5 DJP Barker Memorial Lecture: Reduced myogenesis in fetal growth restriction: basic mechanisms and future therapies

Abstract Abstract: Introduction Redistribution of blood flow to vital organs in fetal growth restriction (FGR) occurs at the expense of skeletal muscle growth. Infants born after FGR have lower muscle mass that persists into adulthood. Objective Understand the mechanisms for how myogenesis rates are slowed in the FGR fetus so that therapies may be developed to support muscle growth before deficits become permanent. Methods Pregnant ewes were exposed to elevated temperature to induce placental insufficiency, and FGR fetuses were compared to control (CON) fetuses (n = 19/group). At 0.9 gestation, fetal lambs were infused with EdU and hindlimb muscles were harvested to measure myofiber size, type, and vascularity by immunohistochemistry; proliferation and differentiation rates by single cell dissociation and flow cytometry; and leucine utilization in isolated myofibers by 13C tracing. Results Fetal weight and summed muscle weights were ∼40% less in FGR vs. CON (P<0.005). Slow twitch oxidative myofiber composition, myofiber cross-sectional area, and capillary relative to myofiber number were reduced in FGR (P<0.05). Fewer myoblasts expressed EdU and were committed to early stages of differentiation in FGR (P<0.05); however, more myoblasts were in late differentiation (P<0.005) indicating impairments in myoblast fusion. Fractional contribution of leucine to intact protein in isolated myofibers was 19% lower in FGR (P<0.05). Conclusion Fetal myogenesis is adversely impacted by placental insufficiency, including slower myoblast proliferation and differentiation rates, slower hypertrophic growth, fewer oxidative myofibers, and reduced angiogenesis. Targeting multiple regulators of myogenesis will likely be required to augment muscle growth in the FGR fetus. (Supported by NIH HD079404)