Branched-chain Amino Acids Research Articles (Page 1)

Introduction This study evaluated the effects of graded supplementation of branched-chain amino acids (BCAAs) in lactating mares on lactation performance, foal growth, and metabolic responses. Methods Twenty mare-foal pairs were assigned to control, low- (38 g/d), medium- (76 g/d), or high-dose (114 g/d) groups. Milk and blood samples were collected over 60 days for composition, hormone, and metabolomic analyses. Fecal microbiota from the foals was also examined. Results BCAAs supplementation interacted with lactation stage, enhancing milk fat yield and increasing milk growth hormone and progesterone. The medium dose (76 g/d) was effective, while 114 g/d showed the strongest effects. High-dose BCAAs altered organic acid abundance, influencing lipid, energy, and BCAA metabolism, correlating with milk composition changes. In foals, altered milk reduced serum BCAAs and other amino acids but elevated growth hormones (GH, INS, IGF-1) dose-dependently. Antioxidant and immune parameters were unaffected. The high dose increased blood urea nitrogen, indicating higher nitrogen load, whereas the medium dose supported growth without metabolic stress. Fecal microbiota analysis revealed enriched amino acid degradation pathways, especially for BCAAs. Discussion We conclude that BCAAs supplementation regulates milk fat synthesis and promotes foal growth via a milk–microbiota–metabolism axis, providing a basis for improving milk quality and offspring development through maternal nutrition.

Non-proteinogenic amino acids, such as L-citrulline and L-theanine, have garnered attention for their potential health benefits, including enhanced immunity, antioxidant activity, and cardiovascular support. The application of natural amino acids in disease treatment and health supplementation is and will remain a research hotspot in pharmaceutics. Plant-derived L-citrulline and L-theanine have demonstrated multifaceted benefits, primarily through mechanisms involving nitric oxide (NO) bioavailability (for L-citrulline) and mitochondrial regulation or immune modulation (for both). Critical gaps are identified: (1) the role of D-amino acids (e.g., D-citrulline and D-theanine) in health and metabolism remains underexplored, particularly regarding chiral-specific bioactivity; (2) derivatives and co-administration strategies of L-forms warrant systematic evaluation for drug. However, while these compounds show promise, evidence is predominantly from animal and cell studies, with limited long-term human data on efficacy and safety. Potential side effects, dosing limitations, and sourcing challenges are discussed. This review emphasizes the need for cautious interpretation of their benefits, acknowledging that while promising, some effects, such as those on muscle protein synthesis, require further validation compared to established nutrients like branched-chain amino acids. By bridging mechanistic insights with translational challenges, this work aims to guide future research toward sustainable nutraceutical production.

To develop and validate a dynamic 13C-MRI acquisition strategy for imaging branched-chain amino acid (BCAA) metabolism catalyzed by branched-chain aminotransferase (BCAT) using hyperpolarized [1-13C]2-ketoisocaproate (KIC), and to assess its scalability to a large-animal model. A multiband spectral-spatial excitation was combined with IDEAL spiral imaging at 3 T to capture conversion of KIC to [1-13C]leucine. Hyperpolarized KIC was produced by dissolution dynamic nuclear polarization (dDNP). The method was validated in phantoms mimicking in vivo conditions and applied in mouse brains, where BCAT activity is well characterized. To assess translational feasibility, the protocol was adapted for pig kidneys, a well-perfused organ with renal physiology and BCAT expression similar to humans. Phantom studies confirmed spectral separation and accurate spatial localization. In mice, the multiband IDEAL spiral sequence generated metabolic maps comparable to chemical-shift imaging but with higher SNR. Dynamic imaging at 1 s temporal resolution captured reproducible KIC-to-leucine conversion across six animals. In pigs, 2 s-resolution imaging revealed KIC uptake in renal vasculature and cortex followed by cortical leucine accumulation and efflux into the vena cava, reflecting localized metabolism and transport. The presented 13C-MRI strategy enables efficient spectral separation and high-temporal-resolution imaging of KIC metabolism in rodents and pigs, establishing a translatable framework for noninvasive studies of BCAA metabolism.

