High Altitude and Acute Mountain Sickness and Changes in Circulating Endothelin-1, Interleukin-6, and Interleukin-17a

Boos, Christopher J.; Woods, David R.; Varias, Andrea; Biscocho, Sheryl; Heseltine, Peter N. R.; Mellor, Adrian

doi:10.1089/ham.2015.0098

Cited by 47 publications

(45 citation statements)

References 36 publications

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“…In the current study, the additional protein provided to the HP group was almost completely oxidized (0.95 6 0.32 g protein/kg/d more than in the SP group), precluding a sustained anabolic response to protein-containing meals and negating the FFM-sparing effects of the HP diet. The increase in whole-body PS at acute HA compared to SL is consistent with other studies showing increased PS in response to acute stress (17,42,43), which may be related to increased synthesis of acute phase proteins at HA (44). The observed suppression of both PS and PB at chronic HA is consistent with that in previous reports of whole-body protein kinetics during prolonged ED at SL (41,45,46), which indicates that protein and energy sparing are adaptive responses to sustained negative energy balance.…”

Section: Discussionsupporting

confidence: 91%

Severe negative energy balance during 21 d at high altitude decreases fat‐free mass regardless of dietary protein intake: a randomized controlled trial

et al. 2018

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In this 2-phase randomized controlled study, we examined whether consuming a higher-protein (HP) diet would attenuate fat-free mass (FFM) loss during energy deficit (ED) at high altitude (HA) in 17 healthy males (mean 6 SD: 23 6 6 yr; 82 6 14 kg). During phase 1 at sea level (SL, 55 m), participants consumed a eucaloric diet providing standard protein (SP; 1.0 g protein/kg,) for 21 d. During phase 2, participants resided at HA (4300 m) for 22 d and were randomly assigned to either an SP or HP (2.0 g protein/kg) diet designed to elicit a 40% ED. Body composition, substrate oxidation, and postabsorptive whole-body protein kinetics were measured. Participants were weight stable during SL and lost 7.9 6 1.9 kg (P < 0.01) during HA, regardless of dietary protein intake. Decrements in wholebody FFM (3.6 6 2.4 kg) and fat mass (3.6 6 1.3 kg) were not different between SP and HP. HP oxidized 0.95 6 0.32 g protein/kg per day more than SP and whole-body net protein balance was more negative for HP than for SP (P < 0.01). Based on changes in body energy stores, the overall ED was 70% (21849 6 511 kcal/d, no group differences). Consuming an HP diet did not protect FFM during severe ED at HA.-Berryman, C. E., Young, A. J., Karl, J. P., Kenefick, R. W., Margolis, L. M., Cole, R. E., Carbone, J. W., Lieberman, H. R., Kim, I.-Y., Ferrando, A. A., Pasiakos, S. M. Severe negative energy balance during 21 d at high altitude decreases fat-free mass regardless of dietary protein intake: a randomized controlled trial. FASEB J. 32, 894-905 (2018 For lowlanders sojourning at high altitude (HA .1500 m), maintaining energy balance can be challenging because of an increase in resting metabolic rate (RMR) (1, 2) and a decrease in appetite (3) caused by physiologic adaptations to hypoxia. The effects of hypoxia on energy balance are frequently compounded by limited access to food and high physical activity levels while at HA. Negative energy balance usually develops at HA and typically leads to weight loss (4). Barnholt et al. (4) showed that individuals sustaining a 40% energy deficit (ED) for 21 d at HA lost more body weight than individuals adhering to the same controlled diet and physical activity at sea level (SL). Furthermore, some studies (5-8) have observed .50% of total body mass (TBM) loss as fat-free mass (FFM) during prolonged ED at HA, which is greater than the 25-35% typically observed at SL (9-11), suggesting protein turnover kinetics and substrate utilization during weight loss at HA may differ from that at SL.At SL, protein intake above the Recommended Dietary Allowance (RDA, 0.8 g protein/kg per day) limits FFM loss during moderate negative energy balance (;40% ED) in healthy, normal weight adults (12)(13)(14). We have shown that consuming a diet containing 1.6 or 2.4 g protein/kg per day (2 and 3 times the RDA, respectively) for 21 d, within the context of a 40% ED, attenuates FFM loss as a percentage of TBM loss (30 6 7 and 36 6 5%, respectively) compared to an isocaloric diet containing 0.8 g protein/kg per d...

