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

OBJECTIVES: Sarcopenia 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. METHODS: After baseline testing in London (75m), 24 investigators ascended from Kathmandu (1300m) to Everest base camp (EBC 5300m) over 13 days. Fourteen investigators climbed above EBC, eight of whom reached the summit (8848m). 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. RESULTS: Participants lost a substantial, but variable, amount of body weight (7.3±4.9kg 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. CONCLUSIONS: The 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

Changes in skeletal muscle oxygenation during exercise measured by near-infrared spectroscopy on ascent to altitude

Introduction: We sought to quantify changes in skeletal muscle oxygenation during exercise using near-infrared spectroscopy (NIRS) in healthy volunteers ascending to high altitude.Methods: Using NIRS, skeletal muscle tissue oxygen saturation (StO2) was measured in the vastus lateralis of 24 subjects. Measurements were performed at sea level (SL; 75 m), at 3,500 m, on arrival at 5,300 m (5,300 m-a; days 15 to 17) and at 5,300 m again (5,300 m-b; days 69 to 71). Amongst the subjects, nine remained at 5,300 m whilst 14 climbed to a maximum of 8,848 m. Exercise was 3 minutes of unloaded cycling followed by an incremental ramp protocol to exhaustion. The absolute StO2 at different stages of exercise along with the difference between StO2 at stages and the rate of change in StO2 were compared between altitudes. Resting peripheral oxygen saturation was recorded.Results: NIRS data achieving predefined quality criteria were available for 18 subjects at 75 m, 16 subjects at 3,500 m, 16 subjects on arrival at 5,300 m and 16 subjects on departure from 5,300 m. At SL, mean StO2 declined from 74.4% at rest to 36.4% at maximal oxygen consumption (P &lt; 0.0001) and then rose to 82.3% (P &lt; 0.0001) 60 seconds after exercise had ceased. At 3,500 m-a and 5,300 m-b, the pattern was similar to SL but absolute values were approximately 15% lower at all stages. At 5,300 m-a, the resting StO2 was similar to SL and the change in StO2 at each exercise stage less marked. At 5,300 m-b, the rate of decline in StO2 during exercise was more rapid than SL (P = 0.008); here the climbers had a smaller decline in StO2 during exercise (41.0%) and a slower rate of desaturation (0.086%/second) than those who had remained at 5,300 m (62.9% and 0.127%/second) (P = 0.031 and P = 0.047, respectively).Conclusions: In most individuals, NIRS can be used to measure exercising skeletal muscle oxygenation in the field. During exercise the patterns of absolute oxygenation are broadly similar at altitude and SL. Following prolonged adaptation to altitude, the rate of muscle desaturation is more rapid than observed at SL but less so in those exposed to extreme hypoxia above 5,300 m.<br/

Reduced coagulation at high altitude identified by thromboeslastography

The impact of hypoxaemia on blood coagulation remains unclear despite use of a variety of measures to address the issue. We report the first use of thromboelastography (TEG) at high altitude to describe the dynamics of clot formation in whole blood samples. Seventeen healthy volunteers ascended to 5,300 m following an identical ascent profile; TEG measurements at 4,250 m and 5,300 m were compared with those from sea level. Peripheral oxygen saturation (SpO2) and haematocrit were also measured. Ascent resulted in a decline in SpO2 from 97.8 (± 1.2) % at sea level to 86.9 (± 3.3) % at 4,250 m and 79.5 (± 5.8) % at 5,300 m (p&lt;0.001); haematocrit rose from 43.7 (± 2.8) % at sea level, to 46.7 (± 3.9) % and 52.6 (± 3.2) % at 4,250 m and 5,300 m, respectively (p&lt;0.01). TEG reaction (R)-time and kinetic (K)-time were both increased at 5,300 m compared to sea level, 8.95 (± 1.37) minutes (min) to 11.69 (± 2.91) min (p=0.016) and 2.40 (± 0.66) min to 4.99 (± 1.67) min (p&lt;0.001), respectively. Additionally the alpha (?)- angle was decreased from 57.7 (± 8.2) to 51.6 (± 6.4) (p&lt;0.001). There was no change in maximum amplitude (MA) on ascent to altitude. These changes are consistent with an overall pattern of slowed coagulation at high altitude

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

Objectives: Sarcopenia 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. Methods: After 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. Results: Participants 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. Conclusions: The 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

Caudwell Xtreme Everest: A prospective study of the effects of environmental hypoxia on cognitive functioning

Background: The neuropsychological consequences of exposure to environmental hypobaric hypoxia (EHH) remain unclear. We thus investigated them in a large group of healthy volunteers who trekked to Mount Everest base camp (5,300 m). Methods: A neuropsychological (NP) test battery assessing memory, language, attention, and executive function was administered to 198 participants (age 44.5±13.7 years; 60% male). These were studied at baseline (sea level), 3,500 m (Namche Bazaar), 5,300 m (Everest Base Camp) and on return to 1,300 m (Kathmandu) (attrition rate 23.7%). A comparable control group (n = 25; age 44.5±14.1 years; 60% male) for comparison with trekkers was tested at/or near sea level over an equivalent timeframe so as to account for learning effects associated with repeat testing. The Reliable Change Index (RCI) was used to calculate changes in cognition and neuropsychological function during and after exposure to EHH relative to controls. Results: Overall, attention, verbal ability and executive function declined in those exposed to EHH when the performance of the control group was taken into account (RCI .05 to -.95) with decline persisting at descent. Memory and psychomotor function showed decline at highest ascent only (RCI -.08 to -.56). However, there was inter-individual variability in response: whilst NP performance declined in most, this improved in some trekkers. Cognitive decline was greater amongst older people (r = .42; p &lt; .0001), but was otherwise not consistently associated with socio-demographic, mood, or physiological variables. Conclusions: After correcting for learning effects, attention, verbal abilities and executive functioning declined with exposure to EHH. There was considerable individual variability in the response of brain function to sustained hypoxia with some participants not showing any effects of hypoxia. This might have implications for those facing sustained hypoxia as a result of any disease