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Summary: Dysphagia and difficulty swallowing, lead to a heightened risk of respiratory disorders and malnutrition. This study aimed to assess the physicochemical and sensory properties of a branched‐chain amino acids‐fortified perilla mousse (PM) and its retorted version (RPM) to determine their suitability for dysphagia patients. PM and RPM were evaluated for texture, colour, free amino acids content, sensory acceptance, and the International Dysphagia Diet Standardisation Initiative (IDDSI) levels were determined. The results showed that PM and RPM met IDDSI Levels 3–4. RPM exhibited a redder, darker colour and a firmer texture compared with PM. Moreover, RPM showed no syneresis and maintained high viscoelasticity from 20 °C to 80 °C. Additionally, retort sterilisation increased essential amino acid levels in RPM, and it received high sensory acceptance. This mousse offers a promising option for dysphagia patients, providing enhanced nutritional value with ease of swallowing. Future research should explore the long‐term impacts on dysphagia management. [ABSTRACT FROM AUTHOR]

Aims: Elevated plasma branched‐chain amino acids (BCAAs) are tightly linked to incident diabetes and its complications, while lower BCAAs are associated with adverse outcomes in the elderly and heart failure (HF) patients. The interplay between body compositions and plasma BCAAs, especially under the influence of co‐morbid diabetes in HF patients, is not well understood. Here, we examined the impact of diabetes on the prognostic value of plasma BCAA and its association with body compositions in HF patients. Methods and results: We retrospectively examined 301 HF patients (70 ± 15 years old; 59% male), among which 36% had diabetes. Blood samples for plasma BCAA measurements were collected in a fasting state after stabilization of HF and analysed using ultraperformance liquid chromatography. A dual‐energy X‐ray absorptiometry scan assessed regional body compositions, and muscle wasting was defined as appendicular skeletal muscle mass index (ASMI) < 7.00 and <5.40 kg/m2 for males and females, respectively, according to the criteria of the Asian Working Group for Sarcopenia. Although analyses of covariance revealed that plasma BCAAs were significantly higher in diabetic patients, low valine (<222.1 nmol/mL) similarly predicted adverse events defined by HF hospitalization, lethal arrhythmia, or all‐cause death in both diabetic and non‐diabetic patients independently of age, sex, and NT‐proBNP (adjusted hazard ratio [HR] 3.1, 95% confidence interval [CI] of 1.1–8.6 and adjusted HR 2.67, 95% CI 1.1–6.5, respectively; P for interaction 0.88). In multivariate linear regression analyses comprising age, sex, and regional body compositions as explanatory variables, plasma BCAAs were positively correlated with visceral adipose tissue area in non‐diabetic patients (standardized β coefficients [β] = 0.44, P < 0.001). In contrast, in diabetic patients, plasma BCAAs were correlated positively with ASMI (β = 0.49, P = 0.001) and negatively with appendicular fat mass index (AFMI; β = −0.42, P = 0.004). Co‐morbid diabetes was independently associated with muscle wasting (adjusted odds ratio 2.1, 95% CI 1.1–4.0) and significantly higher plasma 3‐methylhistidine level, a marker of myofibrillar degradation. In diabetic patients, ASMI uniquely showed a J‐shaped relationship with AFMI, and in a subgroup of HF patients with muscle wasting, diabetic patients showed 12% higher AFMI than non‐diabetic patients despite comparable ASMI reductions. Conclusions: Despite higher plasma BCAA levels in HF patients with diabetes, the prognostic value of low valine remained consistent regardless of diabetes status. However, low BCAAs were distinctly associated with fatty muscle degeneration in the extremities in diabetic patients, suggesting the importance of targeted interventions to prevent such tissue remodelling in this population. [ABSTRACT FROM AUTHOR]

Elevated levels of D-2-hydroxyglutarate (D-2HG) and L-2-hydroxyglutarate (L-2HG) in the brain are associated with various pathological conditions, potentially contributing to neurological symptoms and neurodegeneration. Previous studies on animal models have revealed their capability to interfere with several cellular processes, including mitochondrial metabolism. Both enantiomers competitively inhibit the enzymatic activity of 2-oxoglutarate-dependent dioxygenases. These enzymes also execute several signaling cascades and regulate the level of covalent modifications on nucleic acids or proteins, e.g., methylation, hydroxylation, or ubiquitination, with an effect on epigenetic regulation of gene expression, protein stability, and intracellular signaling. To investigate the potential impact of 2HG enantiomers on human neuronal cells, we utilized the SH-SY5Y human neuroblastoma cell line as a model. We employed proton nuclear magnetic resonance (1H-NMR) spectroscopy of culture media that provided high-resolution insights into the changes in the content of metabolites. Concurrently, we performed biochemical assays to complement the 1H-NMR findings and to estimate the activities of lactate and 3-hydroxybutyrate dehydrogenases. Our results reveal that both 2HG enantiomers can influence the cellular metabolism of human neuroblastoma cells on multiple levels. Specifically, both enantiomers of 2HG comparably stimulate anaerobic metabolism of glucose and inhibit the uptake of several essential amino acids from the culture media. In this respect, both 2HG enantiomers decreased the catabolism capability of cells to incorporate the leucine-derived carbon atoms into their metabolism and to generate the ketone bodies. These results provide evidence that both enantiomers of 2HG have the potential to influence the metabolic and molecular aspects of human cells. Furthermore, we may propose that increased levels of 2HG enantiomers in the brain parenchyma may alter brain metabolism features, potentially contributing to the etiology of neurological symptoms in patients. [ABSTRACT FROM AUTHOR]

Astrocytes are considered to possess a noticeable role in brain metabolism and, as a partners in neuron–glia cooperation, to contribute to the synthesis, bioconversion, and regulation of the flux of substrates for neuronal metabolism. With the aim of investigating to what extent human astrocytes are metabolizing amino acids and by which compounds are they enriching their surroundings, we employed a metabolomics analysis of their culture media by 1H-NMR. In addition, we compared the composition of media with either 5 mM or 25 mM glucose. The quantitative analysis of culture media by 1H-NMR revealed that astrocytes readily dispose from their milieu glutamine, branched-chain amino acids, and pyruvate with significantly high rates, while they enrich the culture media with lactate, branched-chain keto acids, citrate, acetate, ketone bodies, and alanine. Hyperglycemia suppressed the capacity of astrocytes to release branched-chain 2-oxo acids, while stimulating the generation of ketone bodies. Our results highlight the active involvement of astrocytes in the metabolism of several amino acids and the regulation of key metabolic intermediates. The observed metabolic activities of astrocytes provide valuable insights into their roles in supporting neuronal function, brain metabolism, and intercellular metabolic interactions within the brain. Understanding the complex metabolic interactions between astrocytes and neurons is essential for elucidating brain homeostasis and the pathophysiology of neurological disorders. The observed metabolic activities of astrocytes provide hints about their putative metabolic roles in brain metabolism. [ABSTRACT FROM AUTHOR]

Abstract Aims Elevated plasma branched‐chain amino acids (BCAAs) are tightly linked to incident diabetes and its complications, while lower BCAAs are associated with adverse outcomes in the elderly and heart failure (HF) patients. The interplay between body compositions and plasma BCAAs, especially under the influence of co‐morbid diabetes in HF patients, is not well understood. Here, we examined the impact of diabetes on the prognostic value of plasma BCAA and its association with body compositions in HF patients. Methods and results We retrospectively examined 301 HF patients (70 ± 15 years old; 59% male), among which 36% had diabetes. Blood samples for plasma BCAA measurements were collected in a fasting state after stabilization of HF and analysed using ultraperformance liquid chromatography. A dual‐energy X‐ray absorptiometry scan assessed regional body compositions, and muscle wasting was defined as appendicular skeletal muscle mass index (ASMI)

Abstract Background Emerging evidence suggests that alterations in BCAA metabolism may contribute to the pathogenesis of sarcopenia. However, the relationship between branched-chain amino acids (BCAAs) and sarcopenia is incompletely understood, and existing literature presents conflicting results. In this study, we conducted a community-based study involving > 100,000 United Kingdom adults to comprehensively explore the association between BCAAs and sarcopenia, and assess the potential role of muscle mass in mediating the relationship between BCAAs and muscle strength. Methods Multivariable linear regression analysis examined the relationship between circulating BCAAs and muscle mass/strength. Logistic regression analysis assessed the impact of circulating BCAAs and quartiles of BCAAs on sarcopenia risk. Subgroup analyses explored the variations in associations across age, and gender. Mediation analysis investigated the potential mediating effect of muscle mass on the BCAA-muscle strength relationship. Results Among 108,017 participants (mean age: 56.40 ± 8.09 years; 46.23% men), positive associations were observed between total BCAA, isoleucine, leucine, valine, and muscle mass (beta, 0.56–2.53; p

Background: Emerging evidence suggests that alterations in BCAA metabolism may contribute to the pathogenesis of sarcopenia. However, the relationship between branched-chain amino acids (BCAAs) and sarcopenia is incompletely understood, and existing literature presents conflicting results. In this study, we conducted a community-based study involving > 100,000 United Kingdom adults to comprehensively explore the association between BCAAs and sarcopenia, and assess the potential role of muscle mass in mediating the relationship between BCAAs and muscle strength. Methods: Multivariable linear regression analysis examined the relationship between circulating BCAAs and muscle mass/strength. Logistic regression analysis assessed the impact of circulating BCAAs and quartiles of BCAAs on sarcopenia risk. Subgroup analyses explored the variations in associations across age, and gender. Mediation analysis investigated the potential mediating effect of muscle mass on the BCAA-muscle strength relationship. Results: Among 108,017 participants (mean age: 56.40 ± 8.09 years; 46.23% men), positive associations were observed between total BCAA, isoleucine, leucine, valine, and muscle mass (beta, 0.56–2.53; p < 0.05) and between total BCAA, leucine, valine, and muscle strength (beta, 0.91–3.44; p < 0.05). Logistic regression analysis revealed that increased circulating valine was associated with a 47% reduced sarcopenia risk (odds ratio = 0.53; 95% confidence interval = 0.3–0.94; p = 0.029). Subgroup analyses demonstrated strong associations between circulating BCAAs and muscle mass/strength in men and individuals aged ≥ 60 years. Mediation analysis suggested that muscle mass completely mediated the relationship between total BCAA, and valine levels and muscle strength, partially mediated the relationship between leucine levels and muscle strength, obscuring the true effect of isoleucine on muscle strength. Conclusion: This study suggested the potential benefits of BCAAs in preserving muscle mass/strength and highlighted muscle mass might be mediator of BCAA-muscle strength association. Our findings contribute new evidence for the clinical prevention and treatment of sarcopenia and related conditions involving muscle mass/strength loss. [ABSTRACT FROM AUTHOR]

