Role of MicroRNAs on Age and Contraction-induced Skeletal Muscle Growth

MicroRNA 对年龄和收缩诱导的骨骼肌生长的作用

• 批准号: 8821729
• 负责人: Donato A Rivas
• 金额: $ 9.78万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821729
• 关键词: Accounting; Achievement; Address; Adult; Age; Aging; Anabolism; Area; Attenuated; Bioinformatics; Biology; Biometry; Boston; Cardiovascular system; Cell Size; Cessation of life; Clinical; Clinical Trials; Code; Complex; Computational Biology; Data; Development; Development Plans; Elderly; Event; Exercise; Female; Fostering; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genomics; Goals; Growth; Growth and Development function; Human; In Vitro; Institutes; Insulin-Like Growth Factor I; Measures; Mentored Research Scientist Development Award; Mentorship; Messenger RNA; MicroRNAs; Molecular; Molecular Biology; Molecular Profiling; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Muscular Atrophy; Myopathy; Pathway interactions; Pharmacotherapy; Physicians; Physiological; Protein Analysis; Quality of life; Research; Research Personnel; Research Project Grants; Resistance; Role; Sampling; Scientist; Signal Transduction; Skeletal Muscle; Stimulus; Sweden; Testing; Training; Transcriptional Regulation; Universities; Untranslated RNA; Work; age related; aged; aging population; attenuation; authority; base; career; career development; economic cost; improved; in vivo; innovation; insight; male; multidisciplinary; muscle form; myogenesis; novel; older men; public health relevance; research study; response; sarcopenia; skeletal muscle growth; social; success; young adult; young man

DESCRIPTION (provided by applicant): The age-associated loss of skeletal muscle mass and function (sarcopenia) is associated with substantial social and economic costs. The plasticity and adaptability of skeletal muscle to contraction (i.e. resistance-exercise) is a fundamental physiological event leading to larger and more robust skeletal muscle. However, muscle growth in response to resistance exercise (RE), like other anabolic stimuli, is attenuated in older adults The cause of aberrant muscle adaptation with aging is complex. Recent work has revealed a novel role for small non-coding RNAs, called microRNAs (miRNA) in the regulation of gene expression. Using an integrated bioinformatics analysis of protein-coding gene and miRNA array data from young and older men, I identified ten specific miRNAs as important regulators of muscle plasticity (Plasticity Related miRs [PR-miRs]) leading to the transcriptional response to exercise and lean mass in young and older men. However, the precise mechanisms underlying the expression of PR-miRs on age-related changes in muscle anabolism and sarcopenia are currently unknown. Thus, the overall objective of this K01 application will be to determine the mechanistic role(s) of these PR-miRs in skeletal muscle adaptation to anabolic stimulation in 1) healthy young, 2) sarcopenic older and 3) age- and functionally-matched non-sarcopenic older males and females. This will be accomplished by determine the differences in expression of PR-miRs with aging and sarcopenia in response to anabolic stimulation (AIM 1). Mechanistically determine the extent to which manipulation of PR-miR levels in vitro, in human primary myocytes, can reverse anabolic resistance observed with age and sarcopenia (AIM 2) and the effect of altering PR-miRs levels on skeletal muscle growth and development (AIM 3). This project will improve our understanding of the molecular mechanisms that contribute to the loss of skeletal muscle and eventually leading to the development of drug therapies for the treatment of sarcopenia in the ever growing aging population. The mentorship team includes, Dr. Roger Fielding, a leader in aging research and muscle biology, Dr. Kenneth Walsh, a cardiovascular researcher and leading molecular biologist, Dr. Laurence Parnell a computational biologist and authority in gene and miRNA expression analysis, Dr. Thomas Gustafsson a physician-scientist and clinical researcher and Dr. Thomas Travison an expert in biostatistics. The mentorship team has a variety of know-how in every facet of this project including, conducting human clinical trials and skeletal muscle biology, computational biology and genomics and molecular biology and mechanisms. The proposed career development plan includes research-oriented and didactic training at Tufts University, Boston University and the Karolinska Institute in Stockholm, Sweden. The pursuit of the specific aims of the research project, the multidisciplinary mentorship team and the career development plan will facilitate a transition to an independent research career.

描述（由申请人提供）：与年龄相关的骨骼肌肉质量和功能（Sarcopenia）的损失与实质性的社会和经济成本有关。骨骼肌对收缩的可塑性和适应性（即抵抗运动）是一个基本的生理事件，导致更大，更健壮的骨骼肌。然而，与其他合成代谢刺激一样，肌肉生长在耐药性运动（RE）中受到老年人的衰减，导致异常的肌肉适应衰老的原因很复杂。最近的工作揭示了小型非编码RNA的新作用，称为microRNA（miRNA）在基因表达的调节中。利用来自年轻男性和年龄较大男性的蛋白质编码基因和miRNA阵列数据的综合生物信息学分析，我确定了十个特定的miRNA是肌肉可塑性的重要调节剂（可塑性相关miR [PR-MIRS]），从而导致年轻男性和老年男性对运动和瘦肉的转录反应。然而，目前尚不清楚PR-MIRS在与年龄相关的肌肉变化上表达的确切机制目前尚不清楚。因此，该K01应用的总体目标是确定这些PR-M​​IR在骨骼肌适应合成代谢刺激中的机械作用。这将通过确定响应合成代谢刺激的衰老和肌肉减少症的PR-MIR表达差异来实现（AIM 1）。机械学上确定在人类原发性肌细胞中对PR-MIR水平操纵的程度，可以逆转与年龄和肌肉减少症观察到的合成代谢性（AIM 2），以及改变PR-MIRS水平对骨骼肌生长和发育的影响（AIM 3）。该项目将提高我们对有助于骨骼肌肉丧失的分子机制的理解，并最终导致在不断增长的衰老人群中的治疗肌肉减少症治疗药物疗法的发展。指导小组包括衰老研究和肌肉生物学领域的领导者罗杰·菲尔丁（Roger Fielding）博士，心血管研究人员兼领先的分子生物学家肯尼斯·沃尔什（Kenneth Walsh）博士，托马斯·吉斯塔夫（Thomas Gustafsson）的基因生物学家劳伦斯·帕内尔（Laurence Parnell）博士托马斯·古斯塔夫斯森（Thomas Gustafsson）是一名生理学家和生物科学家研究员和博士，指导团队在该项目的各个方面都有各种专有技术，包括进行人类临床试验，骨骼肌肉生物学，计算生物学和基因组学以及分子生物学和机制。拟议的职业发展计划包括塔夫茨大学，波士顿大学和斯德哥尔摩的Karolinska Institute的面向研究和教学培训， 瑞典。追求研究项目，多学科指导团队和职业发展计划的特定目标将有助于过渡到独立的研究职业。