Appetite Suppression and Altered Food Preferences Coincide with Changes in Appetite-Mediating Hormones During Energy Deficit at High Altitude, But Are Not Affected by Protein Intake

Appetite suppression and altered food preferences coincide with changes in appetite-mediating hormones during energy deficit at high altitude, but are not affected by protein intake. High Alt Med Biol. 19:156–169, 2018.—Anorexia and unintentional body weight loss are common during high altitude (HA) sojourn, but underlying mechanisms are not fully characterized, and the impact of dietary macronutrient composition on appetite regulation at HA is unknown. This study aimed to determine the effects of a hypocaloric higher protein diet on perceived appetite and food preferences during HA sojourn and to examine longitudinal changes in perceived appetite, appetite mediating hormones, and food preferences during acclimatization and weight loss at HA. Following a 21-day level (SL) period, 17 unacclimatized males ascended to and resided at HA (4300 m) for 22 days. At HA, participants were randomized to consume measured standard-protein (1.0 g protein/kg/d) or higher protein (2.0 g/kg/d) hypocaloric diets (45% carbohydrate, 30% energy restriction) and engaged in prescribed physical activity to induce an estimated 40% energy deficit. Appetite, food preferences, and appetite-mediating hormones were measured at SL and at the beginning and end of HA. Diet composition had no effect on any outcome. Relative to SL, appetite was lower during acute HA (days 0 and 1), but not different after acclimatization and weight loss (HA day 18), and food preferences indicated an increased preference for sweet- and low-protein foods during acute HA, but for high-fat foods after acclimatization and weight loss. Insulin, leptin, and cholecystokinin concentrations were elevated during acute HA, but not after acclimatization and weight loss, whereas acylated ghrelin concentrations were suppressed throughout HA. Findings suggest that appetite suppression and altered food preferences coincide with changes in appetite-mediating hormones during energy deficit at HA. Although dietary protein intake did not impact appetite, the possible incongruence with food preferences at HA warrants consideration when developing nutritional strategies for HA sojourn

Altitude Acclimatization Alleviates the Hypoxia-Induced Suppression of Exogenous Glucose Oxidation During Steady-State Aerobic Exercise

This study investigated how high-altitude (HA, 4300 m) acclimatization affected exogenous glucose oxidation during aerobic exercise. Sea-level (SL) residents (n = 14 men) performed 80-min, metabolically matched exercise (V˙O2 ∼ 1.7 L/min) at SL and at HA < 5 h after arrival (acute HA, AHA) and following 22-d of HA acclimatization (chronic HA, CHA). During HA acclimatization, participants sustained a controlled negative energy balance (-40%) to simulate the “real world” conditions that lowlanders typically experience during HA sojourns. During exercise, participants consumed carbohydrate (CHO, n = 8, 65.25 g fructose + 79.75 g glucose, 1.8 g carbohydrate/min) or placebo (PLA, n = 6). Total carbohydrate oxidation was determined by indirect calorimetry and exogenous glucose oxidation by tracer technique with 13C. Participants lost (P ≤ 0.05, mean ± SD) 7.9 ± 1.9 kg body mass during the HA acclimatization and energy deficit period. In CHO, total exogenous glucose oxidized during the final 40 min of exercise was lower (P < 0.01) at AHA (7.4 ± 3.7 g) than SL (15.3 ± 2.2 g) and CHA (12.4 ± 2.3 g), but there were no differences between SL and CHA. Blood glucose and insulin increased (P ≤ 0.05) during the first 20 min of exercise in CHO, but not PLA. In CHO, glucose declined to pre-exercise concentrations as exercise continued at SL, but remained elevated (P ≤ 0.05) throughout exercise at AHA and CHA. Insulin increased during exercise in CHO, but the increase was greater (P ≤ 0.05) at AHA than at SL and CHA, which did not differ. Thus, while acute hypoxia suppressed exogenous glucose oxidation during steady-state aerobic exercise, that hypoxic suppression is alleviated following altitude acclimatization and concomitant negative energy balance

Milk Lacking α-Casein Leads to Permanent Reduction in Body Size in Mice

The major physiological function of milk is the transport of amino acids, carbohydrates, lipids and minerals to mammalian offspring. Caseins, the major milk proteins, are secreted in the form of a micelle consisting of protein and calcium-phosphate

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Muscle protein turnover and the molecular regulation of muscle mass during hypoxia