Introduction The high incidence rate of metabolic dysfunction-associated steatotic liver disease (MASLD) has been a big burden on public health globally. Methods To explore microbial and metabolic characteristics of MASLD, we performed 16S rDNA sequencing and untargeted metabolomics on 138 stool samples from MASLD patients. Through the construction of multi-omics featuremaps, we identified relevant changes in microbial and metabolic signatures and evaluated potential clinical value in MASLD. Results The result showed that the high-fat, high-protein dietary pattern in MASLD patients is one of the reasons for the upregulation of Parabacteroides merdae abundance. And it can increase the branched-chain amino acid catabolic capacity in MASLD patients, thereby improving metabolic syndrome and increasing the abundance of beneficial bacteria to improve the intestinal microbiota balance. Then, the downregulation of Lachnospiraceae bacterium in MASLD patients may lead to intestinal inflammatory responses. Moreover, its increasing abundance might result in heightened appetite in MASLD patients, which leads to insulin resistance and liver damage. And the increasing in glycerophospholipid (GP) metabolites in the gut of MASLD patients is highly correlated with metabolic disorders and disease progressionassociated with hepatic fat accumulation and inflammatory responses (AUC > 0.9). Therefore, the levels of GP metabolites in the stool of MASLD patients serve as a reliable diagnostic biomarker for fatty liver and represent a potential target for the diagnosis and treatment of MASLD. Discussion After analysis of gut microbiota and metabolites, we found that Lactobacillus johnsonii down-regulated in MASLD drives 2,6-Dichlorohydroquinone accumulation, provoking toxic buildup and accelerating disease progression.

Ischemia–reperfusion is a rapidly evolving cascade that involves a variety of metabolic shifts whose precise timing and sequential order are still poorly understood. Clarifying these dynamics is critical for understanding the core injury trajectory of stroke and for refining time-delimited therapeutic interventions. More broadly, continuous in situ monitoring of the middle-cerebral-artery occlusion process at the system level has not yet been achieved. Here, we report the first single-subject high-resolution spatiotemporal resolution metabolic maps of the ultra-early phase of ischemic stroke in a rodent model. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) imaging mapped a metabolic abnormality area in the ischemic hemisphere that propagates from the striatum to the cortex. Microdialysis probes were then stereotaxically implanted within this metabolic abnormality area, capturing 10,429 metabolites that resolved into 16 temporally distinct trajectories aligned with probe insertion, ischemic injury, and reperfusion injury. Analysis of specific metabolic pathways mainly revealed that the delayed clearance of metabolic waste (urea and tryptamine) during early reperfusion, the transient attenuation of the citrate-to-oxaloacetate buffering gradient within the TCA cycle, and the accumulation of extracellular branched-chain amino acids all play crucial roles in shaping the injury trajectory. Simultaneously, the depletion of cellular repair mechanisms (pyrimidine synthesis) in the early phase of reperfusion also warrants our attention. These findings provide novel insights into the molecular basis and mechanisms of ischemia–reperfusion and offer a comprehensive resource for further investigation.

Branched-chain amino acids (BCAAs), comprising leucine, isoleucine, and valine, are essential nutrients whose metabolic homeostasis is critical to cardiovascular health. This review synthesizes the dietary sources, physiological roles, and metabolic pathways of BCAAs, explores mechanisms driving their accumulation, and evaluates current detection techniques. We highlight the regulatory impact of BCAAs and their metabolites on cardiovascular disease (CVD) through multiple pathways. We propose a combinatorial strategy integrating dietary modulation, administration of BCAA-catabolizing enzymes (e.g., BT2, JK-1), mammalian target of rapamycin (mTOR) pathway modulation, and utilization of natural compounds (e.g.,Salvia miltiorrhiza,Panax notoginseng) to counteract BCAA metabolic dysregulation-induced cardiovascular pathologies. This review provides a theoretical framework for understanding BCAA metabolism in CVD, emphasizes the importance of combined monitoring of BCAAs and their metabolites (branched-chain α-keto acids [BCKAs], 3-hydroxyisobutyrate [3-HIB]), and advances precision cardiology strategies targeting metabolic pathways.

