Statin treatment reduces leucine turnover, but does not affect endogenous production of beta-hydroxy-beta-methylbutyrate (HMB).

BACKGROUND: Statins, or hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, are one of the most commonly prescribed medications for lowering cholesterol. Myopathic side-effects ranging from pain and soreness to critical rhabdomyolysis are commonly reported and often lead to discontinuation. The pathophysiological mechanism is, in general, ascribed to a downstream reduction of Coenzyme Q10 synthesis, resulting in mitochondrial dysfunction. HMG-CoA is a metabolite of leucine and its corresponding keto acid α-ketoisocaproic acid (KIC) and beta-hydroxy-beta-methylbutyrate (HMB), however little is known about the changes in the metabolism of leucine and its metabolites in response to statins. OBJECTIVE: We aimed to investigate if statin treatment has implications on the upstream metabolism of leucine to KIC and HMB, as well as on other branched chain amino acids (BCAA). DESIGN: 12 hyperlipidemic older adults under statin treatment were recruited. The study was conducted as a paired prospective study. Included participants discontinued their statin treatment for 4 weeks before they returned for baseline measurements (before). Statin treatment was then reintroduced, and the participants returned for a second study day 7 days after reintroduction (after statin). On study days, participants were injected with stable isotope pulses for measurement of the whole-body production (WBP) of all BCAA (leucine, isoleucine and valine) along with their respective keto acids and HMB. RESULTS: We found a reduced leucine WBP (22 %, p = 0.0033), along with a reduction in valine WBP (13 %, p = 0.0224). All other WBP of BCAA and keto acids were unchanged. There were no changes in the WBP of HMB. CONCLUSIONS: Our study shows that statin inhibition of HMG-CoA reductase has an upstream impact on the turnover of leucine and valine. Whether this impairment in WBP of leucine may contribute to the known pathophysiological side effects of statins on muscle remains to be further investigated.

Working Memory Precision and Associative Binding in Mild Cognitive Impairment.

To better understand working memory (WM) deficits in Mild Cognitive Impairment (MCI), we examined information precision and associative binding in WM in 21 participants with MCI, compared to 16 healthy controls, using an item-location delayed reproduction task. WM, along with other executive functions (i.e. Trail Making Task (TMT) and Stroop task), were measured before and after a 2-h nap. The napping manipulation was intended as an exploratory element to this study exploring potential impacts of napping on executive functions.Compared to healthy participants, participants with MCI exhibited inferior performance not only in identifying encoded WM items but also on item-location associative binding and location precision even when only one item was involved. We also found changes on TMT and Stroop tasks in MCI, reflecting inferior attention and inhibitory control. Post-napping performance improved in most of these WM and other executive measures, both in MCI and their healthy peers.Our study shows that associative binding and WM precision can reliably differentiate MCIs from their healthy peers. Additionally, most measures showed no differential effect of group pre- and post-napping. These findings may contribute to better understanding cognitive deficits in MCI therefore improving the diagnosis of MCI.

Amino acid kinetics in the critically ill.

PURPOSE OF REVIEW: Stable isotope methods have been used for many years to assess whole body protein and amino acid kinetics in critically ill patients. In recent years, new isotope approaches and tracer insights have been developed. The tracer pulse approach has some advantages above the established primed-continuous tracer infusion approach because of the high amount of metabolic information obtained, easy applicability, and low tracer costs. Effects of disease severity and sex on amino acid kinetics in ICU patients will also be addressed. RECENT FINDINGS: Current knowledge was synthesized on specific perturbations in amino acid metabolism in critically ill patients, employing novel methodologies such as the pulse tracer approach and computational modeling. Variations were evaluated in amino acid production and linked to severity of critical illness, as measured by SOFA score, and sex. Production of the branched-chain amino acids (BCAAs), glutamine, tau-methylhistidine and hydroxyproline were elevated in critical illness, likely related to increased transamination of the individual BCAAs or increased breakdown of proteins. Citrulline production was reduced, indicative of impaired gut mucosa function. Sex and disease severity independently influenced amino acid kinetics in ICU patients. SUMMARY: Novel tracer and computational approaches have been developed to simultaneously measure postabsorptive kinetics of multiple amino acids that can be used in critical illness. The collective findings lay the groundwork for targeted individualized nutritional strategies in ICU settings aimed at enhancing patient outcomes taking into account disease severity and sex.

