Embryonic muscle-bone crosstalk through exercise-induced apelin-ATF4 axis prevents delayed fetal osteogenesis due to maternal western diet and POLG mutagenesis

Bone and muscle have a cross-bridge interacting with each other through biochemical signals. Of note, these tissues interplay by secretion of osteokines and myokines from each tissue for endocrine, autocrine, and paracrine activities, leading to biological stimulation in local and distant tissues and cells. We previously showed that maternal exercise (ME) induces fetal muscle development by an apelin signaling pathway. Herein, we found the fetal muscle-bone crosstalk, which was activated by ME-induced apelin-ATF4 axis, leading to prevention against impeding fetal osteogenesis caused by maternal obesity (MO) and mitochondrial polymerase γ (PolG) mutation. To test, heterozygote mitochondrial PolG mutated ( PolgA mut/+ ) female mice were fed either a control diet (CD) or a high-fat diet (HFD) during pregnancy, which were mated with age-matched heterozygote male PolgA mice. We had four fetal groups: maternal CD (M-CD)+WT, M-CD+ PolgA mut/mut , M-HFD+WT, and M-HFD +PolgA mut/mut . To determine the therapeutic effect of exogenous apelin on PolG mutation-induced deterioration in fetal osteogenesis, heterozygote PolG mutated ( PolgA mut/+ ) female mice were daily treated with either apelin ([Pyr1]apelin-13) or PBS during pregnancy for 16 days (e1.5 to e16.5). Fetal livers at e18.5 were collected and utilized for biochemical and histochemical analyses. Based on the RNA-seq analysis, we found that maternal western diet during pregnancy increases osteoclast differentiation and decreased skeletal joint and bone development in e18.5 fetal limbs. Even, the maternal western diet exacerbated the deterioration of fetal muscle-bone formation in homozygote PolgA mice. Apelin treatment during pregnancy protected the impeding fetal muscle-bone development due to PolG mutagenesis, showing that apelin mimics the beneficial effect of ME on fetal muscle-bone crosstalk. We also showed that ME-induced apelin administration increases ATF4 expression and coregulation with RUNX2, as a primary transcription factor for osteoblast differentiation. These data suggest that western diet intake during pregnancy has substantial impact on the fetal muscle-bone development concomitant with PolG mutation, whereas ME-induced apelin pathway has a therapeutic potential for muscle-bone interaction and development. This work was supported by the National Institutes of Health (NIH) grants (R01-HD067449; R21-AG084142). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.