The primary objective of this investigation was to explore the beneficial impacts of Enteromorpha prolifera polysaccharide (EP) on dysglycemia in Zucker diabetic fatty (ZDF) rats, while also shedding light on its potential mechanism using 1H‐NMR‐based metabolomics. The results demonstrated a noteworthy reduction in fasting blood glucose (FBG, 46.3%), fasting insulin (50.17%), glycosylated hemoglobin A1c (HbA1c, 44.1%), and homeostatic model assessment of insulin resistance (HOMA‐IR, 59.75%) following EP administration, while the insulin sensitivity index (ISI, 19.6%) and homeostatic model assessment of β‐cell function (HOMA‐β, 2.5‐fold) were significantly increased. These findings indicate that EP enhances β‐cell function, increases insulin sensitivity, and improves insulin resistance caused by diabetes. Moreover, EP significantly reduced serum lipid levels, suggesting improvement of dyslipidemia. Through the analysis of serum metabolomics, 17 metabolites were found to be altered in diabetic rats, 14 of which were upregulated and 3 of which were downregulated. Notably, the administration of EP successfully reversed the abnormal levels of 9 out of the 17 metabolites. Pathway analysis further revealed that EP treatment partially restored metabolic dysfunction, with notable effects observed in valine, leucine, and isoleucine metabolism; aminoacyl‐transfer RNA (tRNA) biosynthesis; and ketone body metabolism. These findings collectively indicate the potential therapeutic efficacy of EP in preventing glycemic abnormalities and improving insulin resistance. Thus, EP holds promise as a valuable treatment option for individuals with diabetes. [ABSTRACT FROM AUTHOR]

Epidemiologic studies show high circulating Branched-chain amino acids (BCAA) are associated with excess body weight, impaired fasting glucose, insulin resistance, high blood pressure, and dyslipidemia. There is scarce data on the association between renal function and circulating levels of BCAA. Therefore, we aim to study this association in a sample of the Brazilian Longitudinal Study of Adults (ELSA-Brasil) We analyzed participants who had at the baseline BCAA: valine, isoleucine, and leucine measured through nuclear magnetic resonance. The outcomes evaluated were estimated glomerular function (eGFR - CKD-EPI without race) and 12h-albumin-creatinine ratio (ACR). In addition, we built unadjusted and adjusted multivariable linear regression models to investigate the association between the BCAA (total and individual) and eGFR and ACR. We studied 4912 participants (age 51.7(±9.0) years, 53.4% women, 59.5% White (59.5%), 32.7% hypertension, and 18.2% diabetes). The mean BCAA level was 429.15 ± 87.15. The mean eGFR was 84.95 ± 15 ml/min/1.73 m2, and the median ACR was 6.5 (1.8–4920) mg/g. Descriptive analyses comparing eGFR stratified <60 ml/min/1.73 m2 and ACR≥30 mg/g demonstrate that BCAA levels are higher in patients with eGFR<60 and ACR ≥30. Regarding eGFR, an inverse association was detected with BCAA levels when adjusted for demographic variables, and it is not maintained after adjustments for other confounders. Also, a positive association was found for ACR≥30 mg/g, and BCAA levels, and this association is not confirmed after adjustments. BCAA levels were inversely associated with eGFR and positively associated with ACR. Further studies are necessary to allow the comprehension of those associations. [ABSTRACT FROM AUTHOR]

Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy.

IntroductionOne major challenge of reducing salt content in food is the risk of the overall taste becoming bland. Enhancing saltiness is an effective strategy for salt reduction, and the development of salt-reduced foods using these saltiness-enhancing flavorants as food additives is underway. However, an increasing number of consumers demand a reduction in additives in clean-label foods.ObjectiveEnzyme processing of food is an attractive strategy for developing clean-label foods because enzymes are not considered additives. We aimed to improve the saltiness and umami intensity of vegetable soups by enzyme treatment while meeting clean-label requirements. We first optimized the enzymatic reaction conditions of a protease and glutaminase blend and then investigated the synergistic effects of this enzyme blend on the taste of vegetable soup.ResultsSensory evaluations indicated that the reaction products (e.g., protein hydrolysates or amino acids) could enhance the umami, kokumi, and saltiness intensity of vegetable soup supplemented with 0.5% NaCl. Notably, the saltiness intensity ratio of the enzyme-treated soup with 0.50, 0.45, and 0.40% NaCl were increased by 1.31-, 1.16-, and 0.99-fold, respectively, when this ratio for the control soup with 0.50% NaCl was set to 1.0. This indicates a 20% salt reduction rate can be achieved by enzyme treatment. Moreover, we found that these enhancements were synergically caused by enzyme-produced glutamic acid and branched-chain amino acids.ConclusionOur findings suggest that using enzyme blends of bacterial and fungal proteases and glutaminase is an effective approach to enhancing the saltiness levels of vegetable soups while meeting clean-label requirements.

Abstract Background Branched-chain amino acid (BCAA) supplementation is one of the most popular strategies used by the general population and athletes to reduce muscle soreness and accelerate the recovery process of muscle damage biomarkers after an intense exercise or training session. Objectives This systematic review and meta-analysis investigated the effects of BCAA supplementation on muscle damage biomarkers and muscle soreness after exercise-induced muscle damage (EIMD). Methods The systematic literature search for randomized controlled trials was conducted using seven databases, up to September 13th, 2022. The eligibility criteria for selecting studies were as follows: studies performed on healthy active participants, using BCAA at least once, controlled with a placebo or control group, performing resistance or endurance exercises, and followed up at least once post-EIMD. The methodological quality of the studies was assessed using the “SIGN RCT checklist”. Random-effects meta-analyses were processed to compute the standardized mean difference (Hedges’ g). Meta-regression analyses were completed with daily and total dosage and supplementation as continuous moderator variables. Results Of the 18 studies included in this meta-analysis, 13 were of high quality and five were of acceptable quality. Our results revealed BCAA supplementation elicits a significant effect on reducing creatine kinase (CK) levels immediately (g = − 0.44; p = 0.006) and 72 h (g = − 0.99; p = 0.002), but not 24 h, 48 h, and 96 h post-EIMD. Additionally, a significant effect on delayed onset of muscle soreness (DOMS) was identified at 24 h (g = − 1.34; p

Tao Wen,1,&ast; Xuan Liu,2,&ast; Tao Pang,1,&ast; Mingming Li,1 Guangyang Jiao,3 Xiangcheng Fan,1 Jigui Tang,4 Ci’an Zhang,4 Zhipeng Wang,1 Xiaoqiang Yue,4,&ast; Wansheng Chen,1,3,5 Feng Zhang1,5 1Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Oncology-Department, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai, People’s Republic of China; 3The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Department of Traditional Chinese Medicine, Changzheng Hospital, Naval Medical University, Shanghai, People’s Republic of China; 5Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng Zhang; Wansheng Chen, Changzheng Hospital, Naval Medical University, No. 415, Fengyang Road, Shanghai, 200003, People’s Republic of China, Email fengzhang@smmu.edu.cn; chenwansheng@smmu.edu.cnPurpose: The aim of this study was to verify the effectiveness and explore the mechanism of Chaihu-Guizhi-Ganjiang decoction (CGGD) in the treatment of chronic non-atrophic gastritis (CNAG) with gallbladder heat and spleen cold syndrome (GHSC) by metabolomics based on UHPLC-Q-TOF/MS.Patients and Methods: An observational controlled before-after study was conducted to verify the effectiveness of CGGD in the treatment of CNAG with GHSC from January to June 2023, enrolling 27 patients, who took CGGD for 28 days. 30 healthy volunteers were enrolled as the controls. The efficacy was evaluated by comparing the traditional Chinese medicine (TCM) syndrome and CNAG scores, and clinical parameters before and after treatment. The plasma levels of hormones related to gastrointestinal function were collected by ELISA. The mechanisms of CGGD in the treatment of CNAG with GHSC were explored using a metabolomic approach based on UHPLC-Q-TOF/MS.Results: Patients treated with CGGD experienced a statistically significant improvement in TCM syndrome and CNAG scores (p < 0.01). CGGD treatment evoked the concentration alteration of 15 biomarkers, which were enriched in the glycerophospholipid metabolism, and branched-chain amino acids biosynthesis pathways. Moreover, CGGD treatment attenuated the abnormalities of the gastrointestinal hormone levels and significantly increased the pepsinogen level.Conclusion: It was the first time that this clinical trial presented detailed data on the clinical parameters that demonstrated the effectiveness of CGGD in the treatment of CNAG with GHSC patients. This study also provided supportive evidence that CNAG with GHSC patients were associated with disturbed branched-chain amino acid metabolism and glycerophospholipid levels, suggesting that CNAG treatment based on TCM syndrome scores was reasonable and also provided a potential pharmacological mechanism of action of CGGD. Keywords: traditional Chinese medicine, chronic gastritis, metabolomics, branched-chain amino acid, glycerophospholipid

Pharmacologic activation of branched-chain amino acid (BCAA) catabolism is protective in models of heart failure (HF). How protection occurs remains unclear, although a causative block in cardiac BCAA oxidation is widely assumed. Here, we use in vivo isotope infusions to show that cardiac BCAA oxidation in fact increases, rather than decreases, in HF. Moreover, cardiac-specific activation of BCAA oxidation does not protect from HF even though systemic activation does. Lowering plasma and cardiac BCAAs also fails to confer significant protection, suggesting alternative mechanisms of protection. Surprisingly, activation of BCAA catabolism lowers blood pressure (BP), a known cardioprotective mechanism. BP lowering occurred independently of nitric oxide and reflected vascular resistance to adrenergic constriction. Mendelian randomization studies revealed that elevated plasma BCAAs portend higher BP in humans. Together, these data indicate that BCAA oxidation lowers vascular resistance, perhaps in part explaining cardioprotection in HF that is not mediated directly in cardiomyocytes.