Sex related differences in muscle health and metabolism in chronic obstructive pulmonary disease.

BACKGROUND & AIMS: Sex differences in muscle function and mass, dyspnea, and clinical outcomes have been observed in patients with Chronic Obstructive Pulmonary Disease (COPD) despite a similar level of airflow obstruction. Protein and amino acid metabolism is altered in COPD, however, it remains unclear whether a difference in metabolic signature exists between males and females with COPD that may explain the observed differences in muscle health and clinical outcomes. METHODS: In 234 moderate to severe COPD patients (males/females: 113/121) and 182 healthy controls (males/females: 77/105), we assessed, besides presence of comorbidities and clinical features, muscle function by handgrip and leg dynamometry, and body composition by dual-energy x-ray absorptiometry. In the postabsorptive state, a mixture of 18 stable isotopes of amino acids was administered by pulse and arterialized blood was sampled for 2 h. Amino acid concentrations and enrichments were analyzed by LC-MS/MS to calculate whole body (net) protein breakdown (WBnetPB) and whole body production (WBP) rates (µmol/hour) of the amino acids playing a known role in muscle health. Statistics was done by ANCOVA to examine the effects of sex, COPD, and sex-by-COPD interaction with as covariates age and lean mass. Significance was set as p < 0.05. RESULTS: Lung function was comparable between males and females with COPD. Being a female and presence of COPD were independently associated with lower appendicular lean mass, muscle strength, and WBnetPB (p < 0.05). Being a male was associated with higher visceral adipose tissue, C-reactive protein (CRP) (p < 0.05), and higher prevalence of heart failure and obstructive sleep apnea. Sex-by-COPD interactions were found indicating lower fat mass (p = 0.0005) and WBPs of phenylalanine (measure of whole body protein turnover) and essential amino acids (p < 0.05), particularly in COPD females. Higher visceral adipose tissue (p = 0.025), CRP (p < 0.0001), and WBP of tau-methylhistidine (p = 0.010) (reflecting enhanced myofibrillar protein breakdown) were observed in COPD males. CONCLUSIONS: Presence of sex specific changes in protein and amino acid metabolism and cardiometabolic health in COPD need to be considered when designing treatment regimens to restore muscle health in males and females with COPD. CLINICAL TRIAL REGISTRY: www. CLINICALTRIALS: gov, NCT01787682, NCT01624792, NCT02157844, NCT02065141, NCT02770092, NCT02780219, NCT03327181, NCT03796455, NCT01173354, NCT01154400.

The Rationale for Vitamin, Mineral, and Cofactor Treatment in the Precision Medical Care of Autism Spectrum Disorder.

Children with autism spectrum disorder may exhibit nutritional deficiencies due to reduced intake, genetic variants, autoantibodies interfering with vitamin transport, and the accumulation of toxic compounds that consume vitamins. Importantly, vitamins and metal ions are essential for several metabolic pathways and for neurotransmitter functioning. The therapeutic benefits of supplementing vitamins, minerals (Zinc, Magnesium, Molybdenum, and Selenium), and other cofactors (coenzyme Q10, alpha-lipoic acid, and tetrahydrobiopterin) are mediated through their cofactor as well as non-cofactor functions. Interestingly, some vitamins can be safely administered at levels far above the dose typically used to correct the deficiency and exert effects beyond their functional role as enzyme cofactors. Moreover, the interrelationships between these nutrients can be leveraged to obtain synergistic effects using combinations. The present review discusses the current evidence for using vitamins, minerals, and cofactors in autism spectrum disorder, the rationale behind their use, and the prospects for future use.

Impact of ß-hydroxy-ß-methylbutyrate (HMB) in critically ill patients on the endocrine axis - A post-hoc cohort study of the HMB-ICU trial.

