Obesity Impairs Embryonic Myogenesis by Enhancing BMP Signaling within the Dermomyotome

• Published in: Advanced science Vol. 8; no. 22; pp. e2102157 - n/a
• Main Authors: Zhao, Liang, Law, Nathan C., Gomez, Noe A., Son, Junseok, Gao, Yao, Liu, Xiangdong, de Avila, Jeanene M., Zhu, Mei‐Jun, Du, Min
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.11.2021; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Bone Morphogenetic Proteins - metabolism; bone morphogenetic proteins signaling; Cell Differentiation; Disease Models, Animal; embryonic myogenesis; Female; Gene expression; Genomics; Hypoxia; maternal obesity; Metabolism; Mice; Mice, Inbred C57BL; Muscle Development; Musculoskeletal system; Myogenesis; Obesity; Obesity, Maternal - embryology; Obesity, Maternal - metabolism; Oxidative stress; Phosphorylation; Pregnancy; Pregnancy Complications - metabolism; Signal Transduction; single cell RNA sequencing; bone morphogenetic proteins signaling; maternal obesity; single cell RNA sequencing; embryonic myogenesis
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202102157

Obesity during pregnancy leads to adverse health outcomes in offspring. However, the initial effects of maternal obesity (MO) on embryonic organogenesis have yet to be thoroughly examined. Using unbiased single‐cell transcriptomic analyses (scRNA‐seq), the effects of MO on the myogenic process is investigated in embryonic day 9.5 (E9.5) mouse embryos. The results suggest that MO induces systematic hypoxia, which is correlated with enhanced BMP signaling and impairs skeletal muscle differentiation within the dermomyotome (DM). The Notch‐signaling effectors, HES1 and HEY1, which also act down‐stream of BMP signaling, suppress myogenic differentiation through transcriptionally repressing the important myogenic regulator MEF2C. Moreover, the major hypoxia effector, HIF1A, enhances expression of HES1 and HEY1 and blocks myogenic differentiation in vitro. In summary, this data demonstrate that MO induces hypoxia and impairs myogenic differentiation by up‐regulating BMP signaling within the DM, which may account for the disruptions of skeletal muscle development and function in progeny. Molecular mechanisms controlling embryonic myogenesis are examined by a pseudo temporal model at the single‐cell level. Moreover, maternal obesity attenuates myogenic differentiation in E9.5 embryos by enhancing bone morphogenetic protein (BMP) signaling within the dermomyotome, which suppresses Mef2c expression. Disrupted embryonic myogenesis provides a mechanistic explanation for the impairments in muscle function of offspring due to maternal obesity.