation of muscle protein synthesis with low-dose amino acid composition in older individuals.

Essential amino acid (EAA)-based compositions have been shown to be effective stimulators of muscle protein synthesis, but the lower limit of effective dosage is not clear. We have used stable isotope tracer methodology to quantify the response of muscle protein fractional synthetic rate (FSR) to a dose of 3.6 g of a high-leucine composition of EAAs plus arginine in older subjects. Muscle protein FSR increased 0.058%/hour over 3 h following consumption. When account was taken of the total muscle mass, this increase in muscle protein FSR represented approximately 80% of ingested EAAs. We conclude that a low dose of an EAA-based composition can effectively stimulate muscle protein synthesis.

Metabolic effects of an essential amino acid supplement in adolescents with PCOS and obesity.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, insulin resistance, and hepatic steatosis (HS). Because dietary essential amino acid (EAA) supplementation has been shown to decrease HS in various populations, this study's objective was to determine whether supplementation would decrease HS in PCOS. METHODS: A randomized, double-blind, crossover, placebo-controlled trial was conducted in 21 adolescents with PCOS (BMI 37.3 ± 6.5 kg/m2, age 15.6 ± 1.3 years). Liver fat, very low-density lipoprotein (VLDL) lipogenesis, and triacylglycerol (TG) metabolism were measured following each 28-day phase of placebo or EAA. RESULTS: Compared to placebo, EAA was associated with no difference in body weight (p = 0.673). Two markers of liver health improved: HS was lower (-0.8% absolute, -7.5% relative reduction, p = 0.013), as was plasma aspartate aminotransferase (AST) (-8%, p = 0.004). Plasma TG (-9%, p = 0.015) and VLDL-TG (-21%, p = 0.031) were reduced as well. VLDL-TG palmitate derived from lipogenesis was not different between the phases, nor was insulin sensitivity (p > 0.400 for both). Surprisingly, during the EAA phase, participants reported consuming fewer carbohydrates (p = 0.038) and total sugars (p = 0.046). CONCLUSIONS: Similar to studies in older adults, short-term EAA supplementation in adolescents resulted in significantly lower liver fat, AST, and plasma lipids and thus may prove to be an effective treatment in this population. Additional research is needed to elucidate the mechanisms for these effects.

Short-Term Ingestion of Essential Amino Acid Based Nutritional Supplements or Whey Protein Improves the Physical Function of Older Adults Independently of Gut Microbiome.

SCOPE: Dietary proteins and essential amino acids (EAAs) are the major nutritional supplements that support the growth and activity of gut microbes contributing to the wellbeing of their host. This study hypothesizes that daily supplementation of the diet with either EAAs or whey protein for 12 weeks would improve the gut microbiome of older adults. METHODS AND RESULTS: The stool samples are processed and subjected to Illumina-based 16S ribosomal ribonucleic acid (rRNA) gene amplicon sequencing. In both groups, the most abundant families are found in order of relative abundance included: Bacteroidaceae, Lachnospiraceae, Ruminococcaceae, Prevotellaceae, Rikenellaceae, Enterobacteriaceae, Oscillospiraceae, Tannerellaceae, and Akkermansiaceae, which indicate that these subjects are able to maintain a same healthy microbial diversity in their guts. A significant finding is a reduction of proinflammatory cytokine, interleukin-18 (IL-18) in the EAAs group. It also uses the standard 6-min walking test (6MWT) as a measure of cardiopulmonary fitness. At the end of the study, the subjects in the EAAs group perform significantly better in the 6MWT as compared to the whey group. CONCLUSION: It seems plausible that the improved physical performance and reduced proinflammatory cytokine, IL-18 seen in the EAAs group, are independent of changes in gut microbiota.

The Importance of Dietary Protein Quality in Mid- to High-Income Countries.