Effects of environmental hypoxia on fat-free mass are well studied. Negative energy balance, increased nitrogen excretion, and fat-free mass loss are commonly observed in lowlanders sojourning at high altitude. Reductions in fat-free mass can be minimized if energy consumption matches energy expenditure. However, in nonresearch settings, achieving energy balance during high-altitude sojourns is unlikely, and myofibrillar protein mass is usually lost, but the mechanisms accounting for the loss of muscle mass are not clear. At sea level, negative energy balance reduces basal and blunts postprandial muscle protein synthesis, with no relevant change in muscle protein breakdown. Downregulations in muscle protein synthesis and loss of fat-free mass during energy deficit at sea level are largely overcome by consuming at least twice the recommended dietary allowance for protein. Hypoxia may increase or not affect resting muscle protein synthesis, blunt postexercise muscle protein synthesis, and markedly increase proteolysis independent of energy status. Hypoxia-induced mTORC1 dysregulation and an upregulation in calpain- and ubiquitin proteasome-mediated proteolysis may drive catabolism in lowlanders sojourning at high altitude. However, the combined effects of energy deficit, exercise, and dietary proteinmanipulations on the regulation of muscle protein turnover have never been studied at high altitude. This article reviews the available literature related to the effects of high altitude on fat-free mass, highlighting contemporary studies that assessed the influence of altitude exposure (or hypoxia) on muscle protein turnover and intramuscular regulation of muscle mass. Knowledge gaps are addressed, and studies to identify effective and feasible countermeasures to hypoxia-induced muscle loss are discussed

Variability in human plasma volume responses during high‐altitude sojourn

Abstract When sea‐level (SL) residents rapidly ascend to high altitude (HA), plasma volume (PV) decreases. A quantitative model for predicting individual %∆PV over the first 7 days at HA has recently been developed from the measurements of %∆PV in 393 HA sojourners. We compared the measured %∆PV with the %∆PV predicted by the model in 17 SL natives living 21 days at HA (4300 m). Fasting hematocrit (Hct), hemoglobin (Hb) and total circulating protein (TCP) concentrations at SL and on days 2, 7, 13, and 19 at HA were used to calculate %∆TCP and %∆PV. Mean [95%CI] measured %∆PV on HA2, 7, 13 and 19 was −2.5 [−8.2, 3.1], −11.0 [−16.6, −5.5], −11.7 [−15.9, −7.4], and −16.8 [−22.2, −11.3], respectively. %∆PV and %∆TCP were positively correlated (P < 0.001) at HA2, 7, 13, and 19 (r2 = 0.77, 0.88, 0.78, 0.89, respectively). The model overpredicted mean [95% CI] decrease in %∆PV on HA2 (−12.5 [−13.9, −11.1]) and HA7 (−21.5 [−23.9, −19.1]), accurately predicted the mean decrease on HA13 (−14.3, [−20.0, −8.7]), and predicted a mean increase in %∆PV on HA19 (12.4 [−5.0, 29.8]). On HA2, 7, 13, and 19 only 2, 2, 6, and 1, respectively, of 17 individual measures of %∆PV were within 95% CI for predicted %∆PV. These observations indicate that PV responses to HA are largely oncotically mediated, vary considerably among individuals, and available quantitative models require refinement to predict %∆PV exhibited by individual sojourners

Effects of carbohydrate supplementation on aerobic exercise performance during acute high altitude exposure and after 22 days of acclimatization and energy deficit

Background The ergogenic effects of supplemental carbohydrate on aerobic exercise performance at high altitude (HA) may be modulated by acclimatization status. Longitudinal evaluation of potential performance benefits of carbohydrate supplementation in the same volunteers before and after acclimatization to HA have not been reported. Purpose This study examined how consuming carbohydrate affected 2-mile time trial performance in lowlanders at HA (4300 m) before and after acclimatization. Methods Fourteen unacclimatized men performed 80 min of metabolically-matched (~ 1.7 L/min) treadmill walking at sea level (SL), after ~ 5 h of acute HA exposure, and after 22 days of HA acclimatization and concomitant 40% energy deficit (chronic HA). Before, and every 20 min during walking, participants consumed either carbohydrate (CHO, n = 8; 65.25 g fructose + 79.75 g glucose, 1.8 g carbohydrate/min) or flavor-matched placebo (PLA, n = 6) beverages. A self-paced 2-mile treadmill time trial was performed immediately after completing the 80-min walk. Results There were no differences (P > 0.05) in time trial duration between CHO and PLA at SL, acute HA, or chronic HA. Time trial duration was longer (P < 0.05) at acute HA (mean ± SD; 27.3 ± 6.3 min) compared to chronic HA (23.6 ± 4.5 min) and SL (17.6 ± 3.6 min); however, time trial duration at chronic HA was still longer than SL (P < 0.05). Conclusion These data suggest that carbohydrate supplementation does not enhance aerobic exercise performance in lowlanders acutely exposed or acclimatized to HA. Trial registration NCT, NCT02731066, Registered March 292,01

PI3K-AKT-FOXO1 pathway targeted by skeletal muscle microRNA to suppress proteolytic gene expression in response to carbohydrate intake during aerobic exercise

