Developmental regulation of muscle mitochondrial function

新生儿出生后，面临着许多新的挑战。它必须建立呼吸，颤抖，以及在许多动物中，第一次运动。心脏也必须更努力地泵血来支持这些新的活动。因此，出生后立即需要更多的能量，以确保新生儿存活。这种能量是由细胞内称为线粒体的小结构提供的，线粒体利用氧气产生富含能量的分子，然后为肌肉和其他生命所必需的过程提供燃料。在许多组织中，确保新生儿存活的准备工作在出生前就开始开始，并依赖于分娩前胎儿血液中激素皮质醇的正常增加。然而，目前，人们对肌肉和其他组织中的线粒体如何为出生时能量需求的增加做好准备，或者这些成熟的变化是否取决于出生前胎儿皮质醇的增加，知之甚少。以前的动物研究表明，出生前发育过程中经历的条件可能会影响成年人线粒体的功能。由于线粒体功能的逐渐下降是正常衰老过程的一部分，因此出生前诱导的线粒体功能变化可能在决定生命质量和生命后期的健康方面很重要。然而，我们对线粒体功能如何随着从胎儿到成年的生长和发育而变化，或者这种轨迹是否可以被分娩前的事件改变知之甚少。胎儿的皮质醇水平不仅在足月时升高，作为即将分娩的正常成熟信号，而且在怀孕早期也会增加，以应对不良的发育条件，如母体压力或营养或氧气短缺。众所周知，这些情况对出生后的健康有影响，并会加速衰老和成年退行性疾病的发生，如糖尿病和高血压，缩短寿命。因此，出生前早期暴露于皮质醇引起的线粒体功能变化可能在解释胎儿生命期间的条件如何影响终身健康和福祉方面发挥重要作用。本研究的目的是确定是否在怀孕后期成熟的肌肉中的线粒体的功能，为出生做准备，作为正常的上升，胎儿皮质醇对术语，但在出生时受损，随着年龄的增长，如果胎儿过度皮质醇过早发生。这些研究将在绵羊中进行，因为它们的胎儿发育比啮齿动物幼崽更接近人类婴儿。它们也足够大，可以在出生前进行实验研究，因为它们出生时就成熟了，肌肉活动的能量需求在出生时就很高。将在具有正常皮质醇特征的胎仔、新生儿和成年动物的心脏和骨骼肌中以及在妊娠后期胎仔皮质醇水平已通过实验改变的动物中测量线粒体功能。通过提供有关肌肉线粒体功能发育和调节的信息，该研究将提供未来健康和治疗目标的潜在生物标志物，以改善出生前事件损害的终身健康。特别是，该研究对出生前生长受限的婴儿具有重要的临床意义，早产或未接受产前糖皮质激素治疗或在怀孕期间经历其他压力条件，从而提高皮质醇浓度。

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.