Rapid clonal selection within early hematopoietic cell compartments presages outcome to ivosidenib combination therapy.

Introduction: Metabolic syndrome has become a global health crisis affecting 25-35% of adults. Conditions of metabolic syndrome increase the risk of cardiovascular disease, stroke, and diabetes. Branched-chain amino acids (BCAAs) are elevated in metabolic syndrome and play important roles in ATP production and modulation of metabolic processes. The dysregulation of BCAA metabolism has been linked to atrial arrhythmias but the mechanisms underlying this link are not clearly understood. Goal: To show that BCAA elevation promotes mitochondrial dysfunction and oxidative stress through mTOR activation causing proarrhythmic electrophysiological remodeling using an in vitro human induced pluripotent stem cell (hiPSC)-derived 3D atrial microtissue platform. Methods: hiPSC-derived 3D atrial microtissues (MTs) were cultured under two conditions for 5 days: 1) control (CTR) media: RPMI 1640 Media+B27+albumin+ antibiotics, 2) BCAA media: control media+7.5 mM Leucine+4.5 mM isoleucine+10 mM valine. Spontaneous or stimulated (1 Hz) atrial microtissue action potentials (APs) were recorded by imaging voltage sensitive dye (3 culture batches, 157~244 MTs/condition). The Seahorse assay was used to assess mitochondrial respiration (2 batches, 21~23 MTs/condition). Mass spectrometry (2 batches, 180~210 MTs/condition) and bioinformatics were used to compare metabolite profiles. Results: Compared to CTR, BCAA treatment significantly increased (mean ± SD, p<0.05, independent t-test) automaticity (cycle length: BCAA=1360±524 vs CTR=1506±220 ms), increased pacemaker potential amplitude (BCAA=46±26 vs CTR=34±28 mV ), and shortened AP duration (APD: BCAA=200±67 vs CTR=236±64 ms) (panel A&B). Preliminary data indicate that adding the mTOR inhibitor rapamycin to the BCAA media (10 nM, 5 days) can restore the APD in BCAA-treated microtissues (panel C), aligning with the hypothesis that BCAA dysregulation operates via the mTOR pathway to promote atrial arrhythmias. BCAA treatment also reduced basal and ATP linked mitochondrial respiration (panel D). Changes in metabolites associated with excitability and ion channel regulation were detected by mass spectrometry: BCAA increases AMP, AMP/ATP ratio, and spermidine (panel E) and decreases NAD levels. Conclusion: The observed effects of treating hiPSC atrial microtissues with BCAA on their action potentials, mitochondrial dysfunction, and changes in metabolite profiles favor ectopic activity and reentry in cardiac atrial tissue.

