Adaptive remodeling of skeletal muscle energy metabolism in high-altitude hypoxia: Lessons from AltitudeOmics

Abstract

Metabolic responses to hypoxia play important roles in cell survival strategies and disease pathogenesis in humans. However, the homeostatic adjustments that balance changes in energy supply and demand to maintain organismal function under chronic low oxygen conditions remain incompletely understood, making it difficult to distinguish adaptive from maladaptive responses in hypoxia-related pathologies. We integrated metabolomic and proteomic profiling with mitochondrial respirometry and blood gas analyses to comprehensively define the physiological responses of skeletal muscle energy metabolism to 16 days of high-altitude hypoxia (5260 m) in healthy volunteers from the AltitudeOmics project. In contrast to the view that hypoxia down-regulates aerobic metabolism, results show that mitochondria play a central role in muscle hypoxia adaptation by supporting higher resting phosphorylation potential and enhancing the efficiency of long-chain acylcarnitine oxidation. This directs increases in muscle glucose toward pentose phosphate and one-carbon metabolism pathways that support cytosolic redox balance and help mitigate the effects of increased protein and purine nucleotide catabolism in hypoxia. Muscle accumulation of free amino acids favor these adjustments by coordinating cytosolic and mitochondrial pathways to rid the cell of excess nitrogen, but might ultimately limit muscle oxidative capacity Collectively, these studies illustrate how an integration of aerobic and anaerobic metabolism is required for physiological hypoxia adaptation in skeletal muscle, and highlight protein catabolism and allosteric regulation as unexpected orchestrators of metabolic remodeling in this context. These findings have important implications for the management of hypoxia-related diseases and other conditions associated with chronic catabolic stress.

COVID-19 Metabolomic Profile: A Link Between Lung Dysfunction Markers and Altered Amino Acid Metabolism

“…shown that BCAA mobilization from skeletal muscle to liver is essential for human adaptability to lower oxygen levels 46 , which is in agreement with our ndings. Recent data highlight the relevance of BCAA administration as an strategy to attenuate protein muscle loss in COVID-19 critical patients 47 .…”

Melatonin Relations With Respiratory Quotient Weaken on Acute Exposure to High Altitude

“…SMC N –SMC D , as well as, absolute values of SMC N and SMC D loosening their relation with RQ at HA ( Figure 3 ) could mean a decoupling of energy metabolism from circadian control, a possibility that certainly has further to be elucidated. It may be noticed, however, that even acute adequation of energy metabolism to HA exposure is yet far from reaching a consensus ( Chicco et al, 2018 ). It may be provisionally assumed, however, that mistiming of melatonin circadian rhythmicity may represent a metabolic risk factor, particularly under conditions combining shift work with hypoxia as being usual in Chilean Andes.…”

Tafazzin deficiency impairs CoA-dependent oxidative metabolism in cardiac mitochondria

“…For some experiments subsarcolemmal (SS) and intermyofibrillar (IF) mitochondria were isolated using trypsin to dissociate IFM from myofibrillar proteins (59). To evaluate the respiratory function of intact cardiac mitochondrial matrices in situ, structurally sound fiber bundles (1.0 -1.2 mg) were dissected from 10-15 mg left ventricular sections and permeabilized with saponin as previously described (60). Permeabilized fiber bundles were gently blotted dry on Whatman paper for 10-15 seconds to remove excess buffer, weighed, and immediately placed in the Oxygraph chamber.…”