Chemotherapy is a major contributor to cachexia, but studies often investigate male animals. Here, we investigated whether sex modifies the effects of chemotherapy on cachexia and BCAA metabolism. Ten‐week‐old CD2F1 male and female mice were treated with the chemotherapy drug cocktail folfiri (50 mg/kg 5‐fluorouracil, 90 mg/kg leucovorin, and 24 mg/kg CPT11) (drug) or vehicle twice a week for 6 weeks. Insulin tolerance tests were conducted and BCAA levels and metabolism were measured in plasma and tissues. Drug treatment reduced body and skeletal muscle weights and anabolic signaling in both sexes, with females showing worsened outcomes (p < 0.05 for all). Drug treatment increased plasma BCAA only in males, but BCAA concentrations in the skeletal muscle of both sexes were decreased; this decrease was more profound in males (p = 0.0097). In addition, muscle expression of the BCAA transporter LAT1 was reduced; this reduction was more severe in females (p = 0.0264). In both sexes, the (inhibitory) phosphorylation of BCKD‐E1αser293 was increased along with decreased BCKD activity. In the liver, drug treatment increased BCAA concentrations and LAT1 expression, but BCKD activity was suppressed in both sexes (p < 0.05 for all). Our results demonstrate that altered BCAA metabolism may contribute to chemotherapy‐induced cachexia in a sex‐dependent manner. [ABSTRACT FROM AUTHOR]

Background: Branched-chain amino acid (BCAA) supplementation is one of the most popular strategies used by the general population and athletes to reduce muscle soreness and accelerate the recovery process of muscle damage biomarkers after an intense exercise or training session. Objectives: This systematic review and meta-analysis investigated the effects of BCAA supplementation on muscle damage biomarkers and muscle soreness after exercise-induced muscle damage (EIMD). Methods: The systematic literature search for randomized controlled trials was conducted using seven databases, up to September 13th, 2022. The eligibility criteria for selecting studies were as follows: studies performed on healthy active participants, using BCAA at least once, controlled with a placebo or control group, performing resistance or endurance exercises, and followed up at least once post-EIMD. The methodological quality of the studies was assessed using the "SIGN RCT checklist". Random-effects meta-analyses were processed to compute the standardized mean difference (Hedges' g). Meta-regression analyses were completed with daily and total dosage and supplementation as continuous moderator variables. Results: Of the 18 studies included in this meta-analysis, 13 were of high quality and five were of acceptable quality. Our results revealed BCAA supplementation elicits a significant effect on reducing creatine kinase (CK) levels immediately (g = − 0.44; p = 0.006) and 72 h (g = − 0.99; p = 0.002), but not 24 h, 48 h, and 96 h post-EIMD. Additionally, a significant effect on delayed onset of muscle soreness (DOMS) was identified at 24 h (g = − 1.34; p < 0.001), 48 h (g = − 1.75; p < 0.001), 72 h (g = − 1.82; p < 0.001), and 96 h (g = − 0.82; p = 0.008), but not immediately post-EIMD. No significant effect was found on lactate dehydrogenase (LDH) levels at any time point. Meta-regression indicated higher daily and total dosages of BCAA, and longer supplementation periods were related to the largest beneficial effects on CK (total dosage and supplementation period) at 48 h, and on DOMS at 24 h (only daily dosage). Conclusion: The overall effects of BCAA supplementation could be considered useful for lowering CK and DOMS after EIMD, but not LDH. The longer supplementation period prior to the EIMD could be more effective for CK and DOMS reduction. Key Points: Branched-chain amino acid supplementation is likely to reduce muscle soreness and creatine kinase, but not lactate dehydrogenase. The responses of muscle damage biomarkers and muscle soreness to branched-chain amino acid supplementation may be influenced by study design, blinding, training status, and sex. Dose-response relationships revealed high daily doses of branched-chain amino acids, with a long supplementation period (i.e., > 7 days), could be more effective in lowering creatine kinase levels. A high total dosage of branched-chain amino acids (i.e., > 5 g/day) could be more effective in reducing muscle soreness. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength. As reported in previous studies, the loss of skeletal muscle mass is associated with poor liver regeneration after hepatectomy. It is considered important to clarify the effect of sarcopenia on liver regeneration; however, there are no reports about model animals for sarcopenia. We focused on the peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha (PGC‐1α) transgenic mice that overexpressed PGC‐1α, specifically for skeletal muscle, and showed significant atrophy of type 2B fiber‐rich muscles like sarcopenia. Methods: We performed 70% hepatectomy using PGC‐1α transgenic mice and examined the liver regeneration rate and the effects of branched‐chain amino acids (BCAA) after hepatectomy. Results: Liver regeneration after 70% hepatectomy was significantly suppressed in the PGC‐1α transgenic mice. In addition, a decrease in the blood BCAA concentration and a decrease in the liver glycogen content after 70% hepatectomy were observed in the PGC‐1α transgenic mice. By administering BCAA before and after surgery, it was clarified that a significant increase in the blood BCAA concentration was observed and the liver regeneration rate was improved in the PGC‐1α transgenic mice. Conclusions: BCAA administration may improve the suppression of liver regeneration in patients with sarcopenia. [ABSTRACT FROM AUTHOR]

Arthrospira platensis is rich in branched-chain amino acids (BCAAs) and serves as a promising alternative material for BCAA-containing peptide production. Herein, Arthrospira platensis whole protein was employed for BCAA-containing peptide preparation by determining BCAA contents of whole protein and C-phycocyanin and allophycocyanin subunits. Released peptidome profiles by different types of proteases were significantly gathered into three clusters through principal component analysis, with only 39 shared sequences in the identified peptidomes, in which the portfolio by papain contained the highest number of BCAA-containing peptides, accounting for a proportion over 95%. A portfolio of 569 peptides with differential abundances among the peptidomes by papain with increased hydrolysis time showed a dynamic change trend, corresponding to the degradation of long peptides into oligopeptides. Therefore, BCAA-containing peptides released from Arthrospira platensis depended on hydrolysis conditions, and changes in BCAA-containing peptidomes were monitored through a peptidomics workflow, contributing to the quality control of target peptides. [ABSTRACT FROM AUTHOR]

Astrocytes are considered to possess a noticeable role in brain metabolism and, as a partners in neuron–glia cooperation, to contribute to the synthesis, bioconversion, and regulation of the flux of substrates for neuronal metabolism. With the aim of investigating to what extent human astrocytes are metabolizing amino acids and by which compounds are they enriching their surroundings, we employed a metabolomics analysis of their culture media by 1H-NMR. In addition, we compared the composition of media with either 5 mM or 25 mM glucose. The quantitative analysis of culture media by 1H-NMR revealed that astrocytes readily dispose from their milieu glutamine, branched-chain amino acids, and pyruvate with significantly high rates, while they enrich the culture media with lactate, branched-chain keto acids, citrate, acetate, ketone bodies, and alanine. Hyperglycemia suppressed the capacity of astrocytes to release branched-chain 2-oxo acids, while stimulating the generation of ketone bodies. Our results highlight the active involvement of astrocytes in the metabolism of several amino acids and the regulation of key metabolic intermediates. The observed metabolic activities of astrocytes provide valuable insights into their roles in supporting neuronal function, brain metabolism, and intercellular metabolic interactions within the brain. Understanding the complex metabolic interactions between astrocytes and neurons is essential for elucidating brain homeostasis and the pathophysiology of neurological disorders. The observed metabolic activities of astrocytes provide hints about their putative metabolic roles in brain metabolism.

Metabolic reprogramming of vascular smooth muscle cell (VSMC) plays a critical role in the pathogenesis of thoracic aortic dissection (TAD). Previous researches have mainly focused on dysregulation of fatty acid or glucose metabolism, while the impact of amino acids catabolic disorder in VSMCs during the development of TAD remains elusive. Here, we identified branched-chain amino acid (BCAA) catabolic defect as a metabolic hallmark of TAD. The bioinformatics analysis and data from human aorta revealed impaired BCAA catabolism in TAD individuals. This was accompanied by upregulated branched-chain α-ketoacid dehydrogenase kinase (BCKDK) expression and BCKD E1 subunit alpha (BCKDHA) phosphorylation, enhanced vascular inflammation, and hyperactivation of mTOR signaling. Further in vivo experiments demonstrated that inhibition of BCKDK with BT2 (a BCKDK allosteric inhibitor) treatment dephosphorylated BCKDHA and re-activated BCAA catabolism, attenuated VSMCs phenotypic switching, alleviated aortic remodeling, mitochondrial reactive oxygen species (ROS) damage and vascular inflammation. Additionally, the beneficial actions of BT2 were validated in a TNF-α challenged murine VSMC cell line. Meanwhile, rapamycin conferred similar beneficial effects against VSMC phenotypic switching, cellular ROS damage as well as inflammatory response. However, co-treatment with MHY1485 (a classic mTOR activator) reversed the beneficial effects of BT2 by reactivating mTOR signaling. Taken together, the in vivo and in vitro evidence showed that impairment of BCAA catabolism resulted in aortic accumulation of BCAA and further caused VSMC phenotypic switching, mitochondrial ROS damage and inflammatory response via mTOR hyperactivation. BCKDK and mTOR signaling may serve as the potential drug targets for the prevention and treatment of TAD. [Display omitted] • Aortic BCAA catabolic defect is a previously unrecognized contributor to the pathogenesis of TAD. • Aortic BCAA catabolic defect results from the inhibitory phosphorylation of BCKDHA by BCKDK. • Aortic BCAA catabolic defect induced VSMC phenotypic switching and inflammatory response via mTOR hyperactivation. • BCKDK and mTOR signaling may serve as the potential drug targets for the treatment of TAD. [ABSTRACT FROM AUTHOR]

