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Six-hour hypoxia-induced protein degradation in M. gastrocnemius of 24-day-old mice by activating FOXO1 and

Jingyi Song1, Marcel Jaklofsky1, Claudia Carmone1

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PubMed
Summary

Acute hypoxia in young mice significantly increases muscle protein breakdown and decreases synthesis by activating FOXO1 signaling. This rapid response in skeletal muscle may impact developing muscle, especially during travel or high altitude exposure.

Keywords:
FOXO1hypoxiamTORC1proteostasisskeletal muscle

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Area of Science:

  • Muscle physiology and proteostasis
  • Environmental hypoxia effects
  • Molecular signaling pathways

Background:

  • Long-term hypoxia is linked to skeletal muscle atrophy.
  • Developing muscle typically exhibits hypertrophy and net protein synthesis.
  • The impact of acute, physiologically relevant hypoxia on young muscle proteostasis is not well understood.

Purpose of the Study:

  • To investigate the effects of acute normobaric hypoxia on skeletal muscle proteostasis in young mice.
  • To elucidate the molecular mechanisms underlying these effects, focusing on signaling pathways involved in protein synthesis and degradation.

Main Methods:

  • Exposure of 24-day-old mice to normobaric hypoxia (12% O2) or normoxia (20.9% O2) for 6 hours.
  • Analysis of M. gastrocnemius transcriptome (RNA-Seq) and proteome.
  • Measurement of key signaling molecules including HIF1, FOXO1, AKT, mTORC1 pathway components, and protein degradation markers.

Main Results:

  • Hypoxia activated hypoxia-inducible factor 1 (HIF1) and forkhead box-O (FOXO) 1 signaling pathways.
  • FOXO1 activation led to decreased protein synthesis (reduced p-S6K/S6K and p-4E-BP1/4E-BP1 ratios) and increased protein degradation (increased FBXO32).
  • A central role for Atf4 was suggested in mediating these hypoxic effects.

Conclusions:

  • Acute (6h) exposure to 12% O2 normobaric hypoxia activates FOXO1 signaling in the M. gastrocnemius of young mice.
  • This activation results in decreased protein synthesis and increased protein degradation, potentially impacting muscle development.
  • Findings are relevant for understanding muscle responses in infants or young animals during air travel or high-altitude exposure.