Intrauterine growth restriction (IUGR) reduces muscle mass and insulin sensitivity in offspring. Insulin sensitivity varies among muscle fiber types, with Type I fibers being most sensitive. Differences in fiber-type ratios are associated with insulin resistance in adults, and thus we hypothesized that near-term IUGR sheep fetuses exhibit reduced size and proportions of Type I fibers. Placental insufficiency-induced IUGR fetuses were ∼54% smaller (P < 0.05) than controls and exhibited hypoxemia and hypoglycemia, which contributed to 6.9-fold greater (P < 0.05) plasma norepinephrine and ∼53% lower (P < 0.05) plasma insulin concentrations. IUGR semitendinosus muscles contained less (P < 0.05) myosin heavy chain-I protein (MyHC-I) and proportionally fewer (P < 0.05) Type I and Type I/IIa fibers than controls, but MyHC-II protein concentrations, Type II fibers, and Type IIx fibers were not different. IUGR biceps femoris muscles exhibited similar albeit less dramatic differences in fiber type proportions. Type I and IIa fibers are more responsive to adrenergic and insulin regulation than Type IIx and may be more profoundly impaired by the high catecholamines and low insulin in our IUGR fetuses, leading to their proportional reduction. In both muscles, fibers of each type were uniformly smaller (P < 0.05) in IUGR fetuses than controls, which indicates that fiber hypertrophy is not dependent on type but rather on other factors such as myoblast differentiation or protein synthesis. Together, our findings show that IUGR fetal muscles develop smaller fibers and have proportionally fewer Type I fibers, which is indicative of developmental adaptations that may help explain the link between IUGR and adulthood insulin resistance.

Recent studies show that adrenergic agonists and inflammatory cytokines can stimulate skeletal muscle glucose uptake, but it is unclear if glucose oxidation is similarly increased. Thus, the objective of this study was to determine the effects of ractopamine HCl (β1 agonist), zilpaterol HCl (β2 agonist), TNFα, and IL-6 on glucose uptake and oxidation rates in unstimulated and insulin-stimulated soleus muscle strips from adult Sprague-Dawley rats. Effects on phosphorylation of Akt (phospho-Akt), p38 MAPK (phospho-p38), and p44/42 MAPK (phospho-p44/42) was also determined. Incubation with insulin increased (P < 0.05) glucose uptake by ~47%, glucose oxidation by ~32%, and phospho-Akt by ~238%. Insulin also increased (P < 0.05) phospho-p38, but only after 2 hours in incubation. Muscle incubated with β2 agonist alone exhibited ~20% less (P < 0.05) glucose uptake but ~32% greater (P < 0.05) glucose oxidation than unstimulated muscle. Moreover, co-incubation with insulin + β2 agonist increased (P < 0.05) glucose oxidation and phospho-Akt compared to insulin alone. Conversely, β1 agonist did not appear to affect basal or insulin-stimulated glucose metabolism, and neither β agonist affected phospho-p44/42. TNFα and IL-6 increased (P < 0.05) glucose oxidation by ~23% and ~33%, respectively, in the absence of insulin. This coincided with increased (P < 0.05) phospho-p38 and phospho-p44/42 but not phospho-Akt. Furthermore, co-incubation of muscle with insulin + either cytokine yielded glucose oxidation rates that were similar to insulin alone, despite lower (P < 0.05) phospho-Akt. Importantly, cytokine-mediated increases in glucose oxidation rates were not concomitant with greater glucose uptake. These results show that acute β2 adrenergic stimulation, but not β1 stimulation, directly increases fractional glucose oxidation in the absence of insulin and synergistically increases glucose oxidation when combined with insulin. The cytokines, TNFα and IL-6, likewise directly increased glucose oxidation in the absence of insulin, but were not additive in combination with insulin and in fact appeared to disrupt Akt-mediated insulin signaling. Rather, cytokines appear to be acting through MAPKs to elicit effects on glucose oxidation. Regardless, stimulation of glucose oxidation by these key stress factors did not rely upon greater glucose uptake, which may promote metabolic efficiency during acute stress by increasing fractional glucose oxidation without increasing total glucose consumption by muscle.