In wealthy countries, the protein intake of adults is usually considered to be adequate, and considerations of protein quality are often deemed irrelevant. The objective was to examine dietary protein intakes of adults in developed countries in the context of dietary protein quality. An analysis of NHANES population data on actual protein intakes in the United States (a developed country) demonstrated that for a dietary Digestible Indispensable Amino Acid Score (DIAAS) of 100%, 11% of the adult (19-50 y) population had habitual protein intakes below the Estimated Average Requirement (EAR) and 22% below the Recommended Dietary Allowance. The percentage of the population with utilizable protein intakes potentially falling below the EAR increased as the assumed DIAAS declined. Analysis of the NHANES data and several other datasets also indicated that total protein intakes can be limiting or close to limiting for the elderly and some vegetarians and vegans. Here, lower dietary protein quality can potentially lead to inadequate utilizable protein intakes. For many people in specific physiological states (e.g., weight loss, endurance sports, resistance exercise) attempting to meet higher dietary protein targets often with accompanying lowered energy intakes, low dietary protein quality can lead to protein calories expressed as a proportion of total calories, falling outside what may be acceptable limits (maximum of 30% protein calories from total calories). In general, individuals within the adult population may be susceptible to macronutrient imbalance (whenever total protein intakes are high, daily energy intakes low) and for diets with lower protein quality (DIAAS <100%). Our analysis shows that dietary protein quality is relevant in mid- to high-income countries.

International Society of Sports Nutrition Position Stand: Effects of essential amino acid supplementation on exercise and performance.

Position Statement: The International Society of Sports Nutrition (ISSN) presents this position based on a critical examination of literature surrounding the effects of essential amino acid (EAA) supplementation on skeletal muscle maintenance and performance. This position stand is intended to provide a scientific foundation to athletes, dietitians, trainers, and other practitioners as to the benefits of supplemental EAA in both healthy and resistant (aging/clinical) populations. EAAs are crucial components of protein intake in humans, as the body cannot synthesize them. The daily recommended intake (DRI) for protein was established to prevent deficiencies due to inadequate EAA consumption. The following conclusions represent the official position of the Society: 1. Initial studies on EAAs' effects on skeletal muscle highlight their primary role in stimulating muscle protein synthesis (MPS) and turnover. Protein turnover is critical for replacing degraded or damaged muscle proteins, laying the metabolic foundation for enhanced functional performance. Consequently, research has shifted to examine the effects of EAA supplementation - with and without the benefits of exercise - on skeletal muscle maintenance and performance. 2. Supplementation with free-form EAAs leads to a quick rise in peripheral EAA concentrations, which in turn stimulates MPS. 3. The safe upper limit of EAA intake (amount), without inborn metabolic disease, can easily accommodate additional supplementation. 4. At rest, stimulation of MPS occurs at relatively small dosages (1.5-3.0 g) and seems to plateau at around 15-18 g. 5. The MPS stimulation by EAAs does not require non-essential amino acids. 6. Free-form EAA ingestion stimulates MPS more than an equivalent amount of intact protein. 7. Repeated EAA-induced MPS stimulation throughout the day does not diminish the anabolic effect of meal intake. 8. Although direct comparisons of various formulas have yet to be investigated, aging requires a greater proportion of leucine to overcome the reduced muscle sensitivity known as "anabolic resistance." 9. Without exercise, EAA supplementation can enhance functional outcomes in anabolic-resistant populations. 10. EAA requirements rise in the face of caloric deficits. During caloric deficit, it's essential to meet whole-body EAA requirements to preserve anabolic sensitivity in skeletal muscle.

Differential plasma protein expression after ingestion of essential amino acid-based dietary supplement verses whey protein in low physical functioning older adults.

In a recent randomized, double-blind, placebo-controlled trial, we were able to demonstrate the superiority of a dietary supplement composed of essential amino acids (EAAs) over whey protein, in older adults with low physical function. In this paper, we describe the comparative plasma protein expression in the same subject groups of EAAs vs whey. The plasma proteomics data was generated using SOMA scan assay. A total of twenty proteins were found to be differentially expressed in both groups with a 1.5-fold change. Notably, five proteins showed a significantly higher fold change expression in the EAA group which included adenylate kinase isoenzyme 1, casein kinase II 2-alpha, Nascent polypeptide-associated complex subunit alpha, peroxiredoxin-1, and peroxiredoxin-6. These five proteins might have played a significant role in providing energy for the improved cardiac and muscle strength of older adults with LPF. On the other hand, fifteen proteins showed slightly lower fold change expression in the EAA group. Some of these 15 proteins regulate metabolism and were found to be associated with inflammation or other comorbidities. Gene Ontology (GO) enrichment analysis showed the association of these proteins with several biological processes. Furthermore, protein-protein interaction network analysis also showed distinct networks between upregulated and downregulated proteins. In conclusion, the important biological roles of the upregulated proteins plus better physical function of participants in the EAAs vs whey group demonstrated that EAAs have the potential to improve muscle strength and physical function in older adults. This study was registered with ClinicalTrials.gov: NCT03424265 "Nutritional interventions in heart failure."

