Developmental regulation of muscle mitochondrial function

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At birth, the newborn faces many new challenges. It must establish breathing, shivering and, in many animals, locomotion for the first time. The heart also has to pump harder to support these new activities. More energy is, therefore, needed immediately after birth to ensure the newborn survives. This energy is provided by small structures within the cells called mitochondria which use oxygen to produce energy rich molecules that then fuel the muscular and other processes essential for life. In many tissues, preparations to ensure neonatal survival begin before birth and are dependent on the normal increase in a hormone, cortisol, in the fetal blood towards delivery. However, at present, little is known about how the mitochondria in muscles and other tissues prepare for the increase in energy demands at birth or whether these maturational changes depend on the increase fetal cortisol before birth. Previous studies in animals have suggested that the conditions experienced during development before birth may affect the way mitochondria function in the adult. Since a progressive decline in mitochondrial function is part of the normal aging process, changes in mitochondrial function induced before birth may be important in determining the quality of life and health much later in life. However, we know little about how mitochondrial function changes with growth and development from fetal to adult life or whether this trajectory can be altered by events before delivery. Cortisol levels in the fetus not only rise towards term as a normal maturational signal of impending delivery but can also increase earlier in pregnancy in response to poor conditions for development such as maternal stress or a shortage of nutrients or oxygen. These conditions are known to have implications for health after birth and can accelerate aging and the onset of adult degenerative diseases like diabetes and high blood pressure that shorten lifespan. Consequently, changes in mitochondrial function induced by early exposure to cortisol before birth may have an important role in explaining how conditions during fetal life affect life-long health and wellbeing. The aim of this study is to determine whether functioning of the mitochondria in muscles matures in late pregnancy in preparation for birth as a result of the normal rise in fetal cortisol towards term but is impaired at birth and with aging, if fetal overexposure to cortisol occurs prematurely. The studies will be carried out in sheep because development of their fetuses more closely resembles the human infant than rodent pups. They are also large enough to study experimentally before birth and, because they born mature, the increase in energy requirements for muscular activity is high at birth. Mitochondrial function will be measured in the heart and skeletal muscles of fetal, newborn and adult animals with normal cortisol profiles and in those in which fetal cortisol levels have been altered experimentally during late pregnancy. By providing information about the development and regulation of muscle mitochondrial function, the study will provide potential biomarkers of future health and therapeutic targets to improve life-long well being if compromised by events before birth. In particular, the study has important clinical implications for infants that were growth restricted before birth, delivered prematurely with or without antenatal glucocorticoid treatment or experienced other stressful conditions during pregnancy which raised cortisol concentrations.