Maternal Exercise Rescues Embryonic Osteogenesis Impaired due to POLG Mutation Through a Potential Apelin-ATF4 Axis

Area of Science:

• Developmental Biology
• Mitochondrial Biology
• Skeletal Biology

Background:

• Bone and muscle development require coordination, with muscle-derived myokines influencing bone.
• Maternal exercise (ME) enhances fetal muscle development via apelin signaling.
• The impact of mitochondrial dysfunction on fetal skeletal development and ME's mitigating effects are unknown.

Purpose of the Study:

• To investigate how mitochondrial dysfunction affects fetal skeletal development.
• To determine if ME can counteract these defects.
• To elucidate the role of apelin signaling in this process.

Main Methods:

• Utilized heterozygous POLG mutant mice to model mitochondrial dysfunction.
• Administered treadmill exercise to pregnant mice.
• Employed apelin receptor knockdown and maternal apelin supplementation to assess apelin signaling.
• Performed RNA-sequencing to analyze gene expression changes.

Main Results:

• POLG mutation impaired fetal osteogenesis and skeletal morphology.
• ME upregulated osteogenesis and fetal development markers.
• ME increased apelin levels, enhancing fetal osteogenesis and muscle development.
• Apelin supplementation improved osteogenesis in mutant fetuses, while knockdown impaired it.
• Apelin enhanced mitochondrial respiration and promoted mitochondrial biogenesis.

Conclusions:

• Maternal exercise-induced apelin signaling is crucial for fetal skeletal development under mitochondrial dysfunction.
• Apelin signaling positively regulates mitochondrial function and osteogenic pathways (ATF4-RUNX2).
• This study highlights a mechanism linking maternal exercise, apelin, and fetal skeletal health.