Chicco 2018 MiP2018c

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Adam J Chicco
Role of mitochondria in skeletal muscle acclimatization to high-altitude.

Link: MiP2018

Chicco AJ, Le CH, Gnaiger E, Dreyer HC, Muyskens JB, D’alessandro A, Nemkov T, Hocker AD, Wolfe LA, Lovering AT, Subudhi AW, Roach RC (2018)

Event: MiP2018

COST Action MitoEAGLE

Metabolic responses to hypoxia play important roles in both 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 conditions. 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, sedentary volunteers from the 2012 AltitudeOmics expedition. In contrast to the view that hypoxia downregulates aerobic metabolism, results show that mitochondrial respiratory capacity is preserved following high-altitude acclimatization, and plays a central role in adaptive responses by supporting higher resting phosphorylation potential and enhancing the efficiency of long-chain acylcarnitine oxidation. This directs increases in muscle glucose towards pentose phosphate and one-carbon metabolism pathways that support cytosolic redox balance and help mitigate the effects of increased protein and purine nucleotide catabolism. Muscle accumulation of free amino acids supports these adjustments by coordinating cytosolic and mitochondrial pathways to rid the cell of excess nitrogen, but also leads to imbalances in citric acid cycle intermediates that might limit muscle oxidative capacity in vivo (e.g., during exercise). Collectively, these studies illustrate how an integration of aerobic and anaerobic metabolism is required for adaptation of skeletal muscle to high-altitude hypoxia. In addition, results highlight protein catabolism and allosteric regulation as unexpected orchestrators of metabolic remodeling at high altitude, rather that tissue hypoxia per se. These findings shed new light on how human skeletal muscle responds to metabolic stress, and may have important implications for the management of hypoxia-related diseases.


Bioblast editor: Plangger M, Kandolf G O2k-Network Lab: US CO Fort Collins Chicco AJ, AT Innsbruck Gnaiger E


Labels: MiParea: Respiration, Comparative MiP;environmental MiP, Exercise physiology;nutrition;life style 

Stress:Hypoxia  Organism: Human  Tissue;cell: Skeletal muscle 



HRR: Oxygraph-2k 


Affiliations

Chicco AJ(1,2), Le CH(2), Gnaiger E(3), Dreyer HC(4), Muyskens JB(4), D’alessandro A(5), Nemkov T(5), Hocker AD(4), Wolfe LA(6), Lovering AT(5), Subudhi AW(7), Roach RC(8)

  1. Dept Biomedical Sciences, Colorado State Univ
  2. Cell Molecular Biology, Colorado State Univ; Fort Collins, CO, USA
  3. Medical Univ Innsbruck, Innsbruck, Austria
  4. Dept Human Physiology, Univ Oregon, Eugene, OR, USA
  5. Biochemistry Molecular Genetics, Univ Colorado-Anschutz Medical Campus, Aurora
  6. Biochemistry Molecular Biology, Colorado State Univ, Fort Collins
  7. Dept Biology, Univ Colorado Colorado Springs; CO, USA
  8. Altitude Research Center, Univ Colorado-Anschutz Medical Campus, Aurora, CO, USA