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Peer-reviewedCC BY 4.0Advanced Science

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

  • Song Ah Chae1,2
  • Ryan C. Riddle3,4
  • Zhihua Jiang5
  • Chaeyoung Shin1,5
  • Min Du5
  • Jun Seok Son1,6
6 affiliations
  1. 1Laboratory of Perinatal Exercise Genomics Department of Obstetrics Gynecology & Reproductive Sciences University of Maryland School of Medicine Baltimore Maryland USA
  2. 2Department of Anesthesiology University of Maryland School of Medicine Baltimore Maryland USA
  3. 3Division of Musculoskeletal Sciences Department of Orthopaedics University of Maryland School of Medicine Baltimore Maryland USA
  4. 4Research and Development Service Baltimore VA Medical Center Baltimore Maryland USA
  5. 5Nutrigenomics & Growth Biology Laboratory Department of Animal Sciences Washington State University Pullman Washington USA
  6. 6Department of Pharmacology & Physiology University of Maryland School of Medicine Baltimore Maryland USA
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Abstract

For proper locomotion, bone and muscle development must be tightly coordinated. Skeletal muscle secretes myokines that affect tissues, including bone. We previously showed that maternal exercise (ME) enhances fetal muscle development through apelin signaling. However, whether mitochondrial dysfunction impairs fetal skeletal development and whether ME mitigates these defects remain unclear. Heterozygous POLG mutant (Polg mut/+) mice were used to examine the effects of ME and apelin signaling on fetal osteogenesis. Pregnant Polg mut/+ females underwent treadmill exercise, and apelin receptor knockdown (Apj KD) mice and maternal apelin supplementation were used to evaluate apelin signaling. POLG mutation impaired fetal osteogenesis and disrupted skeletal morphology. RNA‐seq revealed downregulation of pathways related to cytoskeletal organization and mitochondrial function. ME was associated with upregulation of osteogenesis and development. ME increased apelin abundance in maternal‐fetal circulation and tissues, including fetal muscle and bone. Importantly, apelin administration increased fetal osteogenesis in POLG mutation, whereas Apj KD reduced osteogenic signaling in fetal bone and myogenic gene expression in fetal muscle. Apelin also enhanced mitochondrial respiration in fetal bone‐derived osteogenic cells. Mechanistically, ME‐induced apelin signaling was associated with increased mitochondrial biogenesis and enhanced ATF4‐RUNX2 regulatory signaling. Collectively, these findings suggest that ME‐induced apelin signaling contributes to fetal skeletal development under mitochondrial dysfunction.

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Cite

BibTeXRIS
BibTeX
@article{chae2026maternal,
  title = {{Maternal Exercise Rescues Embryonic Osteogenesis Impaired due to POLG Mutation Through a Potential Apelin‐ATF4 Axis}},
  author = {Song Ah Chae and Ryan C. Riddle and Zhihua Jiang and Chaeyoung Shin and Min Du and Jun Seok Son},
  journal = {Advanced Science},
  year = {2026},
  month = aug,
  doi = {10.1002/advs.77029},
  url = {https://doi.org/10.1002/advs.77029},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Maternal Exercise Rescues Embryonic Osteogenesis Impaired due to POLG Mutation Through a Potential Apelin‐ATF4 Axis
AU  - Song Ah Chae
AU  - Ryan C. Riddle
AU  - Zhihua Jiang
AU  - Chaeyoung Shin
AU  - Min Du
AU  - Jun Seok Son
PY  - 2026
DA  - 2026/08/07
JO  - Advanced Science
DO  - 10.1002/advs.77029
UR  - https://doi.org/10.1002/advs.77029
AB  - For proper locomotion, bone and muscle development must be tightly coordinated. Skeletal muscle secretes myokines that affect tissues, including bone. We previously showed that maternal exercise (ME) enhances fetal muscle development through apelin signaling. However, whether mitochondrial dysfunction impairs fetal skeletal development and whether ME mitigates these defects remain unclear. Heterozygous POLG mutant (Polg mut/+) mice were used to examine the effects of ME and apelin signaling on fetal osteogenesis. Pregnant Polg mut/+ females underwent treadmill exercise, and apelin receptor knockdown (Apj KD) mice and maternal apelin supplementation were used to evaluate apelin signaling. POLG mutation impaired fetal osteogenesis and disrupted skeletal morphology. RNA‐seq revealed downregulation of pathways related to cytoskeletal organization and mitochondrial function. ME was associated with upregulation of osteogenesis and development. ME increased apelin abundance in maternal‐fetal circulation and tissues, including fetal muscle and bone. Importantly, apelin administration increased fetal osteogenesis in POLG mutation, whereas Apj KD reduced osteogenic signaling in fetal bone and myogenic gene expression in fetal muscle. Apelin also enhanced mitochondrial respiration in fetal bone‐derived osteogenic cells. Mechanistically, ME‐induced apelin signaling was associated with increased mitochondrial biogenesis and enhanced ATF4‐RUNX2 regulatory signaling. Collectively, these findings suggest that ME‐induced apelin signaling contributes to fetal skeletal development under mitochondrial dysfunction.
SN  - 2198-3844
ER  -