Reproductive Hormones in Skeletal Muscle Aging in Rhesus Monkeys

 描述（由申请方提供）：在恒河猴中，热量限制（CR）可延迟肌肉减少症（年龄相关的骨骼肌质量下降）的发作。猴子的肌肉减少症与在人类中观察到的表型相似，我们发表的和初步的数据表明，能量代谢不足是肌肉老化的核心。目前还不清楚生殖激素状态在多大程度上影响肌肉质量损失率作为年龄的函数。在人类中，年龄与脂肪储存增加和肌肉质量和功能减少有关。我们对肌肉减少症的研究表明，这些表型可能是相关的。我们推测，肌肉减少症的性别差异与生殖激素对肌肉能量代谢和质量保持的影响有关。为了测试这一点，我们将确定细胞能量签名诱导老化，CR，和性腺切除术，并与细胞内表型的整个组织和整个动物的措施。目标1：确定性别和生殖激素对骨骼肌能量代谢和肌肉减少症动力学的影响（1a）确定骨骼肌能量代谢随年龄和CR的性别差异，这些骨骼肌能量代谢来自我们使用定量成像、生物化学和脂质组学方法进行的CR和老化纵向研究中的~23岁对照和CR雄性和雌性猴（n=29）的股外侧肌库。将根据现有的身体组成数据、骨骼肌基因表达数据和TLC/GC血清脂质组成谱分析这些细胞内测量。(1b)确定生殖激素状态对年龄相关性肌肉质量损失的影响。使用Aim 1a动物生成的现有数据，涵盖约17至约27岁（n=29），我们将确定（i）衰老和CR对生殖激素的影响，（ii）衰老和生殖激素状态对估计肌肉质量的影响，以及（iii）衰老、CR和生殖激素状态对肌肉减少症的相互作用。目的2：确定生殖激素抑制对肌肉代谢和组成的影响。我们将在年龄约15岁的男性和女性中测试手术生殖激素抑制的影响（n=20假手术组，n=20抑制组）。在36个月的时间内，将在股外侧肌活检中评估肌肉质量和组成、生殖激素和细胞内代谢。血糖调节功能、脂联素和脂质组成的血清测量值将指示全身代谢的扰动。我们的研究团队包括灵长类动物衰老，内分泌学和骨骼肌代谢方面的专业知识，并且独特地准备进行这项工作。我们预计，这项高度转化的研究不仅将促进我们对骨骼肌衰老的理解，而且将与更广泛的领域相关，包括生殖激素状态对骨骼肌和全身代谢调节的影响。

 DESCRIPTION (provided by applicant): In rhesus monkeys, caloric restriction (CR) delays the onset of sarcopenia, the age-related decline in skeletal muscle mass. Sarcopenia in monkeys parallels the phenotypes observed in people, and our published and preliminary data suggests that a deficiency in energy metabolism is central to muscle aging. It is unclear the extent to which reproductive hormone status influences the rate of muscle mass loss as a function of age. In humans, age is associated with increased fat storage and reduced muscle mass and function. Our work on sarcopenia suggests that these phenotypes may be linked. We hypothesize that gender differences in sarcopenia are linked to the impact of reproductive hormones on muscle energy metabolism and preservation of mass. To test this we will determine the cellular energetic signature induced by aging, CR, and gonadectomy, and relate intracellular phenotypes to whole tissue and whole animal measures. Aim 1: To determine gender and reproductive hormone effects in skeletal muscle energy metabolism and the dynamics of sarcopenia (1a) To determine gender differences in skeletal muscle energy metabolism with age and CR in banked vastus lateralis from ~23 year old Control and CR male and female monkeys (n=29) from our CR and aging longitudinal study using quantitative imaging, biochemical and lipidomic approaches. These intracellular measures will be analyzed against existing body composition data, skeletal muscle gene expression data, and TLC/GC serum lipid composition profiles. (1b) To determine the impact of reproductive hormone status on age-related muscle mass loss. Using existing data generated from Aim1a animals covering the ages ~17 to ~27 years (n=29), we will determine the (i) impact of aging and CR on reproductive hormones, (ii) impact of aging and reproductive hormone status on estimated muscle mass, and (iii) interaction between aging, CR, and reproductive hormone status on sarcopenia. Aim 2: To determine the impact of reproductive hormone suppression on muscle metabolism and composition. We will test the impact of surgical reproductive hormone suppression in males and females ~15 years of age (n=20 sham, n=20 suppressed). Muscle mass and composition, reproductive hormones, and intracellular metabolism will be assessed in vastus lateralis biopsies over a 36-month period. Serum measures of glucoregulatory function, adiponectin, and lipid composition will index perturbations in systemic metabolism. Our research team includes expertise in primate aging, endocrinology, and skeletal muscle metabolism, and is uniquely poised to conduct this work. We anticipate that this highly translational study will no only advance our understanding of skeletal muscle aging but will be relevant to a wider sphere, including the impact of reproductive hormone status on skeletal muscle and systemic metabolic regulation.