BACKGROUND: ß-hydroxy-ß-methylbutyrate (HMB) might improve muscle function and maintain its mass in critically ill patients. We aimed to investigate whether the administration of HMB influenced the plasma levels of growth hormone (GH)/insulin-like growth factor-1 (IGF-1), C-peptide, and 25-OH vitamin-D. METHODS: Post-hoc analysis of the study HMB-ICU, a randomized, placebo-controlled double-blind trial. INCLUSION CRITERIA: Intensive care unit (ICU) patients depending on mechanical ventilation on day 3 with functional gastrointestinal tract. Patients were randomized to HMB (3 g/day) or placebo (maltodextrin) from day 4 on, for 30 days. Blood samples were collected on days 4 and 15. We determined the GH, C-peptide, 25-OH vitamin-D, and IGF-1. Statistics by ANCOVA. RESULTS: Blood samples of 26 patients were available on day 4, and 23 on day 15. While age and severity of disease did not differ, diabetes was more frequent in the HMB group (p = 0.041), and obesity was more frequent in the placebo group (p = 0.021). Glucose intake, blood glucose (BG) and amount of insulin to maintain blood glucose between 6 and 8 mM did not differ between groups. There was no difference between groups for C-peptide, GH, IGF-1, and 25-OH vitamin-D. IGF-1 increased significantly from day 4-15 (p = 0.026) in both groups. CONCLUSION: Subject to possible insufficient power of the study, we did not reach conclusive results. HMB intervention does not affect significantly the plasma concentrations of insulin, GH/IGF axis activity, C-peptide, and 25-OH vitamin-D. GOV IDENTIFIER: NCT03628365.

Short-chain fatty acid production in accessible and inaccessible body pools as assessed by novel stable tracer pulse approach is reduced by aging independent of presence of COPD.

BACKGROUND: Production rates of the short-chain fatty acids (SCFA) acetate, propionate, and butyrate, which are beneficial metabolites of the intestinal microbiota, are difficult to measure in humans due to inaccessibility of the intestine to perform measurements, and the high first-pass metabolism of SCFAs in colonocytes and liver. We developed a stable tracer pulse approach to estimate SCFA whole-body production (WBP) in the accessible pool representing the systemic circulation and interstitial fluid. Compartmental modeling of plasma enrichment data allowed us to additionally calculate SCFA kinetics and pool sizes in the inaccessible pool likely representing the intestine with microbiota. We also studied the effects of aging and the presence of Chronic Obstructive Pulmonary Disease (COPD) on SCFA kinetics. METHODS: In this observational study, we designed a two-compartmental model to determine SCFA kinetics in 31 young (20-29 y) and 71 older (55-87 y) adults, as well as in 33 clinically stable patients with moderate to very severe COPD (mean (SD) FEV1, 46.5 (16.2)% of predicted). Participants received in the fasted state a pulse containing stable tracers of acetate, propionate, and butyrate intravenously and blood was sampled four times over a 30 min period. We measured tracer-tracee ratios by GC-MS and used parameters obtained from two-exponential curve fitting to calculate non-compartmental SCFA WBP and perform compartmental analysis. Statistics were done by ANCOVA. RESULTS: Acetate, propionate, and butyrate WBP and fluxes between the accessible and inaccessible pools were lower in older than young adults (all q < 0.0001). Moreover, older participants had lower acetate (q < 0.0001) and propionate (q = 0.019) production rates in the inaccessible pool as well as smaller sizes of the accessible and inaccessible acetate pools (both q < 0.0001) than young participants. WBP, compartmental SCFA kinetics, and pool sizes did not differ between COPD patients and older adults (all q > 0.05). Overall and independent of the group studied, calculated production rates in the inaccessible pool were on average 7 (acetate), 11 (propionate), and 16 (butyrate) times higher than non-compartmental WBP, and sizes of inaccessible pools were 24 (acetate), 31 (propionate), and 55 (butyrate) times higher than sizes of accessible pools (all p < 0.0001). CONCLUSION: Non-compartmental production measurements of SCFAs in the accessible pool (i.e. systemic circulation) substantially underestimate the SCFA production in the inaccessible pool, which likely represents the intestine with microbiota, as assessed by compartmental analysis.

Females have a different metabolic response to critical illness, measured by comprehensive amino acid flux analysis.