Background: HFpEF is a highly prevalent yet poorly understood syndrome that lacks disease-modifying therapies. While dysregulation of fuel substrate metabolic pathways is recognized in heart failure, their role in HFpEF remains incompletely defined. We applied untargeted metabolomic profiling across multiple tissues in murine models of HFpEF and HFrEF to investigate alterations in canonical fuel metabolism and identify novel metabolic pathways relevant to disease pathogenesis. Methods: Male C57BL/6N mice were randomized to receive standard chow, high-fat diet plus L-NAME (HFpEF model), or transverse aortic constriction (HFrEF model). HFpEF mice were treated for 5 (short-term) or 15 (long-term) weeks. Serum, liver, and left ventricular tissues were analyzed by untargeted mass spectrometry-based metabolomics. Metabolite levels were compared between HF and standard chow groups. Canonical fuel substrate pathways—branched-chain amino acids (BCAA), fatty acid oxidation (FAO), and ketones—were analyzed alongside discovery-driven profiling. Results: Analysis of canonical fuel substrate pathways revealed evidence of higher myocardial BCAA levels with lower downstream catabolic levels, suggesting higher BCAA uptake with a potential bottleneck at BCKDH in both HFpEF and HFrEF; reductions in myocardial FAO intermediates in HFpEF; and higher ketone body levels in heart and serum of HFpEF vs. standard chow. Discovery analysis identified p-cresol sulfate and p-cresol glucuronide— conjugated derivatives of p -cresol, a microbial metabolite of tyrosine fermentation —as the most significantly and consistently elevated metabolites in HFpEF across tissues. In the long-term model, p-cresol sulfate levels were increased by 42.0-fold in heart, 29.3-fold in liver, and 33.4-fold in serum; p-cresol glucuronide was increased by 13.7-, 28.0-, and 61.0-fold, respectively (all q < 0.05). Notably, these changes were not observed in HFrEF. Elevations in p-Cresol sulfate were corroborated in plasma from human HFpEF subjects. Conclusions: This tissue-wide metabolomic analysis in murine HFpEF and HFrEF models reveals HFpEF-specific metabolic remodeling—marked by impaired BCAA catabolism, reduced myocardial FAO, and enhanced ketone metabolism—mirroring human disease. The striking accumulation of microbial-derived p-cresol conjugates in HFpEF, but not HFrEF, suggests gut-liver-heart axis disruption and nominates these metabolites as candidate biomarkers or therapeutic targets.

Background: Emerging evidence shows that key features of HCM—left-ventricular hypertrophy (LVH), diastolic dysfunction, and impaired cardiac energetics—are linked to systemic metabolic derangements such as insulin resistance. Because skeletal muscle mediates ~80% of post-prandial glucose disposal and ~25% of basal metabolic rate, even modest increases in muscle mass can markedly enhance whole-body insulin sensitivity. Moreover, dysregulated branched-chain amino acid (BCAA) catabolism yields intermediates that blunt insulin signaling and drive pathological cardiac growth, placing BCAA metabolism at the nexus of HCM and systemic insulin resistance. Hypothesis: Pharmacologically induced skeletal-muscle hypertrophy—achieved by myostatin/activin blockade with the murine anti-ActRII antibody CDD866—increases muscle demand for glucose and BCAAs, thereby reducing insulin resistance, restoring cardiac metabolic flexibility, and ameliorating established HCM features. Methods: Male R403Q-HCM mice (24 wk) received CDD866 or isotype control (20 mg/kg s.c. q3d) for 4 wk. End-point tests included echoMRI body composition, skeletal-muscle weights, echocardiography, oral glucose tolerance test (oGTT), grip strength, exercise tolerance test, and LV transcriptomics. Results: CDD866 produced robust muscle hypertrophy (+20% lean mass; body weight +12%; individual muscles +44–87%) and lowered oGTT AUC, indicating improved insulin sensitivity. LVH was reduced (LV wall thickness −9%), diastolic indices improved (E/A and Em ↑), and cardiac gene expression reverted toward WT with up-regulation of fatty-acid oxidation, BCAA catabolism, and mitochondrial oxidative pathways. Functional capacity increased (grip strength +35%, treadmill endurance +29%). Conclusions: Pharmacologic myostatin/activin blockade enlarges skeletal muscle, improves insulin sensitivity, restores cardiac metabolic flexibility, reduces LV hypertrophy, and enhances diastolic function in established HCM. Augmenting muscle mass therefore emerges as a promising adjunct therapy for HCM, especially in insulin-resistant states.

