Macrophage Subpopulation Promotes Skeletal Muscle Regeneration Through HGF/MET Signaling-Mediated Skeletal Muscle...

Area of Science:

• Muscle biology
• Immunology
• Regenerative medicine

Background:

• Macrophages are crucial for skeletal muscle regeneration.
• The specific roles of macrophage subpopulations and their interactions with muscle stem cells are not fully understood.
• Age-related decline in muscle regeneration is a significant clinical challenge.

Purpose of the Study:

• To identify distinct macrophage subpopulations in young and aged mouse skeletal muscle.
• To elucidate the mechanism of macrophage-mediated muscle regeneration and its age-related impairment.
• To investigate the therapeutic potential of targeting macrophage-mediated signaling for muscle repair.

Main Methods:

• Single-cell RNA sequencing of skeletal muscle macrophages from young and aged mice.
• In vivo and 3D-muscle organoid models to study macrophage-muscle satellite cell interactions.
• Assessment of HGF/c-Met signaling pathway and Cdkn1b expression.
• Experimental manipulation of HGF levels and macrophage populations.

Main Results:

• Identified a Mac_1 macrophage subpopulation that promotes muscle satellite cell proliferation via HGF/c-Met signaling, suppressing Cdkn1b.
• Demonstrated the critical role of Mac_1 and HGF/c-Met signaling in muscle regeneration in vivo and in organoid models.
• Found reduced HGF expression in Mac_1 macrophages from aged mice, correlating with impaired regeneration.
• Showed that exogenous HGF administration partially rescued muscle regeneration in aged and macrophage-depleted mice.

Conclusions:

• Mac_1 macrophages are key regulators of skeletal muscle regeneration through HGF/c-Met signaling.
• Age-related decline in HGF production by Mac_1 macrophages contributes to impaired muscle regeneration.
• Targeting the HGF/c-Met pathway in macrophages presents a potential therapeutic strategy for age-related muscle degeneration and sarcopenia.