Essential amino acid enriched meal replacement improves body composition and physical function in obese older adults: A randomized controlled trial.

BACKGROUND: Older adults are threatened by the risk of muscle atrophy and excess accumulation of adipose tissue. The objective of this study was to determine whether an essential amino acid enriched meal replacement would reduce excess fat and foster skeletal muscle retention, potentially improving physical function in this cohort. METHODS: Using a double blind, randomized controlled trial, we compared the influence of an experimental meal replacement enriched with essential amino acids (EMR) to a commercially available, widely used meal replacement (Optifast®) provided once/day (q.d.) for four weeks on body composition, skeletal muscle and physical function in obese older participants. Twenty-eight individuals completed either EMR (n = 13) or Optifast® (n = 15) supplementation protocols. Measurements of body composition, thigh skeletal muscle cross-sectional area (CSA), blood panels, intrahepatic lipid, and physical function were completed pre- and post-supplementation. RESULTS: Body fat mass, visceral fat mass and volume, and intrahepatic lipid were reduced with EMR but not with Optifast®. Thigh muscle CSA increased (Δ 2.4 ± 3.0 cm2) with EMR but not Optifast® (Δ -1.8 ± 6.0 cm2). There was a significant increase in the distance covered during the 6-min walk test with EMR (Δ 23 ± 27 m) but no change in Optifast® (Δ 11 ± 37 m). CONCLUSIONS: Beneficial alterations in fat and muscle support the use of EMR-based meal replacements in obese older adults. CLINICAL TRIAL REGISTRATION: ISRCTN registry under Reference Number ISRCTN15814848.

Tracing metabolic flux to assess optimal dietary protein and amino acid consumption.

There is a general consensus that a dietary protein intake of 0.8 g protein/kg/day will prevent symptoms of protein deficiency in young, healthy individuals. However, individuals in many physiological circumstances may benefit from higher rates of dietary protein intake. Stable isotope tracer methodology enables a variety of approaches to assessing the optimal dietary protein intake in humans. In this paper, we present an overview of a variety of tracer methods, with a discussion of necessary assumptions, as well as the clinical circumstances in which different methods may be preferable. Although we discuss the nontracer method of nitrogen balance, which has historically been used to estimate dietary protein requirements, this paper primarily focuses on tracer methods for estimating dietary protein and essential amino acid requirements under different physiological conditions. We will explain the following approaches: isotopic measurement of urea production; the arterial-venous tracer balance method; measurement of the fractional synthetic and breakdown rates of muscle protein; the indicator and the direct amino acid oxidation methods; and different approaches to measuring whole-body protein synthesis and breakdown. The advantages and limitations of each method are discussed in the context of the optimal approaches for use under different circumstances.

Tracing metabolic flux in vivo: basic model structures of tracer methodology.

Molecules in living organisms are in a constant state of turnover at varying rates, i.e., synthesis, breakdown, oxidation, and/or conversion to different compounds. Despite the dynamic nature of biomolecules, metabolic research has focused heavily on static, snapshot information such as the abundances of mRNA, protein, and metabolites and/or (in)activation of molecular signaling, often leading to erroneous conclusions regarding metabolic status. Over the past century, stable, non-radioactive isotope tracers have been widely used to provide critical information on the dynamics of specific biomolecules (metabolites and polymers including lipids, proteins, and DNA), in studies in vitro in cells as well as in vivo in both animals and humans. In this review, we discuss (1) the historical background of the use of stable isotope tracer methodology in metabolic research; (2) the importance of obtaining kinetic information for a better understanding of metabolism; and (3) the basic principles and model structures of stable isotope tracer methodology using 13C-, 15N-, or 2H-labeled tracers.

Balanced Free Essential Amino Acids and Resistance Exercise Training Synergistically Improve Dexamethasone-Induced Impairments in Muscle Strength, Endurance, and Insulin Sensitivity in Mice.