Background: Myocardial ischemia-reperfusion injury (IRI) arises by abrupt myocardial blood flow restoration after ischemia leading to cardiomyocyte dysfunction and death. Mechanisms of myocardial IRI involve an interplay of metabolic dysfunction, including branched-chain amino acid (BCAAs) imbalance, and mitochondrial dysfunction, resulting in oxidative stress, inflammation, and cardiomyocyte death. Our lab was the first to demonstrate the cardioprotective effects of intralipid (ILP), a safe lipid emulsion, against myocardial IRI in rodents; However, underlying mechanisms remain unclear. Research Hypothesis: We hypothesize that ILP protects IRI by restoring the depletion of BCAAs, thereby attenuating inflammation, oxidative stress, and apoptosis. Methods: Male rats were subjected to sham or IRI by LAD ligation for 30 min followed by 180 min of reperfusion. The IRI group received either a single bolus of ILP (20%, 5ml/kg body weight) or saline at the onset of reperfusion. RNA seq and LC Mass spectrometry were performed on left ventricle (LV). In vitro, H9C2 cardiac myoblasts were exposed to 3h of hypoxia followed by 6h of reoxygenation, with or without 20% ILP during reoxygenation. Seahorse assessed H9C2 mitochondrial function and RT-PCR quantified inflammatory and apoptotic markers expression. Results: LV transcriptomic analysis revealed that IRI significantly downregulated oxidative phosphorylation and fatty acid oxidation, while upregulating glycolysis, hypoxia, inflammation, and apoptosis pathways compared to sham. LV from ILP-treated rats exhibited similar pathway dynamics to levels observed in sham rats. In vitro, ILP administration during reoxygenation significantly enhanced ATP production and oxygen consumption in H9C2 cells compared to controls. Also, ILP-treated H9C2 cells exhibited upregulated expression of respective anti-apoptotic and antioxidant markers Bcl-2 and Sod2, downregulated expression of pro-apoptotic marker Bax, and pro-inflammatory TNA-α. Metabolomic profiling revealed that BCAAs including valine, leucine, and isoleucine were among the downregulated LV metabolites by IRI, but upregulated by ILP treatment upon IRI, with significant changes observed specifically for valine. Conclusion(s): Together, our data suggest that ILP administration at the onset of myocardial reperfusion preserves reduced BCAAs levels caused by IRI and improves mitochondrial function, leading to attenuated cardiomyocyte inflammation, apoptosis and oxidative stress.

Background: Impaired branched-chain amino acid (BCAA) catabolism contributes to the development and progression of heart failure (HF). However, the mechanisms regulating BCAA catabolism under physiological and pathological conditions remain incompletely understood. 3-Mercaptopyruvate sulfurtransferase (3-MST), a mitochondrial hydrogen sulfide (H 2 S)-producing enzyme, may play a critical role in this context. We investigated the role of 3-MST-derived mitochondrial H 2 S in modulating myocardial BCAA catabolism in two distinct HF models. Methods: Global 3-MST knockout (KO) and wild-type (WT) mice were investigated. Heart failure with reduced ejection fraction (HFrEF) was induced by transverse aortic constriction, while HF with preserved ejection fraction (HFpEF) was established via L-NAME administration in conjunction with a high-fat diet. Targeted metabolomic analyses were performed to assess BCAA catabolism. Cardiac function and exercise capacity were evaluated using echocardiography, invasive hemodynamics, and treadmill testing. Results: At baseline, 3-MST KO hearts exhibited reduced mitochondrial H 2 S production accompanied by modest impairment in BCAA catabolism. Under HF conditions, BCAA catabolic defects were markedly aggravated in 3-MST KO mice, as evidenced by the accumulation of BCAA metabolic intermediates in both HFrEF and HFpEF hearts compared to WT controls. These metabolic impairments were associated with worsened HF phenotypes, including reduced left ventricular ejection fraction in HFrEF, increased E/e′ ratio in HFpEF, elevated left ventricular end-diastolic pressure, and diminished exercise performance in both HF models. Additionally, skeletal muscle from 3-MST KO mice showed downregulation of BCAA catabolic enzymes. Notably, treatment with exogenous H 2 S donors restored BCAA catabolism and ameliorated cardiac dysfunction in 3-MST-deficient mice. Conclusion: These findings identify mitochondrial H 2 S produced by 3-MST as a key regulator of myocardial BCAA catabolism and HF pathophysiology. Loss of 3-MST disrupts BCAA catabolic homeostasis and exacerbates cardiac dysfunction in both HFrEF and HFpEF. Therapeutic replenishment of H 2 S may represent an effective strategy to restore metabolic balance and improve outcomes in HF. Ongoing studies aim to further elucidate the molecular interactions between 3-MST and key enzymes of the BCAA catabolic pathway.