Context: Leucine (Leu) is one of the branched-chain amino acids that is necessary for muscle protein synthesis. Basically, poultry feed ingredients contain abundant amounts of Leu. But little is known about dietary Leu deficiency in performance and health-attributing parameters of female broiler chickens, which may occur in crude protein-restricted diets. Aims: This study evaluates the effect of Leu deficiency in diets on the growth performance, body composition, immunity, and caecum microbiota of female broilers. Methods: Female broiler chicks (Cobb 500; 8 days old; n = 540) were randomly divided into six groups with six replicates (15 birds in each replicate) in a completely randomised design. The experimental diets included six concentrations of Leu (80%, 84%, 88%, 92%, 96%, and 100%) fed for 14 days. A basal Leu-deficient diet was formulated at the 80% recommended level, and the experimental diets were created by gradual replacing of crystalline L-glutamic acid with crystalline L-Leu. Average daily intake (ADI), average daily gain (ADG), feed efficiency (gain:feed), body composition, cutaneous basophil hypersensitivity (CBH) test to phytohaemagglutinin-P (PHA-P), antibody response to sheep red blood cell (SRBC) and caecum microbiota were investigated. Key results: The birds receiving the lowest Leu application level had the lowest ADI (P < 0.05) and a 20% higher fat content (P < 0.01) than did the birds fed 96% Leu. The population of Escherichia coli and coliform bacteria count was increased (P < 0.001; by 36% and 10.3% compared with the birds fed 100% Leu in the diet respectively), and Lactobacillus (but not Enterococcus) count was decreased (P < 0.001; by 26.4% compared with the birds fed 100% Leu in the diet) with decreasing concentrations of dietary Leu. Average daily gain, feed efficiency, carcass dry matter, protein and ash percentages, and immunity were not affected markedly by dietary treatments with different Leu concentrations. Conclusions: The Leu deficiency influenced the broiler performance, body composition, and caecum microbiota, but not the immune response. Implications: This study points to the importance of Leu supplementation in the diet of broilers to improve their growth performance, fat content, and intestine health. Poultry diets contain abundant amounts of leucine, a necessary feed ingredient for higher meat production. Leucine is one of the essential amino acids, whose deficiency impairs the broilers' performance, body composition, and caecum microbiota. This study points to the importance of leucine supplementation in the diet of broilers to improve their growth performance, fat content, and intestine health. [ABSTRACT FROM AUTHOR]

Patients with end-stage liver disease after liver transplantation constantly suffer from malnutrition due to primary diseases and transplantation-related factors. Malnutrition will worsen clinical condition of the patients, increase the incidence of complication, length of hospital stay and medical expense after transplantation, and lower the survival rate. Sufficient nutritional support at all stages of liver transplantation is of significance. Accurate assessment of nutritional status and timely intervention are prerequisites for perioperative nutritional treatment in liver transplantation. In this article, the latest nutritional risk screening indexes and evaluation tools, nutritional support methods and other perioperative nutritional intervention measures for liver transplantation were reviewed, aiming to deepen the understanding and cognition of perioperative nutritional therapy for liver transplantation and provide reference for improving nutritional status and clinical prognosis of liver transplant recipients. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: An increasing body of evidence has shown that the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine and valine) is impaired in obese animals and humans, contributing to the development of insulin resistance and type 2 diabetes. Promoting BCAA catabolism benefits glycaemic control. It remains unclear whether BCAA catabolism plays a role in the therapeutic efficacy of currently used glucose-lowering drugs such as metformin. Methods: Mice were treated with vehicle or metformin (250 mg/kg per day) for more than 4 weeks to investigate the effects of metformin in vivo. In vitro, primary mouse hepatocytes and HepG2 cells were treated with 2 mmol/l metformin. The therapeutic efficacy of metformin in the treatment of type 2 diabetes was assessed in genetically obese (ob/ob) mice and high-fat-diet-induced obese (DIO) mice. Enhancing BCAA catabolism was achieved with a pharmacological agent, 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (BT2). The ob/ob mice were treated with a low-BCAA diet or intermittent protein restriction (IPR) to reduce BCAA nutritional intake. Results: Metformin unexpectedly inhibited the catabolism of BCAAs in obese mice, resulting in an elevation of BCAA abundance. AMP-activated protein kinase (AMPK) mediated the impact of metformin on BCAA catabolism in hepatocytes. Importantly, enhancing BCAA catabolism via a pharmacological agent BT2 significantly potentiated the glucose-lowering effect of metformin while decreasing circulating BCAA levels in ob/ob and DIO mice. Similar outcomes were achieved by a nutritional approach of reducing BCAA intake. IPR also effectively reduced the circulating BCAA abundance and enhanced metformin's glucose-lowering effect in ob/ob mice. BT2 and IPR treatments reduced the expression of fructose-1,6-bisphosphatase 1, a rate-limiting enzyme in gluconeogenesis, in the kidney but not liver, indicating the involvement of renal gluconeogenesis. Conclusions/interpretation: Metformin self-limits its therapeutic efficacy in the treatment of type 2 diabetes by triggering the suppression of BCAA catabolism. Enhancing BCAA catabolism pharmacologically or reducing BCAA intake nutritionally potentiates the glucose-lowering effect of metformin. These data highlight the nutritional impact of protein on metformin's therapeutic efficacy and provide new strategies targeting BCAA metabolism to improve metformin's effects on the clinical outcome in diabetes. [ABSTRACT FROM AUTHOR]

Objective: Hyperglycaemia in Type 1 diabetes (T1D) results from an absolute insulin deficiency. However, insulin resistance (IR) may exacerbate glycaemic instability in T1D and contribute to long‐term cardiovascular complications. We previously showed that IR in teenagers with obesity is associated with sex‐dependent derangements in the catabolism of branched‐chain amino acids (BCAA) and fatty acids. Here we hypothesized that byproducts of BCAA and fatty acid metabolism may serve as biomarkers or determinants of glycaemic control and IR in prepubertal or early pubertal children with T1D. Methods: Metabolites, hormones and cytokines from fasting blood samples were analysed in 28 children (15 females, 13 males; age 6–11 years) with T1D. Principal components analysis (PCA) and multiple linear regression models were used to correlate metabolites of interest with glycaemic control, total daily insulin dose (TDD, units/kg/d), adiponectin and the triglyceride (TG) to high‐density lipoprotein (HDL) ratio. Results: Males and females were comparable in age, BMI‐z, insulin sensitivity, glycaemic control, inflammatory markers, BCAAs and C2/C3/C5‐acylcarnitines. The majority of components retained in PCA were related to fatty acid oxidation (FAO) and BCAA catabolism. HbA1c correlated positively with Factor 2 (acylcarnitines, incomplete FAO) and Factor 9 (fasting glucose). TDD correlated negatively with C3 and C5 and Factor 10 (BCAA catabolism) and positively with the ratio of C2 to C3 + C5 and Factor 9 (fasting glucose). Conclusions: These findings suggest that glucose intolerance in prepubertal or early pubertal children with T1D is accompanied by incomplete FAO while TDD is associated with preferential catabolism of fats relative to amino acids. [ABSTRACT FROM AUTHOR]

Abstract Chemotherapy is a major contributor to cachexia, but studies often investigate male animals. Here, we investigated whether sex modifies the effects of chemotherapy on cachexia and BCAA metabolism. Ten‐week‐old CD2F1 male and female mice were treated with the chemotherapy drug cocktail folfiri (50 mg/kg 5‐fluorouracil, 90 mg/kg leucovorin, and 24 mg/kg CPT11) (drug) or vehicle twice a week for 6 weeks. Insulin tolerance tests were conducted and BCAA levels and metabolism were measured in plasma and tissues. Drug treatment reduced body and skeletal muscle weights and anabolic signaling in both sexes, with females showing worsened outcomes (p

ObjectiveWe conducted a two-sample Mendelian randomization （MR） study to assess the causal relationship between circulating isoleucine， leucine and valine levels and the risk of peripheral atherosclerosis.MethodsBased on the large-scale genome-wide association study （GWAS） database， single nucleotide polymorphisms （SNPs） closely related to the circulating levels of isoleucine， leucine and valine were identified as instrumental variables （IVs）. Two-sample MR analysis applying the inverse variance weighted （IVW） method and the weighted median estimator （WME） method were performed to estimate the causal relationship between the risk of peripheral atherosclerosis and the exposure with more than three SNPs that were available as IVs. The pleiotropy was evaluated by using the MR-Egger regression and MR-PRESSO method， and the leave-one-out method was used in sensitivity analysis.ResultsFour， one and one SNPs were identified as IVs for circulating isoleucine， leucine and valine levels， respectively. For isoleucine， the IVW model demonstrated there was no evidence of heterogeneity among the IVs （P=0.715）， and there was a significant causal relationship between the increase of circulating isoleucine level and a higher risk of peripheral atherosclerosis risk. Per every 1 elevated standard deviation （SD） of circulating isoleucine level resulted in increasing 31% of peripheral atherosclerosis risk （OR=1.31， 95%CI： 1.07‒1.61）. Similarly， the OR（95%CI） was 1.33 （1.04‒1.71） in the WME model. The MR-Egger regression and MR-PRESSO analysis indicated no evidence of pleiotropy in IVs （all P>0.05）. The result of the leave-one-out sensitivity analysis was stable. The Wald ratio model displayed that the causal relationship between circulating leucine and valine levels and the risk of peripheral atherosclerosis was not statistically significant. The OR （95%CI） for leucine and valine was 1.13 （0.78‒1.63） and 1.11 （0.82‒1.50）， respectively.ConclusionThere is a significant causal relationship between the increase of circulating isoleucine level and a higher peripheral atherosclerosis risk. The causal relationships between circulating leucine and valine levels and the risk of peripheral atherosclerosis need to be further confirmed in future studies.

