Iron Deficiency Impairs Muscle Stem Cell Proliferation and Skeletal Muscle Regeneration via HIF-2α Stabilization

Area of Science:

• Muscle stem cell biology
• Iron metabolism
• Skeletal muscle regeneration

Background:

• Functional iron deficiency is common in chronic diseases and older adults.
• Iron deficiency is linked to sarcopenia, but mechanisms are unclear.
• This study explores iron depletion's effect on muscle stem cells (MuSC) and regeneration via HIF-2α signaling.

Purpose of the Study:

• To investigate how iron deficiency impacts muscle stem cell proliferation.
• To determine the role of HIF-2α signaling in iron deficiency-induced muscle regeneration defects.
• To assess the therapeutic potential of HIF-2α inhibition for muscle repair in iron deficiency.

Main Methods:

• Mice were fed iron-sufficient or iron-deficient diets, followed by cardiotoxin-induced muscle injury.
• Muscle mass, MuSC proliferation, and histological changes were assessed.
• HIF-2α inhibition was used to explore causal mechanisms.

Main Results:

• Iron deficiency reduced MuSC proliferation, myoblast expansion, and muscle mass recovery.
• HIF-2α inhibition in iron-deficient mice increased MuSC proliferation and restored muscle mass.
• Iron deficiency stabilized HIF-2α, leading to Rb1 upregulation, E2F repression, and cell cycle arrest.

Conclusions:

• Iron deficiency impairs skeletal muscle regeneration by stabilizing HIF-2α in MuSC, inhibiting proliferation.
• Transient HIF-2α inhibition rescues muscle repair in iron deficiency.
• HIF-2α is a potential therapeutic target for sarcopenia in aging and chronic diseases.