Metabolic adaptation of skeletal muscle to high altitude hypoxia: how new technologies could resolve the controversies

Abstract

In most tissues of the body, cellular ATP production predominantly occurs via mitochondrial oxidative phosphorylation of reduced intermediates, which are in turn derived from substrates such as glucose and fatty acids. In order to maintain ATP homeostasis, and therefore cellular function, the mitochondria require a constant supply of fuels and oxygen. In many disease states, or in healthy individuals at altitude, tissue oxygen levels fall and the cell must meet this hypoxic challenge to maintain energetics and limit oxidative stress. In humans at altitude and patients with respiratory disease, loss of skeletal muscle mitochondrial density is a consistent finding. Recent studies that have used cultured cells and genetic mouse models have elucidated a number of elegant adaptations that allow cells with a diminished mitochondrial population to function effectively in hypoxia. This article reviews these findings alongside studies of hypoxic human skeletal muscle, putting them into the context of whole-body physiology and acclimatization to high-altitude hypoxia. A number of current controversies are highlighted, which may eventually be resolved by a systems physiology approach that considers the time-or tissue-dependent nature of some adaptive responses. Future studies using high-throughput metabolomic, transcriptomic, and proteomic technologies to investigate hypoxic skeletal muscle in humans and animal models could resolve many of these controversies, and a case is therefore made for the integration of resulting data into computational models that account for factors such as duration and extent of hypoxic exposure, subjects' backgrounds, and whether data have been acquired from active or sedentary individuals. An integrated and more quantitative understanding of the body's metabolic response to hypoxia and the conditions under which adaptive processes occur could reveal much about the ways that tissues function in the very many disease states where hypoxia is a critical factor.

Tissue-specific changes in fatty acid oxidation in hypoxic heart and skeletal muscle

“…The selection of metabolic substrates by heart and muscle during hypoxia is regulated by a complex signaling network to maintain ATP synthesis while minimizing cellular damage due to ROS production (34). We show here that cardiac and skeletal muscle respond with a similar metabolic pattern during acute hypoxia by decreasing the uptake and use of lipids as a substrate to fuel ATP production.…”

Metabolic basis to Sherpa altitude adaptation

“…Next, we investigated the capacity to derive cellular energy via glycolysis, which is increased in hypoxic cells (40), because glycolysis may allow ATP levels to be maintained when O 2 is limited. Hexokinase activity was the same in both groups at baseline, and did not change at altitude (Fig.…”

Oral Coenzyme Q10 Supplementation Does Not Prevent Cardiac Alterations During a High Altitude Trek to Everest Base Camp

“…In hypoxic human skeletal muscle, downregulation of electron transport chain complex I and loss of mitochondrial density (Murray 2009;Levett et al, 2012) underlie a suppression of tissue oxygen demand, associated with altered energetics (Edwards et al, 2010). Whilst it is not known whether similar responses underlie the impaired energetics of the hypoxic human heart, decreased mitochondrial respiration rates and decreased complex I were found in the mitochondria of the chronically-hypoxic rat heart (Heather et al, 2012).…”