Citations

Abstract IDH mutant gliomas depend on glutaminase for glutamate/glutathione generation from glutamine because R-2-hydroxyglutarate inhibits branched chain amino acid transaminase mediated glutamate biosynthesis. Telaglenastat (CB-839 HCl) is a potent glutaminase-1 specific inhibitor which depletes tumor glutamate in orthotopic IDH mutant glioma PDX models and extends survival in these orthotopic models when added to radiation/temozolomide. NCI-10218 (NCT03528642) is a phase I clinical trial investigating the safety and tolerability of telaglenastat administered orally concurrently with standard doses of radiation (50.4 Gy, grade 2; 59.4 Gy, grade 3) and temozolomide (75 mg/m2 orally daily) in patients (age 16+) with previously untreated IDH mutant grade 2/3 astrocytoma. Telaglenastat dose was escalated in cohorts (400-800 mg twice daily) based on a standard 3 + 3 design to determine the recommended phase 2 dose (RP2D). Toxicities were graded per CTCAE v5.0. An expansion cohort additionally incorporated a seven-day run-in of telaglenastat monotherapy at RP2D prior to radiation to evaluate the pharmacodynamic impact of telaglenastat on plasma and tumor metabolites. 23 patients with IDH mutant astrocytoma (WHO grade 2, n = 5; WHO grade 3, n = 18) were accrued between December 2018 and January 2022 (Dose Escalation: 16; Dose Expansion: 7). Median age was 32 years (range 23-69 years). 61% were male and 70% were ECOG 0. No dose-limiting toxicities were observed. Grade 3/4 adverse events (independent of attribution) included: lymphopenia (3), neutropenia (2), leukocytosis (2), alanine transaminase elevation (2), thrombocytopenia (1), leukopenia (1), maculopapular rash (1), hyperglycemia (1), hyponatremia (1). The RP2D of concurrent telaglenastat was defined as 800 mg twice daily. Following peak absorption on Day 15 at RP2D, the mean (%CV) terminal elimination half-life in the plasma was 4.2 (53.5%) hours (range 2.1-7.1 hours). The Cmax, Tmax, oral clearance, and AUC were 1496 ng/mL, 4.0 hr, 93.6 L/hr/m2, and 7430 ng/mL*hr, respectively.

Skeletal muscle is critical for maintaining mobility, independence, and metabolic health in older adults. However, a common feature of aging is the progressive loss of skeletal muscle mass and function, which is often accompanied by mitochondrial impairments, oxidative stress, and insulin resistance. Exercise improves muscle strength, mitochondrial health, and cardiorespiratory fitness, but older adults often exhibit attenuated anabolic responses to acute exercise. Chronic inflammation associated with aging may contribute to this “anabolic resistance” and therapeutic interventions that target inflammation may improve exercise responsiveness. To this end, we conducted a randomized controlled trial to determine the effect of 6 months of dietary omega-3 polyunsaturated fatty acids (n3-PUFA) supplementation on skeletal muscle function (mass, strength), mitochondrial physiology (respiration, ATP production, ROS generation), and acute exercise responsiveness at the level of the muscle (fractional synthesis rate) and the whole-body (amino acid kinetics) in healthy older adults. When compared with a corn oil placebo (n = 33; 71.5 ± 4.8 years), older adults treated with 4 g/day n3-PUFA (n = 30; 71.4 ± 4.5 years) exhibited modest but significant increases in muscle strength (3.1 ± 14.7% increase in placebo vs. 7.5 ± 14.1% increase in n3-PUFA; p = 0.039). These improvements in muscle strength with n3-PUFA supplementation occurred in the absence of any effects on mitochondrial function and a minor attenuation of the acute response to exercise compared to placebo. Together, these data suggest modest benefits of dietary n3-PUFAs to muscle function in healthy older adults. Future studies may elucidate whether n3-PUFA supplementation improves the exercise response in elderly individuals with co-morbidities, such as chronic inflammatory disease or sarcopenia.

We show how switching from a regular diet to an HCHF increases cholesterol absorption in patients with normal weight and obesity. The decrease in cholesterol absorption from an HCHF to an LCLF, on the other hand, was only seen in normal-weight controls, underlining the importance of body weight in this regulation. In addition, changes in caloric and fat content had an immediate and direct effect on hepatic bile acid production.

Transient insulin deprivation with concurrent hyperglucagonemia is a catabolic state that can occur in type 1 diabetes. To evaluate glucagon’s catabolic effect in the setting of its glucogenic effect, we measured the regional exchanges of amino acid metabolites (amino-metabolites) across muscle and splanchnic beds in 16 healthy humans during either somatostatin followed by glucagon or saline infusion alone. Despite a twofold or greater increase in the regional exchange of amino-metabolites by glucagon, whole-body kinetics and concentrations of amino acids (AA) remained stable. Glucagon increased the splanchnic uptake of not only gluconeogenic but also essential (EAA) AA while increasing their release from the muscle bed. Regional tracer-based kinetics and 3-methylhistidine release indicate that EAA release from muscle is likely caused by reduced protein synthesis rather than increased protein degradation. Furthermore, many metabolites known to affect insulin action and metabolism were altered by hyperglucagonemia including increase in branched-chain AA and keto acids of leucine and isoleucine in arterial plasma. Further, an increase in arterial concentrations of α-aminoadipic acid arising from increased conversion from lysine in the splanchnic bed was noted. These results demonstrate that hyperglucagonemia during hypoinsulinemia increases net muscle protein catabolism and substantially increases the exchange of amino metabolites across splanchnic and muscle beds.