Abstract Background Empagliflozin, a sodium–glucose co-transporter 2 inhibitor (SGLT2i), has been reported to significantly reduce the risk of heart failure in multiple clinical studies. However, the underlying mechanisms remain elusive. This study aimed to investigate the effect of empagliflozin on branched-chain amino acid (BCAA) metabolism in diabetic cardiomyopathy. Methods Thirty male 8-week KK Cg-Ay/J mice were used to study diabetic cardiomyopathy; here, 15 were used as the model group, and the remaining 15 were administered empagliflozin (3.75 mg/kg/day) by gavage daily for 16 weeks. The control group consisted of fifteen male 8-week C57BL/6J mice, whose blood glucose and body weight were measured simultaneously with the diabetic mice until 16 weeks without additional intervention. Echocardiography and histopathology were performed to evaluate cardiac structure and function. Proteomic sequencing and biogenic analysis were performed on mouse hearts. Parallel Reaction Monitoring and western blotting were performed to validate the expression levels of differentially expressed proteins. Results The results showed that empagliflozin improved ventricular dilatation and ejection fraction reduction in diabetic hearts, as well as the elevation of myocardial injury biomarkers hs-cTnT and NT-proBNP. At the same time, empagliflozin alleviates myocardial inflammatory infiltration, calcification foci deposition, and fibrosis caused by diabetes. The results of the proteomics assay showed that empagliflozin could improve the metabolism of various substances, especially promoting the BCAA metabolism of diabetic hearts by up-regulating PP2Cm. Furthermore, empagliflozin could affect the mTOR/p-ULK1 signaling pathway by reducing the concentration of BCAA in diabetic hearts. When mTOR/p-ULK1 protein was inhibited, ULK1, the autophagy initiation molecule, increased. Moreover, autophagy substrate p62 and autophagy marker LC3B were significantly reduced, indicating that the autophagy activity of diabetes inhibition was reactivated. Conclusions Empagliflozin may attenuate diabetic cardiomyopathy-related myocardial injury by promoting the catabolism of BCAA and inhibiting mTOR/p-ULK1 to enhance autophagy. These findings suggest that empagliflozin could be a potential candidate drug against BCAA increase and could be used for other cardiovascular diseases with a metabolic disorder of BCAA.

Abstract Objective Hyperglycaemia in Type 1 diabetes (T1D) results from an absolute insulin deficiency. However, insulin resistance (IR) may exacerbate glycaemic instability in T1D and contribute to long‐term cardiovascular complications. We previously showed that IR in teenagers with obesity is associated with sex‐dependent derangements in the catabolism of branched‐chain amino acids (BCAA) and fatty acids. Here we hypothesized that byproducts of BCAA and fatty acid metabolism may serve as biomarkers or determinants of glycaemic control and IR in prepubertal or early pubertal children with T1D. Methods Metabolites, hormones and cytokines from fasting blood samples were analysed in 28 children (15 females, 13 males; age 6–11 years) with T1D. Principal components analysis (PCA) and multiple linear regression models were used to correlate metabolites of interest with glycaemic control, total daily insulin dose (TDD, units/kg/d), adiponectin and the triglyceride (TG) to high‐density lipoprotein (HDL) ratio. Results Males and females were comparable in age, BMI‐z, insulin sensitivity, glycaemic control, inflammatory markers, BCAAs and C2/C3/C5‐acylcarnitines. The majority of components retained in PCA were related to fatty acid oxidation (FAO) and BCAA catabolism. HbA1c correlated positively with Factor 2 (acylcarnitines, incomplete FAO) and Factor 9 (fasting glucose). TDD correlated negatively with C3 and C5 and Factor 10 (BCAA catabolism) and positively with the ratio of C2 to C3 + C5 and Factor 9 (fasting glucose). Conclusions These findings suggest that glucose intolerance in prepubertal or early pubertal children with T1D is accompanied by incomplete FAO while TDD is associated with preferential catabolism of fats relative to amino acids.

Postnatal muscle growth is impaired in low birth weight (L) neonatal pigs. Leucine supplementation has been established as a dietary intervention to enhance muscle growth in growing animals. The aim of this study was to investigate the efficacy of supplementing L neonatal pig formulas with branched-chain amino acids (B) to enhance the rate of protein accretion. Twenty-four 3-day old pigs were divided into two groups low (L) and normal birth weight (N) based on weight at birth. Pigs were assigned to a control (C) or 1% branched-chain amino acids (B) formulas, and fed at 250 mL·kg body weight −1·d−1 for 28 d. Body weight of pigs in the L group was less than those in the N group (P < 0.01). However, fractional body weight was greater for L pigs compared with their N siblings from day 24 to 28 of feeding regardless of formula (P < 0.01). In addition, feed efficiency (P < 0.0001) and efficiently of protein accretion (P < 0.0001) were greater for L than N pigs regardless of supplementation. Pigs fed the B formula had greater plasma leucine, isoleucine, and valine concentrations compared with those fed the C formula (P < 0.05). Longissimus dorsi Sestrin2 protein expression was less for pigs in the L group compared with those in the N group (P < 0.01), but did not result in a corresponding increase in translation initiation signaling. Longissimus dorsi mRNA expression of BCAT2 was less for LB pigs compared with those in the LC group, and was intermediate for NC and NB pigs (P < 0.05). Hepatic mRNA expression of BCKDHA was greater for pigs in the L compared with those in the N groups (P < 0.05). However, plasma branched-chain keto-acid concentration was reduced for C compared with those in the B group (P < 0.05). These data suggest that branched-chain amino acid supplementation does not improve lean tissue accretion of low and normal birth weight pigs, despite a reduction in Sestrin2 expression in skeletal muscle of low birth weight pigs. The modest improvement in fractional growth rate of low birth weight pigs compared with their normal birth weight siblings was likely due to a more efficient dietary protein utilization. [ABSTRACT FROM AUTHOR]

Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short‐chain enoyl‐CoA hydratase (ECHS1 or crotonase) deficiency, 3‐hydroxyisobutyryl‐CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA), and methylmalonic aciduria (MMA). Isobutyryl‐CoA dehydrogenase (ACAD8) and short/branched‐chain acyl‐CoA dehydrogenase (SBCAD, ACADSB) function in the valine and isoleucine degradation pathways, respectively. Deficiencies of these acyl‐CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences. We investigated whether substrate reduction therapy through inhibition of ACAD8 and SBCAD can limit the accumulation of toxic metabolic intermediates in disorders of valine and isoleucine metabolism. Using analysis of acylcarnitine isomers, we show that 2‐methylenecyclopropaneacetic acid (MCPA) inhibited SBCAD, isovaleryl‐CoA dehydrogenase, short‐chain acyl‐CoA dehydrogenase and medium‐chain acyl‐CoA dehydrogenase, but not ACAD8. MCPA treatment of wild‐type and PA HEK‐293 cells caused a pronounced decrease in C3‐carnitine. Furthermore, deletion of ACADSB in HEK‐293 cells led to an equally strong decrease in C3‐carnitine when compared to wild‐type cells. Deletion of ECHS1 in HEK‐293 cells caused a defect in lipoylation of the E2 component of the pyruvate dehydrogenase complex, which was not rescued by ACAD8 deletion. MCPA was able to rescue lipoylation in ECHS1 KO cells, but only in cells with prior ACAD8 deletion. SBCAD was not the sole ACAD responsible for this compensation, which indicates substantial promiscuity of ACADs in HEK‐293 cells for the isobutyryl‐CoA substrate. Substrate promiscuity appeared less prominent for 2‐methylbutyryl‐CoA at least in HEK‐293 cells. We suggest that pharmacological inhibition of SBCAD to treat PA should be investigated further. [ABSTRACT FROM AUTHOR]

Rice (Oryza sativa L.) is a globally important food source providing carbohydrates, amino acids, and dietary fiber for humans and livestock. The branched-chain amino acid (BCAA) level is a complex trait related to the nutrient quality of rice. However, the genetic mechanism underlying the BCAA (valine, leucine, and isoleucine) accumulation in rice grains remains largely unclear. In this study, the grain BCAA contents and 239,055 SNPs of a diverse panel containing 422 rice accessions were adopted to perform a genome-wide association study (GWAS) using a recently proposed 3VmrMLM model. A total of 357 BCAA-content-associated main-effect quantitative trait nucleotides (QTNs) were identified from 15 datasets (12 BCAA content datasets and 3 BLUP datasets of BCAA). Furthermore, the allelic variation of two novel candidate genes, LOC_Os01g52530 and LOC_Os06g15420, responsible for the isoleucine (Ile) content alteration were identified. To reveal the genetic basis of the potential interactions between the gene and environmental factor, 53 QTN-by-environment interactions (QEIs) were detected using the 3VmrMLM model. The LOC_Os03g24460, LOC_Os01g55590, and LOC_Os12g31820 were considered as the candidate genes potentially contributing to the valine (Val), leucine (Leu), and isoleucine (Ile) accumulations, respectively. Additionally, 10 QTN-by-QTN interactions (QQIs) were detected using the 3VmrMLM model, which were putative gene-by-gene interactions related to the Leu and Ile contents. Taken together, these findings suggest that the implementation of the 3VmrMLM model in a GWAS may provide new insights into the deeper understanding of BCAA accumulation in rice grains. The identified QTNs/QEIs/QQIs serve as potential targets for the genetic improvement of rice with high BCAA levels. [ABSTRACT FROM AUTHOR]

