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The Journal of experimental biology2025; 228(24); jeb250956; doi: 10.1242/jeb.250956

Effects of hypoxia and hyperoxia on exercise-induced metabolomic and transcriptomic profiles in equine skeletal muscle.

Abstract: To explore the molecular mechanisms underlying oxygen-dependent regulation of skeletal muscle adaptations, eight Thoroughbred horses performed 2 min of exercise at a velocity corresponding to 95% maximal O2 uptake under a normoxic condition, while using inspired O2 levels of 0.21 (normoxia), 0.26 (hyperoxia) or 0.16 (hypoxia). At the end of the exercise, arterial O2 saturation was significantly higher with hyperoxia and lower with hypoxia than with normoxia. However, no significant difference in plasma lactate or muscle glycogen concentrations was observed across the O2 conditions. A metabolomic analysis showed that muscle metabolite concentrations involved in glycolysis and the tricarboxylic acid cycle significantly changed in response to exercise but did not significantly differ across the O2 conditions. RNA-sequencing data showed that fewer genes were significantly altered by acute exercise in hyperoxia (upregulated: 523; downregulated: 116) and hypoxia (upregulated: 857; downregulated: 320) compared with normoxia (upregulated: 1628, downregulated: 924). Among them, numerous genes, including well-known exercise-responsive genes, such as NR4A3, PPARGC1A, PDK4 and VEGFA, were altered following exercise, irrespective of the O2 environment. Hyperoxic exercise induced responses of genes related to lysosomal activity, such as M6PR and CTNS, whereas hypoxic exercise triggered hypoxia-responsive gene expression, including PIK3R1, THPO and AKAP1. These findings suggest that arterial O2 availability does not necessarily alter global metabolic or transcriptomic response following a single exercise bout in horses. However, inspired O2 fraction-specific gene responses may play roles in long-term skeletal muscle adaptations and could contribute to the development of optimized training strategies for improved well-being and performance.
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Publication Date: 2025-12-17 PubMed ID: 41199666PubMed Central: PMC12752499DOI: 10.1242/jeb.250956Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This study examined how different oxygen levels during intense exercise affect the molecular responses in equine skeletal muscle.
  • Researchers found that oxygen availability influenced gene expression patterns but did not significantly change metabolic responses immediately after exercise.

Study Purpose

  • To understand how varying oxygen levels (normoxia, hyperoxia, hypoxia) affect molecular mechanisms underlying skeletal muscle adaptation during acute exercise in horses.
  • To explore oxygen-dependent regulation of metabolism and gene expression following short bouts of high-intensity exercise.

Methodology

  • Subjects: Eight Thoroughbred horses were used in the study.
  • Exercise Protocol: Each horse performed 2 minutes of exercise at 95% of their maximal oxygen uptake velocity.
  • Oxygen Conditions:
    • Normoxia: Inspired O2 fraction of 0.21 (normal air).
    • Hyperoxia: Inspired O2 fraction of 0.26 (increased oxygen).
    • Hypoxia: Inspired O2 fraction of 0.16 (reduced oxygen).
  • Measurements:
    • Arterial oxygen saturation levels immediately post-exercise.
    • Plasma lactate and muscle glycogen concentrations.
    • Metabolomic profiling of skeletal muscle focusing on glycolysis and TCA cycle metabolites.
    • RNA sequencing to analyze changes in gene expression in muscle tissue.

