Myostatin, also known as growth differentiation factor 8, is a transforming growth factor-β family member best known as a negative regulator of skeletal muscle growth. Although myostatin has been widely studied in muscle development and metabolism, its role in pregnancy and maternal–fetal communication is less understood. Previous work from our laboratory showed that wild-type offspring born to mothers with genetically reduced myostatin have increased adult muscle mass and improved bone biomechanical strength, even though maternal myostatin is not detectable in fetal circulation. These findings suggest that maternal myostatin may influence fetal development indirectly by altering the intrauterine environment, particularly through effects on placental development and function.

This dissertation investigated how reduced maternal myostatin affects fetal growth, placental structure, placental gene expression, and metabolic adaptation at the maternal–fetal interface. Using mouse pregnancies from wild-type and Mstn+/− dams, placental morphology was assessed to determine whether maternal myostatin deficiency alters major placental compartments and vascular features. Placentas from Mstn+/− dams showed changes in placental architecture, including alterations in regions important for maternal–fetal exchange and endocrine signaling. These structural changes suggest that reduced maternal myostatin may affect fetal development by modifying placental form and function.

To identify molecular pathways affected by maternal myostatin deficiency, placental RNA sequencing was used to evaluate changes in gene expression. Differentially expressed genes included transporters involved in glucose, amino acid, lactate, pyruvate, fatty acid, and organic ion transport. Pathway analysis also showed enrichment of inflammatory and immune-related pathways, including cytokine–cytokine receptor interaction, chemokine signaling, IL-17 signaling, NF-κB signaling, and C-type lectin receptor signaling. A major gene of interest was Acod1, which encodes aconitate decarboxylase 1, the enzyme that converts cis-aconitate to itaconate and links mitochondrial metabolism to inflammatory regulation.

Together, these findings expand the understanding of myostatin beyond skeletal muscle biology and support a model in which maternal myostatin contributes to the regulation of placental development and function. Rather than acting directly on the fetus, maternal myostatin appears to influence fetal growth and developmental programming through changes in placental structure, trophoblast-associated processes, nutrient transporter expression, and inflammatory-metabolic signaling. This work identifies the placenta as a key mediator of maternal myostatin effects and provides new insight into how maternal metabolic signals can shape fetal development and long-term offspring health. 

By understanding how maternal metabolic regulators affect placental biology, we can gain a clearer picture of the mechanisms that govern fetal growth and developmental programming. This work contributes to reproductive biology and placental physiology while also laying the foundation for future studies aimed at improving pregnancy outcomes in conditions linked to altered maternal metabolism.

Publications

Opoku, R., DeCata, J., Phillips, C. L., & Schulz, L. C. (2023). Effect of genetically reduced maternal myostatin on late gestation maternal, fetal, and placental metabolomes in mice. Metabolites, 13(6), 719. 

Crawford, T.K., Lafaver, B.N., Oestreich, A.K., Davis, B.R., Cooper, C.S., Chapman, I.M., Luhmann, M.K., Opoku, R., Schulte, A.K., Mastaitis, J., Ohler, A.M., Schulz, L.C., Phillips, C.L. (2025). Maternal health and safety outcomes of prenatal myostatin inhibition in osteogenesis imperfecta mice. Endocrinology, 166(7): bqaf080.

Doctoral Committee

• Dr. Laura Schulz, Chair
• Dr. Chiswili Chabu
• Dr. Micheal Garcia
• Dr. Charlotte Philips
• Dr. Rocio Rivera