Our previous study shows that an essential amino acid (EAA)-enriched diet attenuates dexamethasone (DEX)-induced declines in muscle mass and strength, as well as insulin sensitivity, but does not affect endurance. In the present study, we hypothesized that the beneficial effects will be synergized by adding resistance exercise training (RET) to EAA, and diet-free EAA would improve endurance. To test hypotheses, mice were randomized into the following four groups: control, EAA, RET, and EAA+RET. All mice except the control were subjected to DEX treatment. We evaluated the cumulative rate of myofibrillar protein synthesis (MPS) using 2H2O labeling and mass spectrometry. Neuromuscular junction (NMJ) stability, mitochondrial contents, and molecular signaling were demonstrated in skeletal muscle. Insulin sensitivity and glucose metabolism using 13C6-glucose tracing during oral glucose tolerance tests were analyzed. We found that EAA and RET synergistically improve muscle mass and/or strength, and endurance capacity, as well as insulin sensitivity, and glucose metabolism in DEX-treated muscle. These improvements are accomplished, in part, through improvements in myofibrillar protein synthesis, NMJ, fiber type preservation, and/or mitochondrial biogenesis. In conclusion, free EAA supplementation, particularly when combined with RET, can serve as an effective means that counteracts the adverse effects on muscle of DEX that are found frequently in clinical settings.

Prevention of Loss of Muscle Mass and Function in Older Adults during COVID-19 Lockdown: Potential Role of Dietary Essential Amino Acids.

As the COVID-19 pandemic became a global emergency, social distancing, quarantine, and limitations in outdoor activities have resulted in an environment of enforced physical inactivity (EPI). A prolonged period of EPI in older individuals accelerates the deterioration of skeletal muscle health, including loss of muscle mass and function, commonly referred to as sarcopenia. Sarcopenia is associated with an increased likelihood of the progression of diabetes, obesity, and/or depression. Well-known approaches to mitigate the symptoms of sarcopenia include participation in resistance exercise training and/or intake of balanced essential amino acids (EAAs) and high-quality (i.e., containing high EEAs) protein. As the pandemic situation discourages physical exercise, nutritional approaches, especially dietary EAA intake, could be a good alternative for counteracting against EPI-promoted loss of muscle mass and function. Therefore, in the present review, we cover (1) the impact of EPI-induced muscle loss and function on health, (2) the therapeutic potential of dietary EAAs for muscle health (e.g., muscle mass and function) in the EPI condition in comparison with protein sources, and finally (3) practical guidelines of dietary EAA intake for optimal anabolic response in EPI.

Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion.

BACKGROUND: Mitochondria are involved in cancer energy metabolism, although the mechanisms underlying the involvement of mitoribosomal dysfunction in hepatocellular carcinoma (HCC) remain poorly understood. Here, we investigated the effects of mitoribosomal impairment-mediated alterations on the immunometabolic characteristics of liver cancer. METHODS: We used a mouse model of HCC, liver tissues from patients with HCC, and datasets from The Cancer Genome Atlas (TCGA) to elucidate the relationship between mitoribosomal proteins (MRPs) and HCC. In a mouse model, we selectively disrupted expression of the mitochondrial ribosomal protein CR6-interacting factor 1 (CRIF1) in hepatocytes to determine the impact of hepatocyte-specific impairment of mitoribosomal function on liver cancer progression. The metabolism and immunophenotype of liver cancer was assessed by glucose flux assays and flow cytometry, respectively. RESULTS: Single-cell RNA-seq analysis of tumor tissue and TCGA HCC transcriptome analysis identified mitochondrial defects associated with high-MRP expression and poor survival outcomes. In the mouse model, hepatocyte-specific disruption of the mitochondrial ribosomal protein CRIF1 revealed the impact of mitoribosomal dysfunction on liver cancer progression. Crif1 deficiency promoted programmed cell death protein 1 expression by immune cells in the hepatic tumor microenvironment. A [U-13C6]-glucose tracer demonstrated enhanced glucose entry into the tricarboxylic acid cycle and lactate production in mice with mitoribosomal defects during cancer progression. Mice with hepatic mitoribosomal defects also exhibited enhanced progression of liver cancer accompanied by highly exhausted tumor-infiltrating T cells. Crif1 deficiency induced an environment unfavorable to T cells, leading to exhaustion of T cells via elevation of reactive oxygen species and lactate production. CONCLUSIONS: Hepatic mitoribosomal defects promote glucose partitioning toward glycolytic flux and lactate synthesis, leading to T cell exhaustion and cancer progression. Overall, the results suggest a distinct role for mitoribosomes in regulating the immunometabolic microenvironment during HCC progression.