BACKGROUND: The trajectory from healthy to critical illness is influenced by numerous factors, including metabolism, which differs substantially between males and females. Whole body protein breakdown is substantially increased in critically ill patients, but it remains unclear whether there are sex differences that could explain the different health outcomes. Hence, we performed a secondary analysis of a study, where we used a novel pulse isotope method in critically ill and matched healthy males and females. METHODS: In 51 critically ill ICU patients (26 males, 15 females) and 49 healthy controls (36 males and 27 females), we assessed their general and disease characteristics and collected arterial(ized) blood in the postabsorptive state after pulse administration of 8 ml of a solution containing 18 stable AA tracers. In contrast to the original study, we now fitted the decay curves and calculated non-compartmental whole body amino acid production (WBP) and compartmental measurements of metabolism, including intracellular amino acid production. We measured amino acid enrichments and concentrations by LC-MS/MS and derived statistics using AN(C)OVA. RESULTS: Critically ill males and females showed an increase in the WBP of many amino acids, including those related to protein breakdown, but females showed greater elevations, or in the event of a reduction, attenuated reductions. Protein breakdown-independent WBP differences remained between males and females, notably increased glutamine and glutamate WBP. Only severely ill females showed a lower increase in WBP of many amino acids in comparison to moderately ill females, suggesting a suppressed metabolism. Compartmental analysis supported the observations. CONCLUSIONS: The present study shows that females have a different response to critical illness in the production of several amino acids and changes in protein breakdown, observations made possible using our innovative stable tracer pulse approach. CLINICAL TRIAL REGISTRY: Data are from the baseline measurements of study NCT02770092 (URL: https://clinicaltrials.gov/ct2/show/NCT02770092) and NCT03628365 (URL: https://clinicaltrials.gov/ct2/show/NCT03628365).

Abdominal obesity in COPD is associated with specific metabolic and functional phenotypes.

BACKGROUND: Abdominal obesity (AO) is linked to reduced health status and mortality. While it is known that AO is prevalent in chronic obstructive pulmonary disease (AO-COPD), the specific metabolic and functional consequences associated with AO-COPD remain understudied. METHODS: We studied 199 older adults with COPD and 168 control subjects with and without AO and assessed visceral adipose tissue (VAT) by dual-energy X-ray absorptiometry. VAT > 70th percentile of the control group qualified a subject as AO in a sex specific manner. We measured plasma concentrations and whole body production (WBP) rates of multiple amino acids to assess the metabolic profile. We assessed medical history, body composition by Dual-Energy X-ray Absorptiometry, muscle strength, and cognitive function. We performed statistics by analysis of covariance (p) and FDR (q) for multiple comparisons. RESULTS: AO-COPD subjects had 27% more VAT (q < 0.01) than AO-Control subjects despite correction for BMI. Branched-chain amino acid concentrations and WBP rates were generally elevated in AO-COPD but whole body clearance rate was only elevated in COPD. Metabolic syndrome comorbidities (p < 0.01) and systemic inflammation (P < 0.05) were most prevalent in the AO-COPD group. Muscle strength was reduced in COPD subjects (p < 0.001), but partially preserved when combined with AO. Cognitive dysfunction and mood disturbances were present in COPD subjects (p < 0.001) with worst performers in AO-COPD (q < 0.05). CONCLUSION: The presence of AO is associated with specific metabolic and functional phenotypes in COPD. Clinical trial registry Trial registration ClinicalTrials.gov. In the present paper, we report an analysis of the baseline measurements of COPD subjects and healthy controls from the study numbers: NCT01787682, NCT01787682, NCT02157844, NCT02082418, NCT02065141, NCT02770092, NCT02908425, NCT03159390, NCT02780219, NCT03327181, NCT03796455, NCT04928872, NCT04461236, NCT01173354, NCT01154400.

Obesity- and sex-related metabolism of arginine and nitric oxide in adults.