Branched-chain amino acids are critical metabolic intermediates that can indicate increased risk of cardiometabolic disease when levels are elevated or, alternatively, suggest sufficient mitochondrial energy metabolism and reserve in old age. The interpretation of BCAA levels can be context-dependent, and it remains unclear whether abnormal levels can inform prognosis. This prospective longitudinal study aimed to determine the interrelationship between mortality hazard and fasting serum BCAA levels among older men and women aged ≥65 years with or without hypertension and diabetes mellitus. At baseline (0Y), fasting serum BCAA concentration in 2997 community-living older men and women were measured. Approximately 14 years later (14Y), 860 study participants returned for repeat measurements. Deaths were analysed and classified into cardiovascular and non-cardiovascular causes using International Classification of Diseases codes. Survival analysis and multivariable Cox regression were performed. During a median follow-up of 17Y, 971 (78.6%) non-cardiovascular and 263 (21.4%) cardiovascular deaths occurred among 1235 (41.2%) deceased (median age, 85.8 years [IQR 81.7–89.7]). From 0Y to 14Y, BCAA levels declined in both sexes, whereas serum creatinine concentration increased (both p < 0.0001). In older adults without hypertension or diabetes mellitus, the relationship between mortality hazard and BCAA level was linear and above-median BCAA levels were associated with improved survival, whereas in the presence of cardiometabolic disease the relationship was U-shaped. Overall, adjusted Cox regression determined that each 10% increment in BCAA concentration was associated with a 7% (p = 0.0002) and 16% (p = 0.0057) reduction in mortality hazard estimated at 0Y and 14Y, respectively. Our findings suggested that abnormally high or low (dyshomeostatic) BCAA levels among older adults with hypertension and/or diabetes mellitus were associated with increased mortality, whereas in those with neither disease, increased BCAA levels was associated with improved survival, particularly in the oldest-old. [ABSTRACT FROM AUTHOR]

Elevations in circling branched‐chain amino acids (BCAAs) levels associated with insulin resistance and type 2 diabetes mellitus (T2DM). Morus alba L. water extracts (MLE) show hypoglycemic function, but the precise mechanism remains obscure. This study is designed to investigate the association of the antidiabetes effect of MLE with the BCAAs co‐metabolism modulated by host and gut microbiota. Tissue‐specific expressions of BCAA‐catabolizing enzymes were detected by RT‐PCR and western blot, respectively. The components of the intestinal microflora were analyzed by high‐throughput 16S rRNA gene sequencing. The results showed that MLE administration improved blood glucose and insulin level, decreased inflammatory cytokines expression, and lowered serum and feces BCAAs levels. Furthermore, MLE reversed the abundance changes of the bacterial genera correlated with serum and feces BCAAs, such as Anaerovorax, Bilophila, Blautia, Colidextribacter, Dubosiella, Intestinimonas, Lachnoclostridium, Lachnospiraceae_NK4A136, Oscillibacter, and Roseburia. Functionality prediction indicated that MLE potentially inhibited bacterial BCAAs biosynthesis, and promoted the tissue‐specific expression of BCAAs catabolic enzyme. More importantly, MLE had obvious impacts on BCAA catabolism in germ‐free‐mimic T2DM mice. Those results indicated that MLE improving T2DM‐related biochemical abnormalities is associated with not only gut microbiota modification but also the tissue‐specific expression of BCAAs catabolic enzyme. [ABSTRACT FROM AUTHOR]

Abstract Background Aging is an inevitable process associated with impairments in multiple organ systems, which increases the risk of comorbidity and disability, and reduces the health-span. Metabolomics is a powerful tool in aging research, which can reflect the characteristics of aging at the level of terminal metabolism, and may contribute to the exploration of aging mechanisms and the formulation of anti-aging strategies. Methods To identify possible biomarkers and pathways associated with aging using untargeted metabolomics methods, we performed liquid chromatography–mass spectrometry (LC–MS)-based untargeted metabolomics profiling on serum samples from 32 older adults and 32 sex-matched young controls. Results Metabolite profiling could distinguish the two groups. Among the 349 metabolites identified, 80—including lysophospholipids whose levels gradually decline—are possible candidate aging biomarkers. Valine, leucine and isoleucine degradation and biosynthesis were important pathways in aging, with reduced levels of l-isoleucine (r = − 0.30, p = 0.017) and l-leucine (r = − 0.32, p = 0.010) observed in older adults. Conclusions We preliminarily revealed the metabolite changes associated with aging in Chinese adults. Decreases in mitochondrial membrane-related lysophospholipids and dysfunction of branched-chain amino acid metabolism were determined to be the characteristics and promising research targets for aging.

Legionella pneumophila (Lp) is a common etiological agent of bacterial pneumonia that causes Legionnaires' disease (LD). The bacterial membrane-associated virulence factor macrophage infectivity potentiator (Mip) exhibits peptidyl-prolyl-cis/trans-isomerase (PPIase) activity and contributes to the intra- and extracellular pathogenicity of Lp. Though Mip influences disease outcome, little is known about the metabolic consequences of altered Mip activity during infections. Here, we established a metabolic workflow and applied mass spectrometry approaches to decipher how Mip activity influences metabolism and pathogenicity. Impaired Mip activity in genetically engineered Lp strains decreases intracellular replication in cellular infection assays, confirming the contribution of Mip for Lp pathogenicity. We observed that genetic and chemical alteration of Mip using the PPIase inhibitors rapamycin and FK506 induces metabolic reprogramming in Lp, specifically branched-chain amino acid (BCAA) metabolism. Rapamycin also inhibits PPIase activity of mammalian FK506 binding proteins, and we observed that rapamycin induces a distinct metabolic signature in human macrophages compared to bacteria, suggesting potential involvement of Mip in normal bacteria and in infection. Our metabolic studies link Mip to alterations in BCAA metabolism and may help to decipher novel disease mechanisms associated with LD. [ABSTRACT FROM AUTHOR]

Background: Empagliflozin, a sodium–glucose co-transporter 2 inhibitor (SGLT2i), has been reported to significantly reduce the risk of heart failure in multiple clinical studies. However, the underlying mechanisms remain elusive. This study aimed to investigate the effect of empagliflozin on branched-chain amino acid (BCAA) metabolism in diabetic cardiomyopathy. Methods: Thirty male 8-week KK Cg-Ay/J mice were used to study diabetic cardiomyopathy; here, 15 were used as the model group, and the remaining 15 were administered empagliflozin (3.75 mg/kg/day) by gavage daily for 16 weeks. The control group consisted of fifteen male 8-week C57BL/6J mice, whose blood glucose and body weight were measured simultaneously with the diabetic mice until 16 weeks without additional intervention. Echocardiography and histopathology were performed to evaluate cardiac structure and function. Proteomic sequencing and biogenic analysis were performed on mouse hearts. Parallel Reaction Monitoring and western blotting were performed to validate the expression levels of differentially expressed proteins. Results: The results showed that empagliflozin improved ventricular dilatation and ejection fraction reduction in diabetic hearts, as well as the elevation of myocardial injury biomarkers hs-cTnT and NT-proBNP. At the same time, empagliflozin alleviates myocardial inflammatory infiltration, calcification foci deposition, and fibrosis caused by diabetes. The results of the proteomics assay showed that empagliflozin could improve the metabolism of various substances, especially promoting the BCAA metabolism of diabetic hearts by up-regulating PP2Cm. Furthermore, empagliflozin could affect the mTOR/p-ULK1 signaling pathway by reducing the concentration of BCAA in diabetic hearts. When mTOR/p-ULK1 protein was inhibited, ULK1, the autophagy initiation molecule, increased. Moreover, autophagy substrate p62 and autophagy marker LC3B were significantly reduced, indicating that the autophagy activity of diabetes inhibition was reactivated. Conclusions: Empagliflozin may attenuate diabetic cardiomyopathy-related myocardial injury by promoting the catabolism of BCAA and inhibiting mTOR/p-ULK1 to enhance autophagy. These findings suggest that empagliflozin could be a potential candidate drug against BCAA increase and could be used for other cardiovascular diseases with a metabolic disorder of BCAA. [ABSTRACT FROM AUTHOR]

ABSTRACT: The 3 branched-chain AA (BCAA), Val, Leu, and Ile, are essential AA used by tissues as substrates for protein synthesis and energy generation. In addition, BCAA are also involved in modulating cell signaling pathways, such as nutrient sensing and insulin signaling. In our previous study, dietary BCAA supplementation was shown to improve protein synthesis and glucose homeostasis in transition cows. However, a more detailed understanding of the changes in metabolic pathways associated with an increased BCAA availability is desired to fine-tune nutritional supplementation strategies. Multiparous Holstein cows (n = 20) were enrolled 28 d before expected calving and assigned to either the BCAA treatment (n = 10) or the control group (n = 10). Cows assigned to BCAA were fed 550 g/d of rumen-protected BCAA mixed with 200 g/d of dry molasses from calving until 35 DIM, whereas the cows assigned to the control were fed only 200 g/d of dry molasses. Serum samples were collected on d 10 before expected calving, as well as on d 4 and d 21 postpartum. Milk samples were collected on d 14 postpartum. From a larger cohort, we selected 20 BCAA-supplemented cows with the greatest plasma urea nitrogen concentration, as an indicator for greater BCAA availability, for the metabolomics analysis herein. Serum and milk samples were subjected to a liquid chromatography–mass spectrometry–based assay, detecting and measuring the abundance of 241 serum and 211 milk metabolic features, respectively. Multivariable statistical analyses revealed that BCAA supplementation altered the metabolome profiles of both serum and milk samples. Increased abundance of serum phosphocholine and glutathione and of milk Val, Ile, and Leu, and decreased abundance of milk acyl-carnitines were associated with BCAA supplementation. Altered phosphocholine and glutathione abundances point to altered hepatic choline metabolism and antioxidant balance, respectively. Altered milk acyl-carnitine abundances suggest changes in mammary fatty acid metabolism. Dietary BCAA supplementation was associated with a range of alterations in serum and milk metabolome profiles, adding to our understanding of the role of BCAA availability in modulating dairy cow protein, lipid, and energy metabolism on a whole-body level and how it affects milk composition.