Background: Heart failure with preserved ejection fraction (HFpEF) is a growing clinical challenge frequently associated with obesity and diabetes. While systemic metabolic abnormalities are known, myocardial-specific impairments in substrate metabolism remain poorly characterized. Hypothesis: HFpEF myocardium exhibits coordinated suppression of mitochondrial fuel oxidation—including fatty acids (FA), ketones, branched-chain amino acids (BCAA), and anaplerotic pathways. Methods: We analyzed myocardial tissue from HFpEF patients and non-failing (NF) controls using bulk RNA-seq (41 HFpEF, 24 NF), targeted metabolomics (38 HFpEF, 20 NF), and Western blotting for key metabolic enzymes. Results: Metabolomics revealed reduced medium- and long-chain acylcarnitines in HFpEF, suggesting impaired FA oxidation. Bulk RNA-seq showed downregulation of FA transport genes (CD36, FATP4, ACSL family, CPT1A). Protein analysis confirmed decreased FA transporters: CPT1A (P=0.0002), CPT1B (P=0.005), ACSL1 (P=0.002), FATPs, and β-oxidation enzymes (ACADs, HADHs), with unchanged CPT2—indicating defects in both FA transport and oxidation. While myocardial and plasma β-hydroxybutyrate (3-HBA) were unchanged, downstream C4-OH β-hydroxybutyryl was significantly reduced. Ketone oxidation enzymes BDH1 and ACAT1 were lower (P=1.2e-6, P=1e-6), despite preserved or elevated transcripts. SLC16A1 was unchanged at both mRNA and protein levels, suggesting intact ketone uptake but impaired oxidation. In BCAA metabolism, myocardial leucine, valine, and isoleucine were elevated in HFpEF, while downstream catabolites were lower. BCAT2 protein was significantly reduced (P=5.6e-7), while total and phosphorylated BCKDH and BCKDK were unchanged, suggesting a bottleneck in BCAA-to-keto-acid conversion. Despite BCAA accumulation, phosphorylation of mTOR effectors (p70S6K, AKT) was unchanged. In the TCA cycle, fumarate, malate, and succinate were reduced, while oxaloacetate was elevated; TCA enzyme transcripts were unchanged, suggesting impaired anaplerosis. GLUD1, ME1, and GOT1 proteins were decreased (P=0.003, P=4.7e-7, P=0.0002), while PCCB and MMUT proteins were increased (P=4.5e-5, P=0.02), suggesting enhanced compensatory propionyl-CoA–derived succinyl-CoA input. Conclusions: HFpEF myocardium shows coordinated suppression of mitochondrial substrate use at gene, protein, and metabolite levels. Targeting these bottlenecks may offer therapeutic opportunities.

