Impact of placental insufficiency on fetal skeletal muscle growth

Abstract

Intrauterine growth restriction (IUGR) caused by placental insufficiency is one of the most common and complex problems in perinatology, with no known cure. In pregnancies affected by placental insufficiency, a poorly functioning placenta restricts nutrient supply to the fetus and prevents normal fetal growth. Among other significant deficits in organ development, the IUGR fetus characteristically has less lean body and skeletal muscle mass than their appropriately-grown counterparts. Reduced skeletal muscle growth is not fully compensated after birth, as individuals who were born small for gestational age (SGA) from IUGR have persistent reductions in muscle mass and strength into adulthood. The consequences of restricted muscle growth and accelerated postnatal "catch-up" growth in the form of adiposity may contribute to the increased later life risk for visceral adiposity, peripheral insulin resistance, diabetes, and cardiovascular disease in individuals who were formerly IUGR. This review will discuss how an insufficient placenta results in impaired fetal skeletal muscle growth and how lifelong reductions in muscle mass might contribute to increased metabolic disease risk in this vulnerable population.

Keywords: Amino acids; Developmental programming; Muscle protein synthesis; Myoblast; Myofiber; Myogenesis.

Figure 1. Redistribution of blood flow in IUGR

Dilation of the ductus venosus and middle cerebral artery shunts oxygen and nutrients from the umbilical vein directly to the heart and brain and away from skeletal muscle (diagram modified from Yainik, 2004).

Figure 2. Schematic representation of fetal myogenesis during pregnancy

The fraction of gestation when primary (embryonic) and secondary (fetal) stages of myogenesis are based on studies from sheep, cow, and human (Du et al., 2010, Romero et al., 2013, Wilson et al., 1992). Pax transcription factors Pax3 and Pax7 define the progenitor cell population during fetal myogenesis (Wang et al., 2010). Pax7 is expressed in fetal myoblasts, in addition to Myf5 and MyoD which commit cells to the myogenic program. Expression of the terminal differentiation genes, Myf6 (also known as Mrf4) and MyoG, are expressed in myotubes(Bentzinger et al., 2012). Myofibers grow by hypertrophy late in gestation and in postnatal life.

Figure 3. Proposed mechanisms for reduced fetal skeletal muscle growth during conditions of placental insufficiency

We propose that the combination of decreased growth factors and amino acids in the IUGR fetus leads to reduced rates of myoblast proliferation and myofiber hypertrophy, ultimately producing reductions in skeletal muscle mass. a) Normal fetal myogenesis and b) progressive decline in fetal insulin, IGF-1, and AA supply in a sheep model of placental insufficiency and IUGR. IUGR, intrauterine growth restriction; dGA, days gestation (term=145 dGA); ↔, no change.