Effects of Hypoxia and Bed Rest on Markers of Cardiometabolic Risk: Compensatory Changes in Circulating TRAIL and Glutathione Redox Capacity

Abstract

In chronic diseases, hypoxia and physical inactivity are associated with atherosclerosis progression. In contrast, a lower mortality from coronary artery disease and stroke is observed in healthy humans residing at high altitude in hypoxic environments. Eleven young, male volunteers completed the following 10-day campaigns in a randomized order: hypoxic ambulatory, hypoxic bed rest and normoxic bed rest. Before intervention, subjects were evaluated in normoxic ambulatory condition. Normobaric hypoxia was achieved in a hypoxic facility simulating 4000 m of altitude. Following hypoxia, either in bed rest or ambulatory condition, markers of cardiometabolic risk shifted toward a more atherogenic pattern consisting of: (a) lower levels of total HDL cholesterol and HDL2 sub-fraction and decreased hepatic lipase; (b) activation of systemic inflammation, as determined by C-reactive protein and serum amyloid A; (c) increased plasma homocysteine; (d) decreased delta-5 desaturase index in cell membrane fatty acids, a marker of insulin sensitivity. Bed rest and hypoxia additively decreased total HDL and delta-5 desaturase index. In parallel to the pro-atherogenic effects, hypoxia activated selected anti-atherogenic pathways, consisting of increased circulating TNF-related apoptosis-inducing ligand (TRAIL), a protective factor against atherosclerosis, membrane omega-3 index and erythrocyte glutathione availability. Hypoxia mediated changes in TRAIL concentrations and redox glutathione capacity (i.e., GSH/GSSG ratio) were greater in ambulatory conditions (+34 ± 6% and +87 ± 31%, respectively) than in bed rest (+17 ± 7% and +2 ± 27% respectively). Hypoxia-induced cardiometabolic risk is blunted by moderate level of physical activity as compared to bed rest. TRAIL and glutathione redox capacity may contribute to the positive interaction between physical activity and hypoxia.Highlights:– Hypoxia and bed rest activate metabolic and inflammatory markers of atherogenesis.– Hypoxia and physical activity activate selected anti-atherogenic pathways.– Hypoxia and physical activity positive interaction involves TRAIL and glutathione.

Statin-Associated Myopathy: Emphasis on Mechanisms and Targeted Therapy

“…Ketoconazole, an antifungal agent, is the most widely used drug in the pharmacotherapy of CS. It is an adrenal steroidogenesis inhibitor, acting on several steroidogenesis enzymes, including the cholesterol side-chain cleavage complex, 17,20-lyase, 11β-hydroxylase, and 17β-hydroxylase [150]. Ketoconazole is also an inhibitor of cholesterol biosynthesis, acting directly by blocking the conversion of methyl sterols to cholesterol and indirectly by suppressing cholesterol synthesis, reducing total, intermediate-density, and LDL-C by approximately 25% [151][152][153].…”

The Vascular Side of Chronic Bed Rest: When a Therapeutic Approach Becomes Deleterious

“…It is known that bed rest activates metabolic and inflammatory markers [29], however a comprehensive analysis of the effect of physical inactivity and advanced aging on inflammatory serum profile was never achieved. By analyzing serum samples, we detected significant changes in the inflammatory profile of the examined subjects.…”

Skeletal Muscle in Hypoxia and Inflammation: Insights on the COVID-19 Pandemic

“…While the link between physical inactivity, chronic inflammation and oxidative stress and muscle dysfunction is well-established (27), the effect on muscle mass of COVID-19related hypoxemia has been insufficiently evaluated. Indeed, hypoxemic chronic cardiopulmonary conditions (e.g., Chronic obstructive pulmonary disease-COPD-, pulmonary fibrosis, Obstructive Sleep Apnea Syndrome-OSAS-or heart failure), induce a hypoxia-related decreased physical capacity (28,29). Systemic hypoxemia determines muscle and bone deterioration (30)(31)(32) by triggering several signaling cascades including innate immune responses and/or changes in redox balance and lipid and glucose metabolism (33,34).…”

“…This approach has been recognized to be of potential clinical relevance for mimicking hospitalrelated physical inactivity since it allows differentiating the catabolic effects induced by a disease from those secondary to skeletal muscle disuse (35). The study of healthy volunteers in facilities that allow a controlled modification of the amount of oxygen in the air in both bed rest and/or ambulatory conditions can be considered an appropriate model to investigate the separate and the combined effect of hypoxia and muscle disuse (28,36,37).…”

“…This review tries to identify some metabolic, immunity-related and redox biomarkers, potentially affected by decreased oxygen blood levels and/or muscle disuse (28,(38)(39)(40), to shed light on the negative impact of SARS-CoV-2 infection on muscle mass and function. Moreover, possible countermeasure are described.…”