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Section: Discussionsupporting

confidence: 91%

Severe negative energy balance during 21 d at high altitude decreases fat‐free mass regardless of dietary protein intake: a randomized controlled trial

et al. 2018

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“…It has been demonstrated in previous studies that inflammatory response is associated with AMS (30, 31). In this study, we have illustrated the questions using a system-level methodology and demonstrated that genes associated with immune and inflammatory response, including chemokine and their receptors, CD and HLA molecules, and inflammatory cytokines were disturbed in AMS individuals by high-altitude exposure acutely.…”

Section: Discussionmentioning

confidence: 80%

IL-10 Dysregulation in Acute Mountain Sickness Revealed by Transcriptome Analysis

et al. 2017

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Acute mountain sickness (AMS), which may progress to life-threatening high-altitude cerebral edema, is a major threat to millions of people who live in or travel to high altitude. Although studies have revealed the risk factors and pathophysiology theories of AMS, the molecular mechanisms of it do not comprehensively illustrate. Here, we used a system-level methodology, RNA sequencing, to explore the molecular mechanisms of AMS at genome-wide level in 10 individuals. After exposure to high altitude, a total of 1,164 and 1,322 differentially expressed transcripts were identified in AMS and non-AMS groups, respectively. Among them, only 328 common transcripts presented between the two groups. Immune and inflammatory responses were overrepresented in participants with AMS, but not in non-AMS individuals. Anti-inflammatory cytokine IL10 and inflammation cytokines IF17F and CCL8 exhibited significantly different genetic connectivity in AMS compared to that of non-AMS individuals based on network analysis. IL10 was downregulated and both IF17F and CCL8 were upregulated in AMS individuals. Moreover, the serum concentration of IL10 significantly decreased in AMS patients after exposure to high altitude (p = 0.001) in another population (n = 22). There was a large negative correlation between the changes in IL10 concentration, r(22) = −0.52, p = 0.013, and Lake Louise Score. Taken together, our analysis provides unprecedented characterization of AMS transcriptome and identifies that genes involved in immune and inflammatory responses were disturbed in AMS individuals by high-altitude exposure. The reduction of IL10 after exposure to high altitude was associated with AMS.

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“…In 48 trekkers studied over a 6-week ascent up to 5129 m, IL-6 and IL-17a levels were found to be significantly higher at high altitude than at sea level, and exercise led to a further significant increase in IL-6 but not IL-17 levels [50]. While IL-6 seems to be critically involved in hypoxia-induced adaptive changes in muscle metabolism [51] it remains to be established whether these responses have also a defined role in the pathogenesis of sarcopenia.…”

Section: Discussionmentioning

confidence: 89%

Does hypoxia play a role in the development of sarcopenia in humans? Mechanistic insights from the Caudwell Xtreme Everest Expedition

et al. 2017

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ObjectivesSarcopenia refers to the involuntary loss of skeletal muscle and is a predictor of physical disability/mortality. Its pathogenesis is poorly understood, although roles for altered hypoxic signaling, oxidative stress, adipokines and inflammatory mediators have been suggested. Sarcopenia also occurs upon exposure to the hypoxia of high altitude. Using data from the Caudwell Xtreme Everest expedition we therefore sought to analyze the extent of hypoxia-induced body composition changes and identify putative pathways associated with fat-free mass (FFM) and fat mass (FM) loss.MethodsAfter baseline testing in London (75 m), 24 investigators ascended from Kathmandu (1300 m) to Everest base camp (EBC 5300 m) over 13 days. Fourteen investigators climbed above EBC, eight of whom reached the summit (8848 m). Assessments were conducted at baseline, during ascent and after one, six and eight week(s) of arrival at EBC. Changes in body composition (FM, FFM, total body water, intra- and extra-cellular water) were measured by bioelectrical impedance. Biomarkers of nitric oxide and oxidative stress were measured together with adipokines, inflammatory, metabolic and vascular markers.ResultsParticipants lost a substantial, but variable, amount of body weight (7.3±4.9 kg by expedition end; p<0.001). A progressive loss of both FM and FFM was observed, and after eight weeks, the proportion of FFM loss was 48% greater than FM loss (p<0.008). Changes in protein carbonyls (p<0.001) were associated with a decline in FM whereas 4-hydroxynonenal (p<0.001) and IL-6 (p<0.001) correlated with FFM loss. GLP-1 (r=−0.45, p<0.001) and nitrite (r=−0.29, p<0.001) concentration changes were associated with FFM loss. In a multivariate model, GLP-1, insulin and nitrite were significant predictors of FFM loss while protein carbonyls were predicted FM loss.ConclusionsThe putative role of GLP-1 and nitrite as mediators of the effects of hypoxia on FFM is an intriguing finding. If confirmed, nutritional and pharmacological interventions targeting these pathways may offer new avenues for prevention and treatment of sarcopenia.

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High Altitude and Acute Mountain Sickness and Changes in Circulating Endothelin-1, Interleukin-6, and Interleukin-17a

Abstract: HA leads to endothelial activation and an inflammatory response. The rise in ET-1 and IL-6 is heavily influenced by the degree of exercise and hypoxia. ET-1 is an independent predictor of both AMS and its severity.

Cited by 47 publications

References 36 publications

Severe negative energy balance during 21 d at high altitude decreases fat‐free mass regardless of dietary protein intake: a randomized controlled trial

Severe negative energy balance during 21 d at high altitude decreases fat‐free mass regardless of dietary protein intake: a randomized controlled trial

IL-10 Dysregulation in Acute Mountain Sickness Revealed by Transcriptome Analysis

Does hypoxia play a role in the development of sarcopenia in humans? Mechanistic insights from the Caudwell Xtreme Everest Expedition

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