BACKGROUND: There is growing interest in the supplementation of arginine (Arg) and citrulline (Cit) in obesity due to their potential anti-obesogenic and anti-inflammatory properties. However, there is no consensus on the metabolic changes in Arg kinetics in obesity. OBJECTIVES: This exploratory cross-sectional study aimed to investigate the association between obesity, sex, and sex-by-obesity interaction on whole-body Arg kinetics in a large group of human subjects. METHODS: We studied 83 nonobese [BMI (kg/m2) <30] and 80 morbidly obese (BMI >30) middle-aged individuals (40% males) enrolled in the MEDIT (Metabolism of Disease with Isotope Tracers) trial. After body-composition measurement by DXA, we collected arterial(ized) blood samples for amino acid (AA) concentrations, markers of inflammation [high-sensitivity C-reactive protein (hs-CRP)], liver function, and glucose in a postabsorptive state. We administered a pulse of AA stable tracers and measured whole-body production (WBP) of Arg, Cit, ornithine (Orn), phenylalanine, and tyrosine, and calculated their clearance (disposal capacity) and metabolite interconversions [markers for NO and de novo Arg production, systemic Arg hydrolysis, and whole-body protein breakdown (wbPB)]. We measured plasma enrichments by LC-MS/MS and statistics by Fisher's exact test or analysis of (co)variance. Significance was set at P < 0.05. RESULTS: Obese individuals were normoglycemic and characterized by low-grade inflammation (P < 0.0001) and greater wbPB (P = 0.0298). We found lower plasma Cit concentration (P < 0.0001) in the obese group but no differences in the WBP of Arg, Cit, and Orn. Furthermore, we observed overproduction of NO (P < 0.0001) in obesity but lower de novo Arg production (P = 0.0007). The WBP of Arg was lower in females for almost all Arg-related AAs, except for plasma Cit and NO production. CONCLUSIONS: Alterations in Arg metabolism are present in morbid obesity. Further studies are needed to investigate if these changes could be related to factors such as increased Arg requirement in obesity or metabolic adaptation.

ω-3 polyunsaturated fatty acid supplementation improves postabsorptive and prandial protein metabolism in patients with chronic obstructive pulmonary disease: a randomized clinical trial.

BACKGROUND: Disturbances in protein metabolism and impaired muscle health have been observed in chronic obstructive pulmonary disease (COPD). The ω-3 (n-3) PUFAs EPA and DHA are known for their anti-inflammatory and muscle health-enhancing properties. OBJECTIVES: We examined whether daily EPA + DHA supplementation can improve daily protein homeostasis in patients with COPD by reducing postabsorptive whole-body protein breakdown (PB) and enhancing the anabolic response to feeding in a dose-dependent way. METHODS: Normal-weight participants with moderate to severe COPD (n = 32) received daily for 4 wk, according to a randomized double-blind placebo controlled 3-group design, a high dose (3.5 g, n = 10) of EPA + DHA, a low dose (2.0 g, n = 10) of EPA + DHA, or placebo (olive oil, n = 12) via gel capsules. At pre- and postintervention, stable isotope tracers were infused to assess postabsorptive netPB [postabsorptive PB - protein synthesis (PS)] and the anabolic response (prandial netPS = prandial PS-PB) to a protein meal. In addition, muscle mass and function were measured. RESULTS: Plasma phosphatidylcholine EPA and DHA concentrations were higher after 4 wk of supplementation in both EPA + DHA groups (P < 0.004), and there was a trend toward higher values for plasma EPA after the high compared with the low dose of EPA + DHA (P = 0.065). Postabsorptive PB was lower after 4 wk of the high dose of EPA + DHA, whereas netPB was lower independent of the dose of EPA + DHA (low dose, P = 0.037; high dose, P = 0.026). Prandial netPS was increased only after the high dose of EPA + DHA (P = 0.03). Extremity lean mass but not muscle function was increased, independent of the EPA + DHA dose (P < 0.05). CONCLUSIONS: Daily n-3 PUFA supplementation for 4 wk induces a shift toward a positive daily protein homeostasis in patients with COPD in part in a dose-dependent way. Daily doses up to 3.5 g EPA and DHA are still well tolerated and lead to protein gain in these patients. This trial was registered at clinicaltrials.gov as NCT01624792.

Acute skeletal muscle loss in SARS-CoV-2 infection contributes to poor clinical outcomes in COVID-19 patients.

