The HIF-1α Pathway Regulates Satellite Cell Fate During Aging Through Histone Lactylation

Area of Science:

• Cell Biology
• Muscle Physiology
• Epigenetics

Background:

• Aging-associated sarcopenia involves loss of muscle fibers and satellite cell (SC) dysfunction.
• Hypoxia-inducible factor-1α (HIF-1α) signaling declines with age, contributing to these defects.

Purpose of the Study:

• To investigate if pharmacological reactivation of HIF-1α can rejuvenate aged SCs and ameliorate sarcopenia.
• To elucidate the molecular mechanisms linking HIF-1α, metabolism, and SC function.

Main Methods:

• Aged mouse tibialis anterior muscle SCs were treated with roxadustat to reactivate HIF-1α.
• Analysis included gene expression, intracellular lactate levels, histone lactylation, cell proliferation, senescence markers, and differentiation capacity.
• Key signaling pathways like IGF-1/PI3K-Akt-mTOR were assessed.

Main Results:

• Roxadustat treatment restored HIF-1α signaling, increased glycolytic enzymes and lactate, and enhanced histone lactylation.
• HIF-1α activation shifted aged SCs from senescence to a quiescent, regenerative state, reducing p16Ink4a and increasing Pax7.
• Pretreated SCs showed improved differentiation into hypertrophic myotubes with higher ATP content and activated myogenic pathways.

Conclusions:

• A HIF-1α-lactate-lactylation axis rejuvenates aged satellite cells.
• Pharmacological HIF-1α reactivation holds promise for treating sarcopenia by enhancing myogenic performance.