Key Findings

  • Arterial oxygen saturation:
    • Increased significantly with hyperoxia compared to normoxia.
    • Decreased significantly with hypoxia compared to normoxia.
  • Metabolic parameters:
    • No significant differences in plasma lactate levels were observed across oxygen conditions.
    • Muscle glycogen concentrations remained similar regardless of oxygen level.
    • Metabolomic analysis showed exercise-induced metabolic changes mainly in glycolysis and the TCA cycle but did not differ with oxygen conditions.
  • Gene expression:
    • Acute exercise induced widespread changes in gene expression, but the number of altered genes differed by oxygen condition:
      • Normoxia: 1628 upregulated and 924 downregulated genes.
      • Hyperoxia: Fewer genes altered (523 upregulated, 116 downregulated).
      • Hypoxia: Moderately fewer genes altered (857 upregulated, 320 downregulated).
    • Common genes altered across all oxygen levels included known exercise-responsive genes such as NR4A3, PPARGC1A, PDK4, and VEGFA.
    • Hyperoxia specifically induced genes related to lysosomal function (e.g., M6PR, CTNS).
    • Hypoxia specifically triggered hypoxia-responsive gene expression (e.g., PIK3R1, THPO, AKAP1).

Interpretation and Implications

  • Arterial oxygen availability during acute exercise does not significantly affect the immediate metabolic response in equine skeletal muscle.
  • Gene expression responses are influenced by oxygen levels, showing distinct patterns under hyperoxia and hypoxia conditions.
  • The oxygen level-specific gene responses might contribute to long-term muscle adaptations with repeated training under altered oxygen conditions.
  • Knowledge of these molecular adaptations could help develop optimized training regimes to enhance horse performance and well-being by manipulating inspired oxygen levels.

Conclusion

  • While short-term metabolic effects of exercise are not markedly affected by oxygen availability, oxygen-dependent transcriptomic changes occur in skeletal muscle.
  • These findings support the idea that manipulating oxygen levels during training could customize molecular adaptations in horses.
  • Future studies should investigate how these gene expression changes translate into physiological adaptations and performance improvements over longer training periods.

Cite This Article

APA
Takahashi K, Mukai K, Takahashi Y, Ebisuda Y, Sugiyama F, Hatta H, Kitaoka Y. (2025). Effects of hypoxia and hyperoxia on exercise-induced metabolomic and transcriptomic profiles in equine skeletal muscle. J Exp Biol, 228(24), jeb250956. https://doi.org/10.1242/jeb.250956

Publication

The Journal of experimental biology
ISSN: 1477-9145
NlmUniqueID: 0243705
Country: England
Language: English
Volume: 228
Issue: 24
PII: jeb250956

Researcher Affiliations

Takahashi, Kenya
  • Department of Sports Sciences, The University of Tokyo, Tokyo 153-8902, Japan.
Mukai, Kazutaka
  • Sports Science Division, Equine Research Institute, Japan Racing Association, Tochigi 329-0412, Japan.
Takahashi, Yuji
  • Sports Science Division, Equine Research Institute, Japan Racing Association, Tochigi 329-0412, Japan.
Ebisuda, Yusaku
  • Sports Science Division, Equine Research Institute, Japan Racing Association, Tochigi 329-0412, Japan.
Sugiyama, Fumi
  • Sports Science Division, Equine Research Institute, Japan Racing Association, Tochigi 329-0412, Japan.
Hatta, Hideo
  • Department of Sports Sciences, The University of Tokyo, Tokyo 153-8902, Japan.
Kitaoka, Yu
  • Department of Human Sciences, Kanagawa University, Kanagawa 221-8686, Japan.

MeSH Terms

  • Animals
  • Horses / physiology
  • Horses / genetics
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / physiology
  • Physical Conditioning, Animal
  • Transcriptome
  • Oxygen / metabolism
  • Hypoxia / metabolism
  • Male
  • Metabolome
  • Hyperoxia / metabolism
  • Female

Grant Funding

  • 20H04071 / Japan Society for the Promotion of Science
  • 24K02812 / Japan Society for the Promotion of Science
  • 21K11459 / Japan Society for the Promotion of Science
  • 21K21249 / Japan Society for the Promotion of Science
  • 23K16718 / Japan Society for the Promotion of Science
  • Kanagawa University

Conflict of Interest Statement

Competing interests The authors declare no competing or financial interests.

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