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.

Figure 1

Mitochondrial energy metabolism. Fatty acid β-oxidation and the TCA cycle produce NADH and FADH₂, which are oxidized by complexes I and II, respectively, of the electron transport chain. Electrons are transferred through the chain to the final acceptor, O₂. The free energy from electron transfer is used to pump H⁺ out of the mitochondria and generate an electrochemical gradient, Δμ_H+, across the inner mitochondrial membrane. This gradient is the driving force for ATP synthesis via the ATP synthase.

Figure 2

Mechanisms of hypoxic adaptation. (a) In normoxia, hypoxia inducible factor-1α (HIF-1α) is degraded, following O₂-dependent hydroxylation by prolyl hydroxylase (PHD) enzymes. (b) In hypoxia, HIF-1α spontaneously accumulates and combines with HIF-1β in the nucleus to activate the transcription of hypoxia-responsive genes and driving a number of metabolic adaptations: (i) BNIP3 upregulation leads to mitochondrial autophagy; (ii) a subunit switch at cytochrome c oxidase (COX), complex IV of the electron transport chain, increases the efficiency of electron (e^-) transfer, and attenuates reactive oxygen species (ROS) production; (iii) glycolytic enzymes and lactate dehydrogenase (LDH) are upregulated, increasing anaerobic ATP production and lactate; (iv) pyruvate dehydrogenase kinase (PDK) enzymes are upregulated, de-activating pyruvate dehydrogenase (PDH) and limiting the conversion of pyruvate to acetyl CoA.