Abstract
Fetal malnutrition decreases skeletal myofiber number and muscle mass in neonatal mammals, which increases the risk of developing obesity and diabetes in adult life. However, the associated molecular mechanisms remain unclear. Here, we investigated how the nutrient (calorie) availability affects embryonic myogenesis using a porcine model. Sows were given a normal or calorie restricted diet, following which skeletal muscle was harvested from the fetuses at 35, 55, and 90 days of gestation (dg) and used for histochemical analysis and high-throughput sequencing. We observed abrupt repression of primary myofiber formation following maternal calorie restriction (MCR). Transcriptome profiling of prenatal muscles revealed that critical genes and muscle-specific miRNAs associated with increased proliferation and myoblast differentiation were downregulated during MCR-induced repression of myogenesis. Moreover, we identified several novel miRNA-mRNA interactions through an integrative analysis of their expression profiles, devising a putative molecular network involved in the regulation of myogenesis. Interestingly, NC_010454.3_1179 was identified as a novel myogenic miRNA that can base-pair with sequences in the 3′-UTR of myogenic differentiation protein 1 (MyoD1). And we found that this UTR inhibited the expression of a linked reporter gene encoding a key myogenic regulatory factor, resulting in suppression of myogenesis. Our results greatly increase our understanding of the mechanisms underlying the nutrient-modulated myogenesis, and may also serve as a valuable resource for further investigation of fundamental developmental processes or assist in rational target selection ameliorating repressed myogenesis under fetal malnutrition.
Highlights
Epidemiological studies have indicated that being small for gestational age (SGA) leads to increased prenatal and neonatal mortality, and increases the risk of developing obesity, coronary heart disease, hypertension, and non-insulin-dependent diabetes in adult life (Valdez et al, 1994)
The repressed myofiber formation and reduced birth weight reflect the maternal calorie restriction (MCR)-induced suppression of prenatal myogenesis
We showed that the expression levels of genes involved in the regulation of progenitor cell migration and proliferation (i.e., SPP1, SIRT1, BMP7, and PPARG) and embryonic organ development (i.e., PIK3IP1, IGFBP2, and EGF) peaked at 35 dg, at this stage, these genes were down-regulated by MCR
Summary
Epidemiological studies have indicated that being small for gestational age (SGA) leads to increased prenatal and neonatal mortality, and increases the risk of developing obesity, coronary heart disease, hypertension, and non-insulin-dependent diabetes in adult life (Valdez et al, 1994). Failure of the fetus to achieve its optimal growth potential can have many causes, Nutrient Modulated Embryonic Myogenesis the main reasons involve poor fetal nutrition or lack of adequate oxygen supply to the fetus (Tuuli et al, 2011). Suppressed fetal skeletal muscle growth cannot generally be fully compensated for after birth, as individuals who are born with low birth weight usually have reduced muscle mass in adulthood (Yliharsila et al, 2007). The importance of muscle mass and function in numerous diseases underpins the necessity of understanding how the prenatal myogenesis is regulated
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