Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCB178

Poster Communications

Thyroid hormone regulation of mitochondrial development in skeletal muscle of the ovine fetus near term

K. Davies1, A. Forhead1, E. Camm1, A. Murray1, A. Fowden1

1. University of Cambridge, Cambridge, United Kingdom.

  • Figure. Mean±SEM a&b) ADP-coupled mitochondrial oxygen consumption rate and c) HOAD activity in ovine fetal skeletal muscle. *P<0.05, TX vs controls at same age or

During late gestation, there is a rapid increase in fetal triiodothyronine (T3) bioavailability1, which has been shown previously to correlate with a rise in mitochondrial density in fetal skeletal muscle2. At birth, there is a thyroid hormone-dependent increase in fetal whole body oxygen uptake and metabolic rate1. Fatty acid availability rises after birth, and there is a metabolic switch from glucose to predominantly fatty acid metabolism in several tissues at birth3. This study examined whether fetal thyroid hormones influence mitochondrial respiration in skeletal muscle during late gestation in preparation for the increased energy demands and altered substrate availability at birth. Under the Animals (Scientific Procedures) Act 1986, 13 twin-bearing ewes were anaesthetised (2mg/kg alfaxalone i.v. and 2% isofluorane in 5:1 O2:NO2 inhaled) at 102-104 days of gestation (d; term ~145d) for fetal thyroidectomy (TX) or sham operation of one of each of the twins. Ewes and fetuses were euthanased (200mg/kg sodium pentobarbitone) at d126-129 (n=7 ewes) or d140-144 (n=6 ewes). Samples of biceps femoris were immediately collected into preservation medium. Muscle fibres were dissected and permeabilised to measure fat (palmitoylcarnitine; 40µM)- and carbohydrate (pyruvate; 5mM)-supported, ADP (5mM)-coupled oxygen consumption4. β-hydroxyacyl-CoA dehydrogenase (HOAD) activity, an enzyme involved in fatty acid oxidation, was measured spectrophotometrically. Fetal plasma T3 concentration was measured by radioimmunoassay. Data were analysed by two-way ANOVA with Tukey's post-hoc test. TX reduced skeletal muscle oxygen consumption with both pyruvate (fig.a; P<0.01) and palmitoylcarnitine (fig.b; P<0.001) as substrates. These effects were more pronounced near term than earlier in gestation. Rates of oxygen consumption were higher for pyruvate than palmitoylcarnitine in all fetuses, irrespective of treatment or age (P<0.01, all cases). HOAD activity was significantly lower in muscle of TX fetuses than controls at both ages (fig.c; P<0.0001). Muscle taken from fetuses near term had significantly higher palmitoylcarnitine-supported respiration rate and HOAD activity than earlier in gestation, and combining all data, there was a significant positive correlation between fetal T3 levels and both palmitoylcarnitine-supported oxygen consumption (r=0.603, n=23, P=0.0023) and HOAD activity (r=0.601, n=22, P=0.0031). Overall, the results show that thyroid hormones regulate mitochondrial respiration rates in skeletal muscle during late gestation. There was also an increased capacity for fat oxidation and utilisation in energy production as the fetus nears term, which may be partly dependent on the prepartum rise in T3.

Where applicable, experiments conform with Society ethical requirements