BACKGROUND: Chronic disease causes skeletal muscle loss that contributes to morbidity and mortality. There are limited data on the impact of dynamic muscle loss on clinical outcomes in COVID-19. We hypothesized that acute COVID-19-related muscle loss (acute sarcopenia) is associated with adverse outcomes. METHODS: A retrospective analysis of a prospective clinical registry of COVID-19 patients was performed in consecutive hospitalized patients with acute COVID-19 (n = 95) and compared with non-COVID-19 controls (n = 19) with two temporally unique CT scans. Pectoralis muscle (PM), erector spinae muscle (ESM) and 30 day standardized per cent change in cross sectional muscle area were quantified. Primary outcomes included mortality and need for intensive care unit (ICU) admission. Multivariate linear and logistic regression were performed. Cox proportional hazard ratios were generated for ICU admission or mortality for the per cent muscle loss standardized to 30 days. RESULTS: The COVID-19 CT scan cohort (n = 95) had an average age of 63.3 ± 14.3 years, comorbidities including COPD (28.4%) and diabetes mellitus (42.1%), and was predominantly Caucasian (64.9%). The proportion of those admitted to the ICU was 54.7%, with 10.5% requiring tracheostomy and overall mortality 16.8%. Median duration between CT scans was 32 days (IQR: 16-63 days). Significant reductions in median per cent loss was noted for PM (-2.64% loss [IQR: -0.28, -5.47] in COVID-19 vs. -0.06 loss [IQR: -0.01, -0.28] in non-COVID-19 CT controls, P < 0.001) and ESM (-1.86% loss [IQR: -0.28, -5.47] in COVID-19 vs. -0.06 loss [IQR: -0.02, -0.11]) in non-COVID-19 CT controls, P < 0.001). Multivariate linear regression analysis of per cent loss in PM was significantly associated with mortality (-10.8% loss [95% CI: -21.5 to -0.19]) and ICU admission (-11.1% loss [95% CI: -19.4 to -2.67]), and not significant for ESM. Cox proportional hazard ratios demonstrated greater association with ICU admission (adj HR 2.01 [95% CI: 1.14-3.55]) and mortality (adj HR 5.30 [95% CI: 1.19-23.6]) for those with significant per cent loss in PM, and greater association with ICU admission (adj HR 8.22 [95% CI: 1.11-61.04]) but not mortality (adj HR 2.20 [95% CI: 0.70-6.97]) for those with significant per cent loss in ESM. CONCLUSIONS: In a well-characterized cohort of 95 hospitalized patients with acute COVID-19 and two temporally distinct CT scans, acute sarcopenia, determined by standardized reductions in PM and ESM, was associated with worse clinical outcomes. These data lay the foundation for evaluating dynamic muscle loss as a predictor of clinical outcomes and targeting acute sarcopenia to improve clinical outcomes for COVID-19.

A low postabsorptive whole body protein balance is associated with markers of poor daily physical functioning in Chronic Obstructive Pulmonary Disease.

BACKGROUND & AIMS: Postabsorptive whole body protein kinetics are related to age, gender, body mass index (BMI), and habitual protein intake level. It is unclear how protein synthesis, breakdown, and postabsorptive protein balance rates are affected in Chronic Obstructive Pulmonary Disease (COPD)) and whether these relate to disease severity, lifestyle characteristics and poor daily functioning. METHODS: We studied 91 COPD (GOLD 1-4) and 56 age matched control subjects without COPD or other chronic or acute health disease/condition in the postabsorptive state and measured body composition by Dual-energy X-ray Absorptiometry, and disease severity and comorbidities by medical screening, blood analysis and questionnaires. We assessed whole body production rates of phenylalanine and tyrosine by pulse stable isotope tracer infusion to calculate whole body protein breakdown (PB) and hydroxylation of phenylalanine to tyrosine, representative of postabsorptive protein balance. We measured muscle and cognitive function, and physical performance by isokinetic dynamometry, cognitive assessments, and 6-min walk test. We assessed physical activity level, mood and dietary protein intake by questionnaires. We measured plasma enrichments by LC-MS/MS and statistics by Fisher's exact test or analysis of covariance. Data are mean [95% CI]. RESULTS: The COPD patients had moderate to severe airflow obstruction, multiple comorbidities, and elevated values for plasma high sensitivity c-reactive protein (hs-CRP) and glucose. Although PB (3630 [3361, 3900] vs 3504 [3297, 3711] umol/h, p = 0.1649) was not different, postabsorptive protein balance was lower in COPD patients (274.2 [242.4, 306.1] vs 212.9 [194.7, 231.0] umol/h, p < 0.0001), both compared to control subjects. A lower postabsorptive protein balance was associated with age (p < 0.0001) and higher levels for systolic blood pressure (p = 0.0051) and hs-CRP (p = 0.0046) but not with lung function. Furthermore, a lower postabsorptive protein balance level was associated with a lower intake of total calories and protein (p < 0.0001) and lower muscle strength (p = 0.0248), while only in COPD with a lower physical performance (p = 0.0343). We found no association with cognitive function or mood. For all subjects, a cumulative model that included group, gender, age, BMI, systolic blood pressure, hs-CRP, caloric intake, protein intake, and leg strength was able to explain 55% of the variation in postabsorptive protein balance. CONCLUSION: These data suggest that systemic inflammation, high blood pressure and low protein intake are risk factors of a lower postabsorptive protein balance in COPD patients. A lower postabsorptive protein balance is associated with markers of poor daily physical functioning.

