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Title: Developmental regulation of mitochondrial function in ovine fetal skeletal muscle
Author: Davies, Katie Louisa
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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Skeletal muscle is a highly metabolically active tissue, both in the adult and the fetus. Mitochondria are essential in providing energy in the form of ATP from the oxidative metabolism of carbohydrates, fats and amino acids. Mitochondrial function is influenced by the abundance and activity of the complexes comprising the electron transfer system (ETS) and the balance between mitochondrial fusion and fission. Any factors which affect the development of skeletal muscle, and mitochondria in particular, may have an impact not only on neonatal health but also on the metabolic health of the adult offspring. However, the normal developmental profile of skeletal muscle mitochondrial function as the fetus prepares for the increased metabolic challenges associated with extrauterine life, is not well characterised. The hormones, cortisol and triiodothyronine (T3) are known to be crucial in the maturation of several physiological processes during late gestation. Further, their role in regulating adult metabolism is well-documented. However, whether they play a role in regulating fetal mitochondrial function is unknown. Using fetal sheep, the aims of this project were twofold: 1) to determine any changes in skeletal muscle mitochondrial function which occur over the last third of gestation and in the first two days of neonatal life and 2) to determine any regulatory roles of cortisol and T3 in these developmental changes. Mixed fibre-type skeletal muscle was collected from fetuses at 3 time points over late gestation and from newborn lambs. In addition, skeletal muscle samples were taken from fetuses which had been thyroidectomised (TX) and fetuses infused with either T3 or cortisol. Respirometry, enzyme assays, qRT-PCR and western blotting were carried out on the skeletal muscle samples in order to assess mitochondrial parameters. Mitochondrial activity, as measured by carbohydrate- and fat- stimulated ADP-coupled oxygen uptake, increased with age in a thyroid hormone dependent manner, rising predominantly postnatally. Mitochondrial density, abundance of ETS complexes I-IV and ATP-synthase and expression of the adenine nucleotide transferase 1 and mitofusin 2 were all positively influenced by age, with the natural prepartum rise being prevented in the thyroidectomised fetuses. However, T3 infusion alone was insufficient to raise any of these factors prematurely. Cortisol infusion resulted in an increase in some aspects of mitochondrial oxidative capacity in a muscle-specific manner. Overall, the data presented shows that there are developmental changes in skeletal muscle mitochondria during the perinatal period. They also suggest that these changes are regulated by both cortisol and thyroid hormones in preparation for birth, although neither hormone alone was sufficient to induce all the functional changes.
Supervisor: Fowden, Abigail ; Murray, Andrew Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: mitochondria ; skeletal muscle ; fetus ; cortisol ; thyroid hormone ; development ; maturation