Developmental regulation of muscle mitochondrial function

在出生时，新生儿面临许多新的挑战。它必须第一次建立呼吸、颤抖和在许多动物中的运动。心脏也必须更加用力地跳动，以支持这些新的活动。因此，出生后立即需要更多的能量来确保新生儿存活。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能量丰富的分子，然后为肌肉和其他生命必不可少的过程提供燃料。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了，并依赖于胎儿血液中一种荷尔蒙皮质醇的正常增加。然而，目前对于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，或者这些成熟变化是否依赖于出生前胎儿皮质醇的增加，人们知之甚少。之前对动物的研究表明，出生前发育过程中经历的条件可能会影响成年线粒体的功能。由于线粒体功能的渐进性下降是正常衰老过程的一部分，出生前诱导的线粒体功能变化可能对决定晚年的生活质量和健康很重要。然而，我们对线粒体功能如何随着从胎儿到成人的生长发育变化知之甚少，也不知道这一轨迹是否会因分娩前的事件而改变。胎儿的皮质醇水平不仅会在足月时升高，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，如母亲的压力或营养或氧气的短缺。众所周知，这些情况会影响出生后的健康，并会加速衰老和糖尿病和高血压等成年人退行性疾病的发病，从而缩短寿命。因此，出生前早期接触皮质醇引起的线粒体功能变化可能在解释胎儿时期的状况如何影响一生的健康和幸福方面发挥重要作用。这项研究的目的是确定如果胎儿过早暴露于皮质醇，肌肉中线粒体的功能是否在妊娠晚期成熟，为分娩做准备，这是胎儿皮质醇正常上升的结果，但在出生时和随着年龄的增长而受损。这些研究将在绵羊身上进行，因为它们的胎儿发育更像人类婴儿，而不是啮齿动物幼崽。它们也足够大，可以在出生前进行实验研究，而且由于它们出生时成熟，肌肉活动所需的能量增加在出生时就很高。将测量皮质醇水平正常的胎儿、新生儿和成年动物的心脏和骨骼肌的线粒体功能，以及怀孕后期胎儿皮质醇水平发生实验变化的动物的心肌和骨骼肌的线粒体功能。通过提供有关肌肉线粒体功能发展和调节的信息，这项研究将提供未来健康的潜在生物标记物和治疗目标，以改善一生的福祉，如果出生前发生的事件损害的话。特别是，这项研究对出生前生长受限、早产或在产前接受或不接受糖皮质激素治疗或在怀孕期间经历其他导致皮质醇浓度升高的压力情况的婴儿具有重要的临床意义。

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.