MATERNAL OBESITY AND EMBRYONIC MUSCLE DEVELOPMENT

Yao Gao

doi:10.7273/000006504

Maternal obesity (MO) impairs fetal skeletal muscle development, which programs long-term metabolic dysfunction of offspring muscle, but the effects of MO on early embryonic myogenesis and the underlying mechanisms remain to be examined. On the other hand, the mechanism of maternal exercise (ME), as a counteraction of negative effects of MO, to improve embryonic myogenesis remains to be established. Therefore, in this dissertation, the effects of MO and ME on embryonic myogenesis were examined in several aspects. (1) Firstly, MO impeded embryonic myogenesis via elevating H19 expression but blocking its conversion into microRNA675 (miR675). H19 is a paternally imprinted and maternally expressed long non-coding RNA (lncRNA), which has anti-myogenic function, while H19-derived miR675 promotes myogenesis. We found MO blocked phosphorylation of KH-type splicing regulatory protein (KHSRP), by which miR675 biogenesis was inhibited. On the contrary, H19 expression was increased in MO embryos due to bi-allelic expression of H19. MO also reduced myogenic gene expression and myogenic cell populations in E11.5 embryonic cell samples. (2) Moreover, the spatial transcriptomic alteration in E13.5 embryos limbs due to MO was resolved using GeoMx RNA assay. Data showed MO impaired myogenic cell migration, which is indispensable for limb skeletal muscle formation. A total of 2224 genes were downregulated in the MO group. The migration related signaling pathways such as hepatocyte growth factor signaling, fibroblast growth factor signaling, Wnt signaling and GTPase signaling were downregulated in the MO limb tip. Expression levels of genes involved in myogenic cell migration, such as Pax3, Gab1, Pxn, Tln2 and Arpc, were all decreased in the MO limb. In addition, myogenic differentiation related genes were also downregulated in the MO limb, demonstrating inhibited myogenesis in the embryonic limb. (3) On the other hand, ME elevated thyroid hormone receptor (THR) signaling in E12.5 embryos, which promoted embryonic myogenesis. ME elevated thyroid hormone (TH) levels in both maternal circulation and embryos. Myogenic related genes expression levels including Pax3, Pax7, Myf5 and Myod were elevated in ME embryos. ME increased THRα protein content and transcript level of TH transporter Slc16a2. In addition, the binding of THRα, as a transcription factor, to the promoters of Pax3/7 was enhanced in ME. Taken together, MO inhibits embryonic myogenesis via enhancing lncRNA H19 expression, while inhibits limb muscle formation by repression of myogenic cell migration. As a contrast, ME promotes TH delivery to the embryos and enhances embryonic myogenesis.

MATERNAL OBESITY AND EMBRYONIC MUSCLE DEVELOPMENT

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