Obesity is associated with several skeletal muscle impairments which can be improved through an aerobic exercise prescription. The possibility that exercise responsiveness is diminished in people with obesity has been suggested but not well‐studied. PURPOSE The purpose of this study was to investigate how obesity influences acute exercise responsiveness within skeletal muscle. METHODS Non‐obese (NO; n=19; 10F/9M; BMI=25.1 ± 2.8 kg/m 2 ) and Obese (O; n=21; 14F/7M; BMI=37.3 ± 4.6 kg/m 2 ) adults performed 30 minutes of single‐leg cycling at 70% of VO 2 peak. Serial muscle biopsies (vastus lateralis) were collected before exercise and 3 and 6 hours post‐exercise to measure protein synthesis and gene expression. RESULTS The exercise‐induced fold change in mixed muscle protein synthesis trended (p=0.058) higher in NO (1.28 ± 0.54‐fold) compared to O (0.95 ± 0.42‐fold) and was inversely related to BMI (r=‐.374, p=0.027). RNA sequencing revealed 331 and 280 genes that were up or downregulated after exercise in NO and O, respectively. Gene set enrichment analysis showed O had blunted post‐exercise pathways related to MAPK signaling, chemokine‐mediated signaling, FC receptor mediated stimulation signaling, cell proliferation, apoptosis, and RNA polymerase II promotion. Quantitative polymerase chain reaction of select metabolic ( PGC1a, PGC1b, TFAM, PDK4, IRS, MAPK, and PRKAA1 ) and muscle growth ( SLC, TBC, MSTN, MyoD, TRIM32, FOX03, and FBXO3) genes were similar between groups 3 and 6 hours after exercise. Conclusion These data highlight several unique pathways in individuals with obesity that result in a blunted exercise response.

AbstractObjectiveThe health benefits of exercise are well documented, but several exercise‐response parameters are attenuated in individuals with obesity. The goal of this pilot study was to identify molecular mechanisms that may influence exercise response with obesity.MethodsA multi‐omics comparison of the transcriptome, proteome, and phosphoproteome in muscle from a preliminary cohort of lean individuals (n = 4) and individuals with obesity (n = 4) was performed, before and after a single bout of 30 minutes of unilateral cycling at 70% maximal oxygen uptake (VO2 peak). Mass spectrometry and RNA sequencing were used to interrogate the proteome, phosphoproteome, and transcriptome from muscle biopsy tissue.ResultsThe main findings are that individuals with obesity exhibited transcriptional and proteomic signatures consistent with reduced mitochondrial function, protein synthesis, and glycogen synthesis. Furthermore, individuals with obesity demonstrated markedly different transcriptional, proteomic, and phosphoproteomic responses to exercise, particularly biosynthetic pathways of glycogen synthesis and protein synthesis. Casein kinase II subunit alpha and glycogen synthase kinase‐3β signaling was identified as exercise‐response pathways that were notably altered by obesity.ConclusionsOpportunities to enhance exercise responsiveness by targeting specific molecular pathways that are disrupted in skeletal muscle from individuals with obesity await a better understanding of the precise molecular mechanisms that may limit exercise‐response pathways in obesity.

Dietary salt intake has significant effects on arterial blood pressure and the development of hypertension. Mechanisms underlying salt-dependent changes in blood pressure remain poorly understood. The goal of the present study was to utilize urine samples from the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial and a targeted metabolomic approach to identify associations of urinary metabolites with blood pressure phenotypes on low- or high-sodium intake. We examined urinary levels of metabolites in 103 participants of the DASH-Sodium trial after 30 days on a defined diet containing high sodium (targeting 150 mmol sodium intake per day) or low sodium (50 mmol sodium per day). Systolic or diastolic pressure was 10 or more mmHg higher on the high-sodium intake in 51 of the 103 participants. Targeted chromatography/mass spectrometry analysis was performed in 24-h urine samples for 10 metabolites related to the tricarboxylic acid cycle and 47 amino metabolites. Urinary metabolite levels improved the prediction of classification of blood pressure salt-sensitivity based on race, age and sex. Random forest and generalized linear mixed model analyses identified significant (false discovery rate <0.05) associations between 24 h excretions of β-aminoisobutyric acid, cystine, citrulline, homocysteine and lysine and systolic blood pressure and between cystine and diastolic blood pressure. The differences of 24 h excretion of homocysteine between low- and high-sodium intakes were significantly associated with the differences in diastolic blood pressure. These associations were significant with or without considering demographic factors. Treatment with β-aminoisobutyric acid significantly attenuated high-salt-induced hypertension in Dahl salt-sensitive rats. These findings support the presence of new mechanisms of blood pressure regulation involving metabolic intermediaries.

To our knowledge, this is the first study to suggest that skeletal muscle mitochondrial deficits are associated with cancer-associated weight loss in humans. Mitochondrial deficits and alterations in the phospholipid metabolome were concurrent with reductions in whole body and skeletal muscle functional capacity. Whether mitochondrial deficits are causal or secondary to cancer-associated weight loss and functional deficits remains to be determined, but this study supports further exploration of mitochondria as a driver of cancer-associated losses in muscle mass and function.