Background: Skeletal muscle (SKM) dysfunction is a critical determinant of exercise intolerance and frailty in heart failure with preserved ejection fraction (HFpEF). Perturbed SKM metabolism and mitochondrial dysfunction are considered to be major components of SKM dysfunction, but the mechanisms and pathways are understudied and poorly defined. Molecular elucidation of dysregulated metabolism in SKM in HFpEF is essential to determine viable targets for the treatment of exercise intolerance in HFpEF. Methods: 26-week-old Male ZSF1 Obese rats (HFpEF) and WKY lean normotensive controls. Gastrocnemius was subjected to bulk RNA-seq, proteomics, and metabolomics analysis. Limma was used to determine significant differential expression of genes and proteins, with an adjusted p-value (FDR) of < 0.1. Pathway enrichment analysis was performed on transcriptomics and proteomics datasets via the fGSEA package in R. Differentially expressed metabolites were also identified via limma with a cutoff of nominal p-value <0.01 for statistical significance, and metabolites of interest were mapped onto KEGG pathways. Results: Pathway level analysis of the Wikipathways database for transcriptomics and proteomics revealed significant downregulation of oxidative phosphorylation (NES -2.1, p<0.005), ETC (NES -2.0 p<0.005), and TCA cycle (-1.8, p<0.05) in HFpEF. The most upregulated pathways were PPAR signaling (NES 2.2, p<0.001), tryptophan metabolism (NES 1.8, P<0.005), and amino acid oxidation (NES 1.8, p<0.005) pathways. Metabolomics revealed an accumulation of TCA cycle intermediates (isocitrate, 2.4 FC), and phosphate reduction (0.9 FC). Branched-chain amino acids were significantly increased in HFpEF whereas amino acids related to tryptophan metabolism (kynurenine, 0.3 FC) were reduced and shifted towards increased serotonin (1.8 FC) accumulation. Phospholipid species were differentially regulated with increased palmitoylated phosphatidylcholines (~1.6 FC) but reduced arachidonoyl-PC species (~0.7). Phosphatidylethanolamines (PE) species (16:0/16:1-18:0/18:2) were increased (2.2 FC) in HFpEF. Conclusion: Our multi-omics analysis of skeletal muscle in HFpEF revealed severe mitochondrial dysfunction characterized by the slowing of TCA cycle flux with accelerated lipid influx. The accumulation of lipids results in a shift in membrane phospholipid accumulation. Reduced BCAA oxidation and dysregulation of tryptophan metabolism are key features of SKM dysfunction in HFpEF.