Continuous oral stable isotope ingestion to measure whole-body protein turnover.

BACKGROUND & AIMS: Protein kinetic responses to nutrition and exercise interventions are commonly evaluated using a primed-constant infusion of stable isotope tracers. While this methodology is state-of-the-art, the required preparation at a certified pharmacy makes the utilization of isotope infusion both expensive and logistically cumbersome. Oral tracer ingestion has been used to quantify 24-h whole-body protein status; however, this does not permit examination of acute interventional effects. Ingestion of a priming bolus, followed by continuous ingestion of stable isotope tracer in a 'sip feeding' fashion may provide a more feasible alternative for quantifying acute kinetic responses. Therefore, the purpose of this study was to evaluate the viability of a primed continuous oral sip-ingestion method of stable isotope tracers for the evaluation of whole-body protein kinetics. METHODS: In a randomized, crossover design, eight healthy adults (63% female; Age: 29.4 ± 5.8 yrs; BMI: 24.3 ± 2.7 kg/m2) completed two, two-period stable isotope oral ingestion studies, consisting of a 3 h basal fasted period, followed by a 4-h post-ingestion period. After the basal period, subjects ingested either 6.3 g (Low) or 12.6 g (High) of an essential amino acid (EAA) enriched whey protein supplement. The continuous oral sip-feed method was initiated with a primed oral bolus dose of L-[ring-2H5]phenylalanine, L-[ring-2H2]tyrosine, and L-[ring-2H4]tyrosine, followed by oral sip doses of L-[ring-2H5]phenylalanine, L-[ring-2H2]tyrosine every 10 min to approximate steady state tracer enrichment. Blood samples were taken throughout the basal and post-meal periods to determine tracer enrichment. Whole-body net protein balance (NB), synthesis (PS), breakdown (PB), and exogenous hydroxylation were calculated for each period. Repeated measure ANOVAs (treatment × time) were used to assess differences in protein kinetics. RESULTS: Using the sip feed method, NB, PS, and hydroxylation were significantly increased with ingestion of protein (p < 0.05) during the postprandial period, regardless of amount of protein ingested; ΔNB from the postabsorptive to postprandial period was significantly greater for high compared to low protein (p = 0.026; low = 6.2 ± 5.1 g protein·240 min-1; high = 11.8 ± 3.9 g protein·240 min-1). CONCLUSION: The current study provides preliminary evidence that continuous oral sip-feeding of stable isotope tracer is a feasible method that provides physiologically relevant measures of protein metabolism. Assessments of variance and individual responses revealed high measurement variability with the sip-feed method compared to previously published constant infusion responses, but ΔNB, ΔPS, and ΔPB were comparable. In situations where constant infusion is not feasible, oral sip-feeding could be used as an alternative method for measurement of acute, postprandial protein metabolism.

The potential role of beef and nutrients found in beef on outcomes of wellbeing in healthy adults 50 years of age and older: A systematic review of randomized controlled trials.

Shifts in wellbeing and health occur as we age. As life expectancy increases, maintenance of wellbeing and health becomes increasingly important. Nutrients found in beef are associated with outcomes of wellbeing such as physical and cognitive function, lean body mass, and mood in older adults and individuals with chronic disease. However, it is unclear how beef and nutrients found in beef impact wellbeing in healthy adults ≥50 years of age. This study systematically reviewed evidence linking the intake of beef and nutrients found in beef to markers of wellbeing in healthy adults. PubMed, CINAHL, and Web of Science were searched up to August 31, 2021 for eligible randomized controlled trials (RCTs). Nutrients included in the analysis were beef, red meat, dietary protein, essential amino acids, branched chain amino acids, tryptophan, arginine, cysteine, glycine, glutamate, vitamin B6, vitamin B12, choline, zinc, and iron. We identified nine RCTs with results from 55 measurements of markers of wellbeing. An overall positive effect was found of beef and beef's nutrients on wellbeing. There was an overall positive effect of amino acids and protein on wellbeing, with no effect of arginine, vitamin B-12, leucine, and zinc. Physical function was also influenced by beef and nutrients found in beef. Eight of the studies found focused on specific nutrients found in beef, and not beef itself in older adults with one or more chronic diseases. This study identified a need for further research regarding the effect of beef and nutrients found in beef on defined functional outcomes of wellbeing in healthy adults ≥50 years of age.

