Abstract
In this study, we determined the effect of maternal undernutrition in the periconceptional (PCUN: ∼80 days before to 6 days after conception) and preimplantation (PIUN: 0–6 days after conception) periods on the mRNA and protein abundance of key factors regulating myogenesis and protein synthesis, and on the relationship between the abundance of these factors and specific microRNA expression in the quadriceps muscle of singleton and twin fetal sheep at 135–138 days of gestation. PCUN and PIUN resulted in a decrease in the protein abundance of MYF5, a factor which determines the myogenic lineage, in singletons and twins. Interestingly, there was a concomitant increase in insulin-like growth factor-1 mRNA expression, a decrease in the protein abundance of the myogenic inhibitor, myostatin (MSTN), and an increase in the mRNA and protein abundance of the MSTN inhibitor, follistatin (FST), in the PCUN and PIUN groups in both singletons and twins. These promyogenic changes may compensate for the decrease in MYF5 protein abundance evoked by early embryonic undernutrition. PCUN and PIUN also increased the protein abundance of phosphorylated eukaryotic translation initiation factor binding protein 1 (EIF4EBP1; T70 and S65) in fetal muscle in singletons and twins. There was a significant inverse relationship between the expression of miR-30a-5p, miR-30d-5p, miR-27b-3p, miR106b-5p, and miR-376b and the protein abundance of mechanistic target of rapamycin (MTOR), FST, or MYF5 in singletons or twins. In particular, the expression of miR-30a-5p was increased and MYF5 protein abundance was decreased, in PCUN and PIUN twins supporting the conclusion that the impact of PCUN and PIUN is predominantly on the embryo.
Highlights
A series of epidemiological and experimental studies have demonstrated that exposure to poor maternal nutrition during oocyte, embryonic, or fetal development results in an increased risk of poor metabolic outcomes including insulin resistance and glucose intolerance in later life (Joshi et al 2003; Gardner et al 2005; McMillen and Robinson 2005; Roseboom et al 2006; Kwong et al 2007)
IGF1 mRNA expression in fetal muscle was higher (P < 0.01) in the PCUN and PIUN groups compared to controls in both singleton and twin pregnancies (Fig. 2)
We have demonstrated that maternal undernutrition during the periconceptional and/or preimplantation periods results in significant changes in the mRNA expression and/or protein abundance of factors regulating myogenesis and protein synthesis in the fetal quadriceps muscle and that these effects are different in singletons and twins in late gestation
Summary
A series of epidemiological and experimental studies have demonstrated that exposure to poor maternal nutrition during oocyte, embryonic, or fetal development results in an increased risk of poor metabolic outcomes including insulin resistance and glucose intolerance in later life (Joshi et al 2003; Gardner et al 2005; McMillen and Robinson 2005; Roseboom et al 2006; Kwong et al 2007). In singleton and twin fetuses exposed to maternal undernutrition during the first week of pregnancy alone (i.e., preimplantation undernutrition; PIUN), there was an increase in the protein abundance of key insulin signaling molecules in fetal skeletal muscle. The mechanisms by which exposure to undernutrition in early development result in the emergence of insulin-resistant or -sensitive phenotype in skeletal muscle may include programmed changes in pathways that regulate myogenesis and muscle growth and differentiation It has been demonstrated, for example, that periconceptional or early gestational undernutrition in sheep resulted in a decrease in the total number of muscle fibers and altered muscle fiber composition, in singleton fetuses in late gestation (Quigley et al 2005; Costello et al 2008). A reduction in muscle fiber number could result from either a decrease in myoblast proliferation and differentiation or a decrease in protein synthesis in skeletal muscle during development, decreasing muscle mass that can lead to insulin resistance and hyperglycemia in adult life
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