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.