Background: The human heart primarily metabolizes fatty acids, and this decreases as alternative fuel use rises in heart failure with reduced ejection fraction (HFrEF). Patients with severe obesity and diabetes are thought to have increased myocardial fatty acid metabolism, but whether this is found in those who also have heart failure with preserved ejection fraction (HFpEF) is unknown. Methods: Plasma and endomyocardial biopsies were obtained from HFpEF (n=38), HFrEF (n=30), and nonfailing donor controls (n=20). Quantitative targeted metabolomics measured organic acids, amino acids, and acylcarnitines in myocardium (72 metabolites) and plasma (69 metabolites). The results were integrated with reported RNA sequencing data. Metabolomics were analyzed using agnostic clustering tools, Kruskal-Wallis test with Dunn test, and machine learning. Results: Agnostic clustering of myocardial but not plasma metabolites separated disease groups. Despite more obesity and diabetes in HFpEF versus HFrEF (body mass index, 39.8 kg/m2 versus 26.1 kg/m2; diabetes, 70% versus 30%; both P <0.0001), medium- and long-chain acylcarnitines (mostly metabolites of fatty acid oxidation) were markedly lower in myocardium from both heart failure groups versus control. In contrast, plasma levels were no different or higher than control. Gene expression linked to fatty acid metabolism was generally lower in HFpEF versus control. Myocardial pyruvate was higher in HFpEF whereas the tricarboxylic acid cycle intermediates succinate and fumarate were lower, as were several genes controlling glucose metabolism. Non–branched-chain and branched-chain amino acids (BCAA) were highest in HFpEF myocardium, yet downstream BCAA metabolites and genes controlling BCAA metabolism were lower. Ketone levels were higher in myocardium and plasma of patients with HFrEF but not HFpEF. HFpEF metabolomic-derived subgroups were differentiated by only a few differences in BCAA metabolites. Conclusions: Despite marked obesity and diabetes, HFpEF myocardium exhibited lower fatty acid metabolites compared with HFrEF. Ketones and metabolites of the tricarboxylic acid cycle and BCAA were also lower in HFpEF, suggesting insufficient use of alternative fuels. These differences were not detectable in plasma and challenge conventional views of myocardial fuel use in HFpEF with marked diabetes and obesity and suggest substantial fuel inflexibility in this syndrome. [ABSTRACT FROM AUTHOR]

The rhythmic pattern of biological processes controlled by light over 24 h is termed the circadian rhythm. Disturbance of circadian rhythm due to exposure to light at night (LAN) disrupts the sleep-wake cycle and can promote cardiovascular disease, diabetes, cancer, and metabolic disorders in humans. We studied how dim LAN affects the circadian rhythm and metabolism using male Drosophila. Wild-type flies exposed to the dim light of 10 lux at night displayed altered 24 h sleep-wake behavior and expression patterns of circadian rhythm genes. In addition, the flies became more vulnerable to metabolic stress, such as starvation. Whole-body metabolite analysis revealed decreased amounts of branched-chain amino acids (BCAAs), such as isoleucine and valine. The dim light exposure also increased the expression of branched-chain amino acid aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKDC) enzyme complexes that regulate the metabolism of BCAAs. Flies with the Bcat heterozygous mutation were not vulnerable to starvation stress, even when exposed to dim LAN, and hemolymph BCAA levels did not decrease in these flies. Furthermore, the vulnerability to starvation stress was also suppressed when the Bcat expression level was reduced in the whole body, neurons, or fat body during adulthood using conditional GAL4 and RNA interference. Finally, the metabolic vulnerability was reversed when BCAAs were fed to wild-type flies exposed to LAN. Thus, short-term dim light exposure at night affects the expression of circadian genes and BCAA metabolism in Drosophila, implying a novel function of BCAAs in suppressing metabolic stress caused by disrupted circadian rhythm. [ABSTRACT FROM AUTHOR]

Branched-chain amino acids (BCAA) showed multiple functions in glycolipid metabolism and protein synthesis. However, the impacts on the metabolic health of low or high dietary BCAA remain controversial due to the various experimental conditions. Gradient levels of BCAA were supplemented in lean mice for four weeks: 0BCAA (without BCAA), 1/2BCAA (half BCAA), 1BCAA (regular BCAA), and 2BCAA (double BCAA). The results showed that the diet without BCAA caused energy metabolic disorders, immune defects, weight loss, hyperinsulinemia, and hyperleptinemia. 1/2BCAA and 2BCAA diets reduced body fat percentage, but 1/2 BCAA also decreased muscle mass. 1/2BCAA and 2BCAA groups improved lipid and glucose metabolism by affecting metabolic genes. Meanwhile, significant differences between low and high dietary BCAA were observed. The results of this study provide evidence and reference for the controversy about dietary BCAA levels, which indicates that the main difference between low and high BCAA dietary levels may present in the longer term. [ABSTRACT FROM AUTHOR]

The production of antimicrobial components and the formation of less-permeable tight junctions (TJs) are important in the defense system of lactating mammary glands and for safe dairy production. Valine is a branched-chain amino acid that is actively consumed in the mammary glands and promotes the production of major milk components like β-casein; additionally, branched-chain amino acids stimulate antimicrobial component production in the intestines. Therefore, we hypothesized that valine strengthens the mammary gland defense system without influencing milk production. We investigated the effects of valine in vitro using cultured mammary epithelial cells (MECs) and in vivo using the mammary glands of lactating Tokara goats. Valine treatment at 4 mM increased the secretion of S100A7 and lactoferrin as well as the intracellular concentration of β-defensin 1 and cathelicidin 7 in cultured MECs. In addition, an intravenous injection of valine increased S100A7 levels in the milk of Tokara goats without influencing milk yield and milk components (i.e., fat, protein, lactose, and solids). In contrast, valine treatment did not affect TJ barrier function either in vitro or in vivo. These findings indicate that valine enhances antimicrobial component production without influencing milk production and TJ barrier function in lactating mammary glands; thus, valine contributes to safe dairy production. [ABSTRACT FROM AUTHOR]

Several observational studies have indicated an association between high serum levels of branched-chain amino acids (BCAAs) and an increased risk of cardiovascular disease (CVD). To assess whether theses associations reflect causality, we carried out two-sample Mendelian randomization (MR). Single-nucleotide polymorphisms (SNPs) associated with BCAA were evaluated in 10 studies, including 24,925 participants. The association between SNPs and coronary artery disease (CAD) were assessed using summary estimates from the CARDIoGRAMplusC4D consortium. Further MR analysis of BCAAs and seven CVD outcomes was performed. The BCAA-raising gene functions were also analyzed. MR analyses revealed a risk-increasing causal relationship between serum BCAA concentrations and CAD (odds ratio 1.08; 95% confidence interval (CI) 1.02–1.14), which was partly mediated by blood pressure and type 2 diabetes. BCAA also demonstrated a causal relationship with ischemic CVD events induced by plaque rupture and thrombosis (false discovery rate <0.05). Two BCAA-raising genes (MRL33 and CBLN1) were preferentially associated with myocardial infarction risk in the presence of atherosclerosis (p < 0.003). Functional analysis of the BCAA-raising genes suggested the causal involvement of two pathophysiological pathways, including glucose metabolism (PPM1K and TRMT61A) related to plaque progression, and the newly discovered neuroendocrine disorders regulating blood pressure (MRPL33, CBLN1, and C2orf16) related to plaque rupture and thrombosis. This comprehensive MR analysis provided insights into the potential causal mechanisms linking BCAA with CVD risk and suggested targeting neuroendocrine disorders as a potential strategy for the prevention of CVD. These results warrant further studies to elucidate the mechanisms underlying these reported causal associations. [ABSTRACT FROM AUTHOR]

Background: Aging is an inevitable process associated with impairments in multiple organ systems, which increases the risk of comorbidity and disability, and reduces the health-span. Metabolomics is a powerful tool in aging research, which can reflect the characteristics of aging at the level of terminal metabolism, and may contribute to the exploration of aging mechanisms and the formulation of anti-aging strategies. Methods: To identify possible biomarkers and pathways associated with aging using untargeted metabolomics methods, we performed liquid chromatography–mass spectrometry (LC–MS)-based untargeted metabolomics profiling on serum samples from 32 older adults and 32 sex-matched young controls. Results: Metabolite profiling could distinguish the two groups. Among the 349 metabolites identified, 80—including lysophospholipids whose levels gradually decline—are possible candidate aging biomarkers. Valine, leucine and isoleucine degradation and biosynthesis were important pathways in aging, with reduced levels of l-isoleucine (r = − 0.30, p = 0.017) and l-leucine (r = − 0.32, p = 0.010) observed in older adults. Conclusions: We preliminarily revealed the metabolite changes associated with aging in Chinese adults. Decreases in mitochondrial membrane-related lysophospholipids and dysfunction of branched-chain amino acid metabolism were determined to be the characteristics and promising research targets for aging. [ABSTRACT FROM AUTHOR]

ABSTRACT: We investigated the effects of supplementing arginine (Arg) and branched-chain amino acids (BCAA) in broilers fed reduced-protein diets and challenged with Eimeria spp. All birds were fed the same starter diet meeting Cobb 500 nutrient specifications from d 1 to 9. Four grower diets: positive control (PC) with 20.0% crude protein (CP); reduced-protein negative control (NC) with 17.5% CP; or NC supplemented with Arg or BCAA at 50% above recommendations (ARG or BCAA) were fed to the birds from d 9 to 28. Birds were allocated in a 2 × 4 factorial arrangement (4 diets, each with or without challenge), with 8 replicates per treatment. On d 14, the challenge groups were orally gavaged with mixed Eimeria spp. Intestinal permeability was higher (P < 0.05) in NC than PC, whereas the permeability of ARG and BCAA groups did not differ significantly from PC. On d 28, a significant interaction (P < 0.01) was observed in CD8+: CD4+ ratios in cecal tonsils (CT), Eimeria challenge increased the ratios in all groups except for the ARG group. On d 21, a significant interaction was found for CD4+CD25+ percentages in CT (P < 0.01) that Eimeria challenge increased the percentages only in PC and NC groups. On d 21 and 28, significant interactions (P < 0.01) were found for macrophage nitric oxide (NO) production. In nonchallenged birds, NO was higher in the ARG group than other groups, but in challenged birds, NO was higher in both ARG and BCAA groups. On d 21, a significant interaction was found for bile anticoccidial IgA concentrations (P < 0.05) that Eimeria challenge increased IgA only in NC and ARG groups. The results suggest that a reduced-protein diet exacerbates the impact of the Eimeria challenge on intestinal integrity, but this could be mitigated by Arg and BCAA supplementations. Arginine and BCAA supplementations in reduced-protein diets could be beneficial for broilers against Eimeria infection by enhancing the immune responses. The beneficial effects of Arg supplementation tended to be more pronounced compared to BCAA supplementation.