Ingesting protein and carbohydrate together during aerobic exercise suppresses the expression of specific skeletal muscle microRNA and promotes muscle hypertrophy. Determining whether there are independent effects of carbohydrate and protein on microRNA will allow for a clearer understanding of the mechanistic role microRNA serve in regulating skeletal muscle protein synthetic and proteolytic responses to nutrition and exercise. This study determined skeletal muscle microRNA responses to aerobic exercise with or without carbohydrate, and recovery whey protein (WP). Seventeen males were randomized to consume carbohydrate (CHO; 145 g; n = 9) or non-nutritive control (CON; n = 8) beverages during exercise. Muscle was collected before (BASE) and after 80 min of steady-state exercise (1.7 ± 0.3 V̇O 2 L·min −1 ) followed by a 2-mile time trial (17.9 ± 3.5 min; POST), and 3-h into recovery after consuming WP (25 g; REC). RT-qPCR was used to determine microRNA and mRNA expression. Bioinformatics analysis was conducted using the mirPath software. Western blotting was used to assess protein signaling. The expression of six microRNA (miR-19b-3p, miR-99a-5p, miR-100-5p, miR-222-3p, miR-324-3p, and miR-486-5p) were higher (P \u3c 0.05) in CHO compared to CON, all of which target the PI3K-AKT, ubiquitin proteasome, FOXO, and mTORC1 pathways. p-AKT Thr473 and p-FOXO1 Thr24 were higher (P \u3c 0.05) in POST CHO compared to CON. The expression of PTEN was lower (P \u3c 0.05) in REC CHO than CON, while MURF1 was lower (P \u3c 0.05) POST CHO than CON. These findings suggest the mechanism by which microRNA facilitate skeletal muscle adaptations in response to exercise with carbohydrate and protein feeding is by inhibiting markers of proteolysis

Severe energy deficit at high altitude inhibits skeletal muscle mTORC1-mediated anabolic signaling without increased ubiquitin proteasome activity

Muscle loss athighaltitude (HA) is attributable to energydeficit andapotentialdysregulationof anabolic signaling. Exercise and protein ingestion can attenuate the effects of energy deficit on muscle at sea level (SL). Whether these effects are observed when energy deficit occurs atHAis unknown. To address this,muscle obtained from lowlanders (n = 8 males) at SL, acute HA (3 h, 4300 m), and chronic HA (21 d, 21766 kcal/d energy balance) before [baseline (Base)] and after 80 min of aerobic exercise followed by a 2-mile time trial [postexercise (Post)] and 3 h into recovery (Rec) after ingestingwhey protein (25 g)were analyzed using standard molecular techniques. At SL, Post, and REC, p-mechanistic target of rapamycin (mTOR)Ser2448, p-p70 ribosomal protein S6 kinase (p70S6K)Ser424/421, and p-ribosomal protein S6 (rpS6)Ser235/236 were similar and higher (P \u3e 0.05) than Base. At acute HA, Post p-mTORSer2448 and Post and REC p-p70S6KSer424/421 were not different from Base and lower than SL (P \u3c 0.05). At chronicHA, Post and Rec p-mTORSer2448 and p-p70S6KSer424/421 were not different from Base and lower than SL, and, independent of time, p-rpS6Ser235/236 was lower than SL (P \u3c 0.05). Post proteasome activity was lower (P \u3c 0.05) than BaseandRec, independent of phase.Our findings suggest thatHAexposure inducesmuscle anabolic resistance that is exacerbated by energy deficit during acclimatization, with no change in proteolysis

Muscle Fn14 gene expression is associated with fat-free mass retention during energy deficit at high altitude

Intramuscular factors that modulate fat-free mass (FFM) loss in lowlanders exposed to energy deficit during high-altitude (HA) sojourns remain unclear. Muscle inflammation may contribute to FFM loss at HA by inducing atrophy and inhibiting myogenesis via the tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible protein 14 (Fn14). To explore whether muscle inflammation modulates FFM loss reportedly developing during HA sojourns, muscle inflammation, myogenesis, and proteolysis were assessed in 16 men at sea level (SL) and following 21 days of energy deficit (−1862 ± 525 kcal/days) at high altitude (HA, 4300 m). Total body mass (TBM), FFM, and fat mass (FM) were assessed using DEXA. Gene expression and proteolytic enzymatic activities were assessed in muscle samples collected at rest at SL and HA. Participants lost 7.2 ± 1.8 kg TBM (P \u3c 0.05); 43 ± 30% and 57 ± 30% of the TBM lost was FFM and FM, respectively. Fn14, TWEAK, TNF alpha-receptor (TNFα-R), TNFα, MYOGENIN, and paired box protein-7 (PAX7) were upregulated (P \u3c 0.05) at HA compared to SL. Stepwise linear regression identified that Fn14 explained the highest percentage of variance in FFM loss (r2 = 0.511, P \u3c 0.05). Dichotomization of volunteers into HIGH and LOW Fn14 gene expression indicated HIGH lost less FFM and more FM (28 ± 28% and 72 ± 28%, respectively) as a proportion of TBM loss than LOW (58 ± 26% and 42 ± 26%; P \u3c 0.05) at HA. MYOGENIN gene expression was also greater for HIGH versus LOW (P \u3c 0.05). These data suggest that heightened Fn14 gene expression is not catabolic and may protect FFM during HA sojourns