Molecular Mechanisms of High-Altitude Acclimatization

Abstract

High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hypoxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeostasis. In addition, discussed are genetic factors and the resultant proteomic profiles determining these hypoxia-modifying mechanisms culminating in successful high-altitude acclimatization. Lastly, the article discusses practical considerations related to the molecular aspects of acclimatization and altitude training strategies.

MFN2 deficiency promotes cardiac response to hypobaric hypoxia by reprogramming cardiomyocyte metabolism

“…1 High-altitude natives and altitude-acclimatized sojourners exhibit remarkable physical performance, allowing them to survive, reproduce and free from the diseases inferred by high-altitude environment. 2,3 However, after ascent to high altitudes, unacclimatized individuals may suffer from high-altitude diseases such as chronic mountain sickness, pulmonary hypertension (PH) and heart failure syndrome. [4][5][6] The onset and development of cardio-pulmonary diseases is considered a valid marker of maladaptation to chronic hypoxia.…”

“…[4][5][6] The onset and development of cardio-pulmonary diseases is considered a valid marker of maladaptation to chronic hypoxia. 2,3 In high-altitude environments characterized by hypobaric hypoxia (HH), the cardiovascular system adapts to maintain oxygen delivery in the face of decreased arterial oxygen saturation. Generally, during acute exposure to high altitude, heart rate and cardiac output is increased via sympathetic activation.…”

“…Around 40 million people venture into high‐altitude regions each year for work or leisure 1 . High‐altitude natives and altitude‐acclimatized sojourners exhibit remarkable physical performance, allowing them to survive, reproduce and free from the diseases inferred by high‐altitude environment 2,3 . However, after ascent to high altitudes, unacclimatized individuals may suffer from high‐altitude diseases such as chronic mountain sickness, pulmonary hypertension (PH) and heart failure syndrome 4–6 .…”

The Oxygen Cascade from Atmosphere to Mitochondria as a Tool to Understand the (Mal)adaptation to Hypoxia

“…The ability to adapt to environmental changes is a key feature in the evolution of species. While the mechanisms underlying the cardiac, nervous, and pulmonary tissues’ initial adaptation, or acclimatization, to hypoxic conditions have recently been worked out [ 27 ], the rules for recognizing the onset of long-term adaptation should include the appearance of complex characters that are too well-fitted to the environment for the fit to have arisen by chance and that help their bearers to survive and reproduce. The concept of adaptation physiology greatly depends on semantic problems related to the meaning of this term [ 28 ].…”

Cardio-Respiratory and Muscle Oxygenation Responses to Submaximal and Maximal Exercise in Normobaric Hypoxia: Comparison between Children and Adults

“…Exposure to altitude or hypoxia provokes many physiological responses, with their magnitude directly related to the hypoxic intensity and/or duration (i.e., hypoxic dose) [ 1 , 2 , 3 , 4 ]. Prominent acute hypoxia-related effects, aimed at counterbalancing the oxygen flux reductions, include increases in the resting alveolar rate and thereby the minute ventilation ( E ) and increased heart rate (HR) which, subsequently, is also reflected in the augmented cardiac output [ 3 , 5 , 6 ].…”