Abstract
Antenatal steroids reduce the severity of initial respiratory distress of premature newborn babies but may have an adverse impact on other body organs. The study aimed to examine the effect of maternal steroids on postnatal respiratory muscle function during development and elucidate the mechanisms underlying the potential myopathy in newborn rats. Pregnant rats were treated with intramuscular injections of 0.5 mg/kg betamethasone 7 d and 3 d before birth. Newborn diaphragms were dissected for assessment of contractile function at 2 d, 7 d or 21 d postnatal age (PNA), compared with age-matched controls. The expression of myosin heavy chain (MHC) isoforms and atrophy-related genes and activity of intracellular molecular signalling were measured using quantitative PCR and/or Western blot. With advancing PNA, neonatal MHC gene expression decreased progressively while MHC IIb and IIx isoforms increased. Protein metabolic signalling showed high baseline activity at 2 d PNA, and significantly declined at 7 d and 21 d. Antenatal administration of betamethasone significantly decreased diaphragm force production, fatigue resistance, total fast fibre content and anabolic signalling activity (Akt and 4E-BP1) in 21 d diaphragm. These responses were not observed in 2 d or 7 d postnatal diaphragm. Results demonstrate that maternal betamethasone treatment causes postnatal diaphragmatic dysfunction at 21 d PNA, which is attributed to MHC II protein loss and impairment of the anabolic signalling pathway. Developmental modifications in MHC fibre composition and protein signalling account for the age-specific diaphragm dysfunction.
Highlights
Women at risk of preterm birth are routinely given two 12 mg doses of betamethasone at 24 h intervals, to promote structural and functional maturation of the fetal lung
We show that maternal steroid administration impaired rat pup diaphragmatic contractility and reduced myosin heavy chain (MHC)
The change of muscle contractile function and fibre type expression is accompanied by depression of the protein synthesis pathway (Akt/4E-BP1)
Summary
Women at risk of preterm birth are routinely given two 12 mg doses of betamethasone (a glucocorticoid: a class of steroid hormones) at 24 h intervals, to promote structural and functional maturation of the fetal lung. Infants born preterm are frequently exposed to antenatal glucocorticoid treatment. Preterm infants have reduced diaphragm contractility compared to their term gestation counterparts [1,2]. As preterm infants often breathe against an increased mechanical load, diaphragm integrity is critical for self-sufficient ventilation. Antenatal steroid exposure could precipitate or accelerate the development of postnatal respiratory failure through inducing additional compromise of the functional and phenotypic integrity of the fragile immature diaphragm. The contribution of antenatal steroid exposure to preterm diaphragm dysfunction and increased susceptibility to respiratory failure is unknown
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