Fetal Origins of Impaired Muscle Growth and Metabolic Dysfunction: Lessons from the Heat-Stressed Pregnant Ewe.

The link between low birthweight and lifelong metabolic dysfunction is well established in humans and animals. Placental insufficiency and other low birthweight etiologies limit fetal nutrients and induce nutrient-sparing adaptations that manifest intrauterine growth restriction (IUGR). Fetal adaptations that produce IUGR profoundly increase metabolic health risks in humans and reduce growth efficiency and carcass value in livestock. The heat-stressed pregnant sheep is a dynamic animal model that has been instrumental in characterizing the IUGR fetus and identifying pathologies that predispose offspring to metabolic dysfunction. Maternal heat stress naturally induces placental stunting, which causes progressively-worsening fetal hypoxemia and hypoglycemia over the third trimester of pregnancy. These hallmark conditions stimulate greater circulating catecholamines and cytokines, which in turn lead to adaptive changes in sensitivity that increase the inhibitory tone of adrenergic and inflammatory signaling, causing dysregulation in several tissues. Skeletal muscle is a primary target for nutrient-sparing adaptations due to its high glucose consumption and metabolic plasticity, and IUGR fetuses and offspring are characterized by disproportionately reduced muscle mass and impaired glucose metabolism. Muscle growth is facilitated by myoblasts (muscle stem cells), and IUGR myoblasts exhibit intrinsically reduced functional capacity that results in smaller muscle fibers with fewer myonuclei. Moreover, IUGR muscle maintains normal rates of glucose uptake, but utilization is shifted from oxidative to glycolytic metabolism. The metabolic shift coincides with reduced ratios of oxidative fibers, which may further impede metabolic responsiveness. Changes in adrenergic and cytokine sensitivities produce muscle deficits through direct signaling and by altering insulin action. Reduced expression of β2 adrenergic receptors (Adrβ2), which synergize with insulin, combined with normal expression of Adrβ1, which antagonize insulin, help explain the impaired responsiveness of IUGR muscle fibers and myoblasts to insulin. Moreover, direct Adrβ2 stimulation of myoblast function and glucose oxidation is diminished. It is noteworthy that insulin-stimulated glucose oxidation is improved in IUGR-born lambs treated with an Adrβ2 agonist/Adrβ1 antagonist cocktail for the first month of life. Coincidentally, sensitivity to inflammatory cytokines appears enhanced in IUGR muscle, to the detriment of myoblast differentiation and insulin action. Restricted muscle growth capacity and glucose oxidation allows the IUGR fetus to re-appropriate limited nutrients to more vital tissues but causes deficits in muscle mass, strength, and metabolic function in IUGR-born offspring. Developing techniques to prevent or correct these adaptations is crucial for recovering metabolic health in IUGR-born humans as well as growth performance and value in food animals.