Impaired intestinal function is associated with lower muscle and cognitive health and well-being in patients with congestive heart failure.

BACKGROUND: Small- and large-intestinal perturbations have been described as prevalent extracardiac systemic manifestations in congestive heart failure (CHF), but alterations in protein digestion and absorption and plasma short-chain fatty acid (SCFA) concentrations and the potential link with other systemic effects (muscle and cognitive health) have not been investigated in CHF. METHODS: We analyzed protein digestion and absorption with dual stable tracer method in 14 clinically stable, noncachectic CHF outpatients (mean left ventricular ejection fraction: 35.5% [95% CI, 30.9%-40.1%]) and 15 controls. Small-intestinal non-carrier-mediated permeability and active carrier-mediated glucose transport were quantified by sugar permeability test. Plasma SCFA (acetate, propionate, butyrate, isovalerate, valerate) concentrations were measured as intestinal microbial metabolites. Muscle function was assessed by isokinetic dynamometry, cognition by a battery of tests, and well-being by questionnaire. RESULTS: Protein digestion and absorption were impaired by 29.2% (P = .001) and active glucose transport by 38.4% (P = .010) in CHF. Non-carrier-mediated permeability was not altered. Whereas plasma propionate, butyrate, and isovalerate concentrations were lower in CHF (P < .05), acetate and valerate concentrations did not differ. Overall, intestinal dysfunction was associated with impaired leg muscle quality, emotional distress, and cognitive dysfunction (P < .05). CONCLUSIONS: We identified impaired protein digestion and absorption and altered SCFA concentrations as additional intestinal dysfunctions in CHF that are linked to reduced muscle and cognitive health and well-being. More research is needed to implement strategies to improve intestinal function in CHF and to investigate the mechanisms underlying its link with other systemic manifestations.

The importance of protein sources to support muscle anabolism in cancer: An expert group opinion.

This opinion paper presents a short review of the potential impact of protein on muscle anabolism in cancer, which is associated with better patient outcomes. Protein source is a topic of interest for patients and clinicians, partly due to recent emphasis on the supposed non-beneficial effect of proteins; therefore, misconceptions involving animal-based (e.g., meat, fish, dairy) and plant-based (e.g., legumes) proteins in cancer are acknowledged and addressed. Although the optimal dietary amino acid composition to support muscle health in cancer is yet to be established, animal-based proteins have a composition that offers superior anabolic potential, compared to plant-derived proteins. Thus, animal-based foods should represent the majority (i.e., ≥65%) of protein intake during active cancer treatment. A diet rich in plant-derived proteins may support muscle anabolism in cancer, albeit requiring a larger quantity of protein to fulfill the optimal amino acid intake. We caution that translating dietary recommendations for cancer prevention to cancer treatment may be inadequate to support the pro-inflammatory and catabolic nature of the disease. We further caution against initiating an exclusively plant-based (i.e., vegan) diet upon a diagnosis of cancer, given the presence of elevated protein requirements and risk of inadequate protein intake to support muscle anabolism. Amino acid combination and the long-term sustainability of a dietary pattern void of animal-based foods requires careful and laborious management of protein intake for patients with cancer. Ultimately, a dietary amino acid composition that promotes muscle anabolism is optimally obtained through combination of animal- and plant-based protein sources.

