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

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.