BackgroundRecent studies have shown that circulating branched-chain amino acids (BCAAs) are elevated in obese, insulin-resistant individuals. However, it is not known if supplementation of additional BCAAs will further impair glucose metabolism.ObjectivesThe aim of this pilot study was to determine the effects of BCAA supplementation on glucose metabolism in obese, prediabetic individuals.MethodsThis is a randomized crossover study involving 12 obese individuals with prediabetes. Participants were randomly assigned to receive a daily supplement containing either 20 g BCAA or protein low in BCAAs for 4 wk with a 2-wk washout in between. At each visit, an oral-glucose-tolerance test (OGTT) was performed. Collected blood samples were used to measure glucose, insulin, and insulin resistance-associated biomarkers.ResultsBCAA supplementation tended to decrease the plasma glucose area under the curve (AUC) measured by the OGTT (AUC percentage change from supplementation baseline, BCAA: -3.3% ± 3%; low-BCAA: 10.0% ± 6%; P = 0.08). However, BCAA supplementation did not affect plasma insulin during OGTT challenge (BCAA: -3.9% ± 8%; low-BCAA: 14.8% ± 10%; P = 0.28). The plasma concentrations of nerve growth factor (BCAA: 4.0 ± 1 pg/mL; low-BCAA: 5.7 ± 1 pg/mL; P = 0.01) and monocyte chemoattractant protein-1 (BCAA: -0.4% ± 9%; low-BCAA: 29.0% ± 18%; P = 0.02) were significantly lowered by BCAA supplementation compared to low-BCAA control. Plasma interleukin 1β was significantly elevated by BCAA supplementation (BCAA: 231.4% ± 187%; low-BCAA: 20.6% ± 33%; P = 0.05). BCAA supplementation did not affect the circulating concentrations of the BCAAs leucine (BCAA: 9.0% ± 12%; low-BCAA: 9.2% ± 11%), valine (BCAA: 9.1% ± 11%; low-BCAA: 12.0% ± 13%), or isoleucine (BCAA: 2.5% ± 11%; low-BCAA: 7.3% ± 11%).ConclusionsOur data suggest that BCAA supplementation did not impair glucose metabolism in obese, prediabetic subjects. Further studies are needed to confirm the results seen in the present study. This study was registered at clinicaltrials.gov as NCT03715010.

Abstract Background Intravenous administration of amino acid (AA) formulation (IVAA) as intradialytic parenteral nutrition is widely used for malnourished patients with end-stage kidney disease (ESKD) treated with hemodialysis (HD) or hemodiafiltration (HDF). Although various therapy recipes such as AA compositions or simultaneous administration of glucose and/or lipids have been attempted, the specific effects of each recipe on AA behaviors and metabolic consequences have not been well investigated. To clarify the effect of simultaneous glucose administration with IVAA, we investigated the behavior of AAs, insulin as a metabolic hormone, and energy-related metabolites during an HDF session in two patients. Case presentation We aimed to determine the effect of IVAA with or without simultaneous glucose administration. The plasma levels of AAs, branched-chain AAs (leucine, isoleucine, and valine), major nonessential AAs (alanine and glutamine with glutamate), insulin, glucose, and ketone bodies were measured before HDF and at the second hour (prior to the meal in the HDF session). Lost AAs in the spent dialysate were also measured for the first two hours during the HDF session. Conclusion In the absence of glucose administration, plasma AA levels and the loss of AAs in the dialysate increased owing to IVAA, with the increase in plasma levels in ketone bodies occurring because of scarce secretion of plasma insulin. In the presence of glucose administration, plasma levels and the loss of AA decreased even when the same amount of AAs was injected, possibly because of the profound secretion of insulin with a decrease in ketone bodies. The present findings suggest that the metabolic effects of simultaneous glucose administration on IVAAs enhanced AA uptake into the body during HDF sessions, which might increase the effectiveness of IVAAs.

Abstract Background Endurance exercise training promotes the catabolism of branched-chain amino acids (BCAAs) in skeletal muscles. We have previously shown that mitochondrial DNA (mtDNA) haplogroups J and K are markers of low responders in endurance training. In this paper, we hypothesize that BCAA catabolism is a surrogate marker of lower respiratory chain activity attributed to these haplogroups. We evaluated whether exercise-induced changes in amino acid concentrations differ between subjects harbouring mtDNA haplogroups J or K and those with non-JK haplogroups. Methods Finnish male conscripts (N = 633) undertook the 12-min Cooper running test at the beginning and end of their military service. The intervention during the service mainly included endurance aerobic exercise and sports-related muscle training. Concentrations of seven amino acids were analysed in the serum using a high-throughput 1H NMR metabolomics platform. Total DNA was extracted from whole blood, and restriction fragment analysis was used to determine mtDNA haplogroups J and K. Results The concentrations of the seven amino acids were higher following the intervention, with the exception of phenylalanine; interestingly, the increase in the concentrations of three BCAAs was larger in subjects with haplogroup J or K than in subjects with non-JK haplogroups (p = 0.029). MtDNA haplogroups J and K share two common nonsynonymous variants. Structural analysis based on crystallographic data on bovine complexes I and III revealed that the Leu18 variant in cytochrome b encoded by m.14798T > C may interfere with ubiquinone binding at the Qi site in complex III. Conclusions The increase in the concentrations of serum BCAAs following exercise intervention differs between subjects harbouring mtDNA haplogroup J or K and those harbouring non-JK haplogroups. Lower response in endurance training and difference in exercise-induced increase in the concentrations of serum BCAAs suggest decreased respiratory chain activity. Haplogroups J and K share m.14798T > C in MT-CYB, which may hamper the function of complex III.

Objectives: Insulin resistance (IR) in adolescents with obesity is associated with a sex‐dependent metabolic 'signature' comprising the branched‐chain amino acids (BCAAs), glutamate/glutamine, C3/C5 acylcarnitines and uric acid. Here, we compared the levels of branched‐chain α‐keto acids (BCKAs) and glutamate/glutamine, which are the byproducts of BCAA catabolism and uric acid among adolescents with obesity prior to and following a 6‐month lifestyle‐intervention program. Methods: Fasting plasma samples from 33 adolescents with obesity (16 males, 17 females, aged 12–18 year) were analysed by flow‐injection tandem MS and LC–MS/MS. Multiple linear regression models were used to correlate changes in BCKAs, glutamate/glutamine and uric acid with changes in weight and insulin sensitivity as assessed by HOMA‐IR, adiponectin and the ratio of triglyceride (TG) to HDL. In predictive models, BCKAs, glutamate/glutamine and uric acid at baseline were used as explanatory variables. Results: Baseline BCKAs, glutamate/glutamine and uric acid were higher in males than females despite comparable BMI‐metrics. Following lifestyle‐intervention, α‐keto‐β‐methylvalerate (α‐KMV, a metabolic by product of isoleucine) decreased in males but not in females. The ratio of BCKA/BCAA trended lower in males. In the cohort as a whole, BCKAs correlated positively with the ratio of TG to HDL at baseline and HOMA‐IR at 6‐month‐follow‐up. Glutamate/glutamine was positively associated with HOMA‐IR at baseline and 6‐month‐follow‐up. A reduction in BCKAs was associated with an increase in adiponectin, and those with higher BCKAs at baseline had higher adiponectin levels at 6‐month‐follow‐up. Interestingly those adolescents with higher uric acid levels at baseline had greater reduction in weight. Conclusions: BCKAs and glutamate/glutamine may serve as biomarkers of IR in adolescents with obesity, and uric acid might serve as a predictor of weight loss in response to lifestyle‐intervention. Differential regulation of BCAA catabolism in adolescent males and females implicates critical roles for sex steroids in metabolic homeostasis. [ABSTRACT FROM AUTHOR]

Branched‐chain amino acid (BCAA) metabolism is a central hub for energy production and regulation of numerous physiological processes. Controversially, both increased and decreased levels of BCAAs are associated with longevity. Using genetics and multi‐omics analyses in Caenorhabditis elegans, we identified adaptive regulation of the ubiquitin‐proteasome system (UPS) in response to defective BCAA catabolic reactions after the initial transamination step. Worms with impaired BCAA metabolism show a slower turnover of a GFP‐based proteasome substrate, which is suppressed by loss‐of‐function of the first BCAA catabolic enzyme, the branched‐chain aminotransferase BCAT‐1. The exogenous supply of BCAA‐derived carboxylic acids, which are known to accumulate in the body fluid of patients with BCAA metabolic disorders, is sufficient to regulate the UPS. The link between BCAA intermediates and UPS function presented here sheds light on the unexplained role of BCAAs in the aging process and opens future possibilities for therapeutic interventions. [ABSTRACT FROM AUTHOR]