The most frequently reported symptom of exposure to high altitude is loss of body mass and decreased performance which has been attributed to altered protein metabolism affecting skeletal muscles mass. The present study explores the mechanism of chronic hypobaric hypoxia mediated skeletal muscle wasting by evaluating changes in protein turnover and various proteolytic pathways. Male Sprague-Dawley rats weighing about 200 g were exposed to hypobaric hypoxia (7,620 m) for different durations of exposure. Physical performance of rats was measured by treadmill running experiments. Protein synthesis, protein degradation rates were determined by (14)C-Leucine incorporation and tyrosine release, respectively. Chymotrypsin-like enzyme activity of the ubiquitin-proteasome pathway and calpains were studied fluorimetrically as well as using western blots. Declined physical performance by more than 20%, in terms of time taken in exhaustion on treadmill, following chronic hypobaric hypoxia was observed. Compared to 1.5-fold increase in protein synthesis, the increase in protein degradation was much higher (five-folds), which consequently resulted in skeletal muscle mass loss. Myofibrillar protein level declined from 46.79 ± 1.49 mg/g tissue at sea level to 37.36 ± 1.153 (P < 0.05) at high altitude. However, the reduction in sarcoplasmic proteins was less as compared to myofibrillar protein. Upregulation of Ub-proteasome pathway (five-fold over control) and calpains (three-fold) has been found to be important factors for the enhanced protein degradation rate. The study provided strong evidences suggesting that elevated protein turnover rate lead to skeletal muscle atrophy under chronic hypobaric hypoxia via ubiquitin-proteasome pathway and calpains.

High altitude pulmonary edema (HAPE) susceptibility is associated with EGLN1 polymorphisms, we hypothesized that HAPE-susceptible (HAPE-S, had HAPE episode in past) subjects may exhibit abnormal HIF1α levels in normoxic conditions. We measured HIF1α levels in HAPE-S and HAPE resistant (HAPE-R, no HAPE episode) individuals with similar pulmonary functions. Hemodynamic responses were also measured before and after normobaric hypoxia (Fi02 = 0.12 for 30 min duration at sea level) in both groups. . HIF1α was higher in HAPE-S (320.3 ± 267.5 vs 58.75 ± 33.88 pg/ml, P < 0.05) than HAPE-R, at baseline, despite no significant difference in baseline oxygen saturations (97.7 ± 1.7% and 98.8 ± 0.7). As expected, HAPE-S showed an exaggerated increase in pulmonary artery pressure (27.9 ± 6 vs 19.3 ± 3.7 mm Hg, P < 0.05) and a fall in peripheral oxygen saturation (66.9 ± 11.7 vs 78.7 ± 3.8%, P < 0.05), when exposed to hypoxia. HIF1α levels at baseline could accurately classify members of the two groups (AUC = 0.87). In a subset of the groups where hemoglobin fractions were additionally measured to understand the cause of elevated hypoxic response at baseline, two of four HAPE-S subjects showed reduced HbA. In conclusion, HIF 1 α levels during normoxia may represent an important marker for determination of HAPE susceptibility.

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The importance of hypoxia inducible factor (HIF) as the master regulator of hypoxic responses is well established. Oxygen-dependent prolyl hydroxylase domain enzymes (PHDs) negatively regulate HIF directing it to the path of degradation under normoxia and are, consequently, attractive therapeutic targets. Inhibition of PHDs might upregulate beneficial HIF-mediated processes. In this study, we have examined the efficacy of PHD inhibitor ethyl 3,4-dihydroxy benzoate (EDHB) in affording protection against hypoxia-induced oxidative damage in L6 myoblast cells. L6 cells were exposed to hypoxia (0.5 % O2) after preconditioning with EDHB for different times. Levels of HIF-1α, oxidative stress and antioxidant status were measured after hypoxia exposure. Preconditioning with EDHB significantly improved cellular viability, and the diminished levels of protein oxidation and malondialdehyde indicated a decrease in oxidative stress when exposed to hypoxia. EDHB treatment also conferred enhanced anti-oxidant status, as there was an increase in the levels of glutathione and antioxidant enzymes like superoxide dismutase and glutathione peroxidase. Further, augmentation of the levels of HIF-1α boosted protein expression of antioxidative enzyme heme-oxygenase I. There was enhanced expression of metallothioneins which also have antioxidant, anti-inflammatory properties. These results thus accentuate the potential cytoprotective efficacy of EDHB against hypoxia-induced oxidative damage.