In-vivo production of branched-chain amino acids, branched-chain keto acids, and ß-hydroxy ß-methylbutyric acid.

PURPOSE OF REVIEW: The branched-chain amino acids (BCAA), branched-chain keto acids (BCKA), and ß-hydroxy ß-methylbutyric acid (HMB) have regained interest as food ingredients in health and disease. To support nutritional strategies, it is critical to gain insight into the whole body and transorgan kinetics of these components. We, therefore, reviewed the most recent literature in this field on in vivo analysis of BCAA, BCKA, and HMB kinetics in health and disease. RECENT FINDINGS: With a new comprehensive metabolic flux analysis BCAA, BCKA, and HMB whole body production, interconversion and disposal rates can be measured simultaneously. Recent studies have provided us with a better understanding of whole-body and transorgan kinetics under postabsorptive, postprandial, hibernating, and lactating conditions. In human pathophysiological conditions like COPD, obesity, and diabetes, the added value of BCAA kinetic measurements over the commonly used concentration measurements only, is discussed. SUMMARY: This article highlights the importance of implementing BCAA, BCKA, and HMB kinetic studies to further advance the field by gaining more mechanistic insights and providing direction to the development of new targeted (nutritional) strategies.

Disturbances in branched-chain amino acid profile and poor daily functioning in mildly depressed chronic obstructive pulmonary disease patients.

BACKGROUND: Depression is one of the most common and untreated comorbidities in chronic obstructive pulmonary disease (COPD), and is associated with poor health outcomes (e.g. increased hospitalization/exacerbation rates). Although metabolic disturbances have been suggested in depressed non-diseased conditions, comprehensive metabolic phenotyping has never been conducted in those with COPD. We examined whether depressed COPD patients have certain clinical/functional features and exhibit a specific amino acid phenotype which may guide the development of targeted (nutritional) therapies. METHODS: Seventy-eight outpatients with moderate to severe COPD (GOLD II-IV) were stratified based on presence of depression using a validated questionnaire. Lung function, disease history, habitual physical activity and protein intake, body composition, cognitive and physical performance, and quality of life were measured. Comprehensive metabolic flux analysis was conducted by pulse stable amino acid isotope administration. We obtained blood samples to measure postabsorptive kinetics (production and clearance rates) and plasma concentrations of amino acids by LC-MS/MS. Data are expressed as mean [95% CI]. Stats were done by graphpad Prism 9.1.0. ɑ < 0.05. RESULTS: The COPD depressed (CD, n = 27) patients on average had mild depression, were obese (BMI: 31.7 [28.4, 34.9] kg/m2), and were characterized by shorter 6-min walk distance (P = 0.055), physical inactivity (P = 0.03), and poor quality of life (P = 0.01) compared to the non-depressed COPD (CN, n = 51) group. Lung function, disease history, body composition, cognitive performance, and daily protein intake were not different between the groups. In the CD group, plasma branched chain amino acid concentration (BCAA) was lower (P = 0.02), whereas leucine (P = 0.01) and phenylalanine (P = 0.003) clearance rates were higher. Reduced values were found for tyrosine plasma concentration (P = 0.005) even after adjustment for the large neutral amino acid concentration (= sum BCAA, tyrosine, phenylalanine and tryptophan) as a marker of dopamine synthesis (P = 0.048). CONCLUSION: Mild depression in COPD is associated with poor daily performance and quality of life, and a set of metabolic changes in depressed COPD that include perturbation of large neutral amino acids, specifically the BCAAs. Trial registration clinicaltrials.gov: NCT01787682, 11 February 2013-Retrospectively registered; NCT02770092, 12 May 2016-Retrospectively registered; NCT02780219, 23 May 2016-Retrospectively registered; NCT03796455, 8 January 2019-Retrospectively registered.