Breastfeeding duration modifies the association between maternal weight status and offspring dietary palmitate oxidation.

BACKGROUND: Offspring of obese rodents develop a metabolic phenotype that favors fat deposition. Data regarding the impact of maternal obesity programing of offspring fuel usage in humans is scarce. OBJECTIVE: The objective of this study was to explore the association between maternal weight status and dietary palmitate oxidation (DPO) in 2-y-old offspring, taking into consideration potential confounders and modifiers. METHODS: Women (n = 56) were enrolled by the first trimester of gestation. Maternal physical activity (PA; measured with accelerometers) at enrollment and gestational weight gain (GWG) were measured. Offspring sex, race, and breastfeeding (BF) duration were self-reported. Human milk (HM) composition was determined at 6 mo postpartum. At age 2 y, dietary quality [healthy eating index (HEI)] and parental feeding practices [Child Feeding Questionnaire (CFQ)] were assessed. DPO in 2-y-olds (2-yo-DPO) was measured using deuterated palmitic acid. Generalized linear regression analysis was used to model the associations of 2-yo-DPO with maternal weight status [normal weight (NW), BMI <25 (in kg/m2) compared with excessive weight (EW), BMI ≥25]. RESULTS: DPO was higher in offspring of women with EW compared with NW (2.1 ± 1.2%/h compared with 1.4 ± 0.7%/h, P = 0.03). Maternal weight status interacted with BF duration in association with 2-yo-DPO (log ß: 0.05, P = 0.04). Specifically, 2-yo-DPO was higher in the EW compared with NW group if BF duration was ≥9 mo. HM insulin (log ß: 0.35, P = 0.002) and HM leptin (log ß: 0.81, P = 0.001) concentrations directly associated with 2-yo-DPO. PA (log ß: 0.06, P = 0.013), parental feeding restriction (log ß: 0.05, P < 0.0001), and male sex (log ß: 0.54, P < 0.001) were positively associated with 2-yo-DPO. HEI was negatively associated with 2-yo-DPO (log ß:-0.03, P < 0.0001). CONCLUSIONS: Higher 2-yo-DPO in offspring of women with EW compared with NW were driven by BF duration. Higher HM insulin and leptin concentrations in women with EW may explain these finding. More studies are needed to confirm these results. This trial was registered at clinicaltrials.gov as NCT03281850.

Essential Amino Acid-Enriched Diet Alleviates Dexamethasone-Induced Loss of Muscle Mass and Function through Stimulation of Myofibrillar Protein Synthesis and Improves Glucose Metabolism in Mice.

Dexamethasone (DEX) induces dysregulation of protein turnover, leading to muscle atrophy and impairment of glucose metabolism. Positive protein balance, i.e., rate of protein synthesis exceeding rate of protein degradation, can be induced by dietary essential amino acids (EAAs). In this study, we investigated the roles of an EAA-enriched diet in the regulation of muscle proteostasis and its impact on glucose metabolism in the DEX-induced muscle atrophy model. Mice were fed normal chow or EAA-enriched chow and were given daily injections of DEX over 10 days. We determined muscle mass and functions using treadmill running and ladder climbing exercises, protein kinetics using the D2O labeling method, molecular signaling using immunoblot analysis, and glucose metabolism using a U-13C6 glucose tracer during oral glucose tolerance test (OGTT). The EAA-enriched diet increased muscle mass, strength, and myofibrillar protein synthesis rate, concurrent with improved glucose metabolism (i.e., reduced plasma insulin concentrations and increased insulin sensitivity) during the OGTT. The U-13C6 glucose tracing revealed that the EAA-enriched diet increased glucose uptake and subsequent glycolytic flux. In sum, our results demonstrate a vital role for the EAA-enriched diet in alleviating the DEX-induced muscle atrophy through stimulation of myofibrillar proteins synthesis, which was associated with improved glucose metabolism.