OGG1 increases exercise endurance via elevated skeletal muscle FGF21

Area of Science:

• Genomic integrity and DNA repair
• Metabolic health and mitochondrial function
• Muscle physiology and endurance

Background:

• The base excision repair (BER) pathway, initiated by DNA glycosylases like 8-oxoguanine DNA glycosylase (OGG1), is crucial for maintaining genomic stability against oxidative damage.
• OGG1 is implicated in various diseases, including cancers and neurodegenerative disorders, and its proteins influence metabolic health.
• Previous studies show OGG1-deficient mice are prone to obesity, while OGG1 overexpression reverses these metabolic issues.

Purpose of the Study:

• To investigate the novel effects of OGG1 overexpression on muscle physiology and endurance.
• To explore the molecular mechanisms underlying OGG1's impact on muscle function and metabolic health.

Main Methods:

• Utilized OGG1-transgenic (Ogg1^Tg) mice with overexpressed human OGG1.
• Assessed muscle endurance, mitochondrial content and size, and gene/protein expression in skeletal muscle.
• Measured circulating FGF21 levels and peripheral markers of FGF21 action.

Main Results:

• OGG1 overexpression led to a significant, over 3-fold increase in muscle endurance in Ogg1^Tg mice.
• Mitochondrial content and size were significantly increased in the skeletal muscle of Ogg1^Tg mice.
• Selective upregulation of the myokine Fgf21 in skeletal muscle was observed, alongside elevated circulating FGF21 and peripheral markers of its action.

Conclusions:

• Skeletal muscle OGG1 plays a novel role in enhancing muscle endurance.
• OGG1 overexpression improves mitochondrial health and function within skeletal muscle.
• The observed benefits are mediated through increased FGF21 secretion and signaling, linking OGG1 to improved metabolic and muscle performance.