Background: Heart failure with preserved ejection fraction (HFpEF) is a syndrome that may manifest differently in different people, and doctors lack clear tools for predicting how it will progress or how well medications will work. Traditional clinical risk assessments fail to capture the molecular complexity of HFpEF. Using machine learning (ML) to aggregate multi-omic data is a potential strategy for improving risk classification and discovering new biological subtypes. Objective: To develop and validate a multi-omic ML model that integrates clinical variables, genomic, proteomic, and metabolomic data to predict 1-year mortality and heart failure hospitalization in HFpEF patients. Methods: We analyzed data from 1,802 UK Biobank participants with validated HFpEF (LVEF > 50%). The patients' healthcare records, echocardiograms, genotyping arrays, proteomic profiles (Olink platform), and metabolomic profiles (Nightingale Health) were all connected. The main outcome was either death from any cause or hospitalization for heart failure within one year after the baseline evaluation. We built a machine learning pipeline with 10-fold cross-validation that used the XGBoost and random forest algorithms. We used recursive feature elimination and SHAP (Shapley Additive Explanations) to find features and make the model easier to understand. Results: The integrated multi-omic ML model had an AUC of 0.91 (95% CI: 0.88-0.93), significantly outperforming models based only on clinical factors (AUC 0.74) or individual omic layers (genomic: 0.79; proteomic: 0.82; metabolomic: 0.84). Key predictors were NT-proBNP, IL-6, GDF-15, branched-chain amino acids, and SNPs in myocardial fibrosis genes (TITIN, COL1A1). SHAP analysis revealed different high-risk molecular clusters, supporting the hypothesis of physiologically driven HFpEF subphenotypes. Conclusion: This study shows that a multi-omic ML method outperforms existing clinical models for predicting outcomes in HFpEF. The ability to combine molecular and clinical data may pave the way for physiologically informed, personalized HFpEF therapy. Prospective validation and implementation studies are required to translate these results into clinical practice.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a prevalent and morbid syndrome strongly linked with obesity. The Glucagon-like Peptide-1 (GLP-1) agonists have emerged as promising therapeutic tools, but their multifarious mechanisms remain under investigation. We investigated proteomic changes in the heart and liver in a pre-clinical model of cardiometabolic HFpEF and the effects of the GLP-1 agonist, semaglutide, with particular focus on lipid and fibrosis signaling. Methods: 10-week-old male ZSF1 obese rats (HFpEF) were treated with low-dose semaglutide (30 nmol/kg subcutaneously twice weekly, n=5) or vehicle (n=5) for 16 weeks. Myocardial and hepatic tissue were collected for mass spectrometry-based proteomics and histology evaluating lipid deposition (TEM and Oli red O) and fibrosis (Sirius Red/Fast Green collagen stain). Protein was labeled using tandem mass tags (TMT-16plex) for multiplexing and quantitation. Post-processing analysis included linear mixed modeling for differential abundance and pathway enrichment analysis (false discovery rate was 0.25). Results: The dose of semaglutide used in this study did not alter body weight. Myocardial enriched pathways for proteins upregulated by semaglutide were related to the ribosome and branch chain amino acid degradation (Fig. 1A). Myocardial enriched pathways for proteins downregulated by semaglutide were related to PPAR signaling, protein-lipid complex, and calmodulin binding. Hepatic enriched pathways for proteins upregulated by semaglutide were related to the ribosome and rRNA binding. Hepatic enriched pathways for proteins downregulated by semaglutide were related to the inflammatory response, oxidative phosphorylation, and SNARE proteins (Fig. 2A). Intracellular myocardial LD quantity and size were decreased as well as were numerous proteins related to lipid homeostasis with semaglutide treatment (Fig. 1B). Left ventricular fibrosis was also reduced with GLP-1 therapy (representative images in Fig. 1C). Similarly, hepatic lipid deposition and fatty acid/lipid protein signaling and fibroblast proliferation pathways were mitigated by semaglutide (Fig. 2B and 2C). Conclusion: These studies provide the first myocardial and hepatic proteomic atlas of the effects of GLP-1 agonism in a pre-clinical model of obese HFpEF. These results link the protective systemic actions of semaglutide on cardiac and hepatic lipid handling and fibrosis in a weight loss independent fashion.

This commentary explores the pervasive challenge of malnutrition and diarrhea, particularly among vulnerable populations such as children and cancer patients, and highlights the limitations of conventional treatments such as standard oral rehydration solutions (ORSs). Drawing on recent evidence, it examines the emerging role of amino acid-based nutritional formulations, with a focus on branched-chain amino acids (BCAAs), VS001, and VS002A, in addressing both nutrient deficiencies and gut dysfunction. The commentary reviews mechanistic and clinical data demonstrating that BCAAs and specialized amino acid-enriched ORSs can promote mucosal healing, improve nutrient absorption, and reduce gastrointestinal symptoms, including those related to chemotherapy. Clinical studies show promising results for VS001 and VS002A in reducing the severity of diarrhea, enhancing hydration, and supporting recovery in both pediatric and oncology settings. While these interventions show considerable potential for transforming supportive care for malnutrition-related diarrhea, further large-scale randomized trials are needed to establish their efficacy across diverse patient populations.

The Effect of Oral Pure Branched-Chain Amino Acid Supplementation on Exercise Performance and Body Composition: A Systematic Review

BCAA exaggerated acute and chronic ischemic heart disease through promotion of NLRP3 via Sirt1.

Branched-chain amino acids in bone health: From molecular mechanisms to therapeutic potential.