Intrauterine growth restriction (IUGR) is the second leading cause of perinatal mortality and predisposes offspring to metabolic disorders at all stages of life. Muscle-centric fetal adaptations reduce growth and yield metabolic parsimony, beneficial for IUGR fetal survival but detrimental to metabolic health after birth. Epidemiological studies have reported that IUGR-born children experience greater prevalence of insulin resistance and obesity, which progresses to diabetes, hypertension, and other metabolic disorders in adulthood that reduce quality of life. Similar adaptive programming in livestock results in decreased birth weights, reduced and inefficient growth, decreased carcass merit, and substantially greater mortality rates prior to maturation. High rates of glucose consumption and metabolic plasticity make skeletal muscle a primary target for nutrient-sparing adaptations in the IUGR fetus, but at the cost of its contribution to proper glucose homeostasis after birth. Identifying the mechanisms underlying IUGR pathophysiology is a fundamental step in developing treatments and interventions to improve outcomes in IUGR-born humans and livestock. In this review, we outline the current knowledge regarding the adaptive restriction of muscle growth and alteration of glucose metabolism that develops in response to progressively exacerbating intrauterine conditions. In addition, we discuss the evidence implicating developmental changes in β adrenergic and inflammatory systems as key mechanisms for dysregulation of these processes. Lastly, we highlight the utility and importance of sheep models in developing this knowledge.

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Maternal inflammation causes fetal intrauterine growth restriction (IUGR), but its impact on fetal metabolism is not known. Thus, our objective was to determine the impact of sustained maternal inflammation in late gestation on fetal inflammation, skeletal muscle glucose metabolism, and insulin secretion. Pregnant ewes were injected every third day from the 100th to 112th day of gestation (term = 150 d) with saline (controls) or lipopolysaccharide (LPS) to induce maternal inflammation and IUGR (MI-IUGR). Fetal femoral blood vessels were catheterized on day 118 to assess β-cell function on day 123, hindlimb glucose metabolic rates on day 124, and daily blood parameters from days 120 to 125. Fetal muscle was isolated on day 125 to assess ex vivo glucose metabolism. Injection of LPS increased (P &lt; 0.05) rectal temperatures, circulating white blood cells, and plasma tumor necrosis factor α (TNFα) concentrations in MI-IUGR ewes. Maternal leukocytes remained elevated (P &lt; 0.05) and TNFα tended to remain elevated (P &lt; 0.10) compared with controls almost 2 wk after the final LPS injection. Total white blood cells, monocytes, granulocytes, and TNFα were also greater (P &lt; 0.05) in MI-IUGR fetuses than controls over this period. MI-IUGR fetuses had reduced (P &lt; 0.05) blood O2 partial pressures and greater (P &lt; 0.05) maternofetal O2 gradients, but blood glucose and maternofetal glucose gradients did not differ from controls. Basal and glucose-stimulated insulin secretion were reduced (P &lt; 0.05) by 32% and 42%, respectively, in MI-IUGR fetuses. In vivo hindlimb glucose oxidation did not differ between groups under resting conditions but was 47% less (P &lt; 0.05) in MI-IUGR fetuses than controls during hyperinsulinemia. Hindlimb glucose utilization did not differ between fetal groups. At day 125, MI-IUGR fetuses were 22% lighter (P &lt; 0.05) than controls and tended to have greater (P &lt; 0.10) brain/BW ratios. Ex vivo skeletal muscle glucose oxidation did not differ between groups in basal media but was less (P &lt; 0.05) for MI-IUGR fetuses in insulin-spiked media. Glucose uptake rates and phosphorylated-to-total Akt ratios were less (P &lt; 0.05) in muscle from MI-IUGR fetuses than controls regardless of media. We conclude that maternal inflammation leads to fetal inflammation, reduced β-cell function, and impaired skeletal muscle glucose metabolism that persists after maternal inflammation ceases. Moreover, fetal inflammation may represent a target for improving metabolic dysfunction in IUGR fetuses.