Using in vitro approaches to improve muscle regrowth in atrophied older humans

使用体外方法改善萎缩的老年人的肌肉再生

基本信息

批准号：
8708726
负责人：
Michael John Stec
金额：
$ 4.27万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-12 至 2015-09-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708726
关键词：
Adjuvant Therapy Adult Affect Age-Years Aging Atrophic Attenuated Cells Cellular Stress Chronic Chronic Disease Conditioned Culture Media Contractile Proteins Creatine Kinase Crossover Design Data Disease Effectiveness of Interventions Elderly Energy Metabolism Environment Enzyme-Linked Immunosorbent Assay Enzymes Exercise Genetic Translation Genomics Gold Growth Factor Harvest Heart Hormones Human Hypertrophy In Vitro Individual Intervention Kidney Knowledge Laboratories Lead Life Link Lung Measures Mechanical Stress Mechanics Metabolic Metabolic stress Mind Motor Muscle Muscle Fibers Muscular Atrophy Myosin Heavy Chains Nutrient Outcome Phenotype Population Production Protein Biosynthesis Proteins Proteomics Publishing Quality of life Reporting Resistance Risk Series Signal Transduction Signaling Protein Skeletal Muscle Stimulus Stress Stretching Testing Time Training Translation Initiation Translations age related aging population autocrine base cellular imaging deprivation disability experience functional disability impaired capacity improved mortality muscle form novel promoter research study response sarcopenia signal processing treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Age-related muscle atrophy (i.e., sarcopenia) affects the entire population of adults 65+ years of age. Sarcopenia results in functional disability, loss of independence, and increased all-cause mortality in older adults. Currently, the most effective strategy for restoring muscle mass in sarcopenic, older adults is resistance exercise training (RT), which results in marked myofiber hypertrophy in most adults. However, the extent of muscle regrowth is extremely variable between individuals, with some individuals failing to increase myofiber hypertrophy following long-term RT (i.e., nonresponders). The extent of myofiber hypertrophy is typically less in older adults when compared to young following RT, and recent data from the Bamman laboratory have shown that ~40% of sarcopenic, older adults are nonresponders to RT. This is particularly concerning; as these individuals are in desperate need of muscle regrowth, and without adjuvant therapies, sarcopenic nonresponders will inevitably suffer the negative consequences of muscle atrophy. It is therefore of great importance to develop effective strategies to regrow muscle in older, sarcopenic adults who respond poorly to RT alone. Based on novel genomic and proteomic preliminary data, it is our central hypothesis that the nonresponder phenotype is driven by aberrant, intrinsic cellular responses to the homeostatic challenges imposed by RT (e.g., mechanical and metabolic stress). This hypothesis will be tested in a series of in vitro experiments using primary myogenic cells harvested from 60-75 y sarcopenic responders and nonresponders. Differentiated, primary myotubes will be subjected to various anabolic and stress-generating stimuli with the following specific aims in mind: Specific Aim 1. We will determine key translational signaling processes associated with impaired protein synthesis responses to mechanical stress in myotubes from nonresponders. It is expected that defective translation initiation signaling and possibly autocrine growth factor signaling regulate the blunted protein synthesis response in nonresponders myotubes. Specific Aim 2. We will determine if blunted hypertrophy of nonresponder myotubes is linked with an impaired capacity for cellular energy production. Inability to sustain sufficient energy production for protein synthesis is likely to be a major caue of attenuated hypertrophy in nonresponder myotubes. These experiments are fully expected to advance our understanding of the mechanisms responsible for the nonresponder phenotype. The knowledge gained from these experiments will be valuable for developing adjuvant therapies to enhance RT-induced muscle regrowth in sarcopenic, older adults.

描述（由申请人提供）：与年龄相关的肌肉萎缩（即肌肉减少症）会影响65岁以上成年人的整个人群。肌肉减少症会导致功能障碍，损失独立性，并增加了老年人的全因死亡率。目前，恢复肌肉减少症的肌肉质量的最有效策略是耐药运动训练（RT），这导致大多数成年人在大多数成年人中都显着肌肥大。但是，肌肉再生的程度在个体之间是极大的，有些人在长期RT后没有增加肌纤维肥大（即非反应者）。与RT之后的年轻人相比，老年人的肌纤维肥大的程度通常较小，而BAMMAN实验室的最新数据表明，约有40％的肌肉减少症，老年人对RT无反应。这尤其令人担忧。由于这些人迫切需要肌肉再生，并且没有辅助疗法，因此肌肉减少症无反应者将不可避免地遭受肌肉萎缩的负面影响。因此，制定有效的策略来重新生长肌肉的肌肉肌肉，他们对RT的反应不佳是非常重要的。基于新型的基因组和蛋白质组学初步数据，我们的核心假设是，无反应的表型是由对RT施加的稳态挑战的异常，内在的细胞反应驱动的（例如，机械和代谢应激）。该假设将在一系列的体外实验中进行测试，使用从60-75 y肌肉减少剂反应者和非反应者收获的原代肌生成细胞。差异化的原代肌管将经过各种合成代谢和应激产生刺激，考虑到以下特定目的：特定目标1。我们将确定与蛋白质合成受损相关的关键转化信号传导过程，这些蛋白质合成受损反应反应于非反应器中的肌管中机械应力。预计有缺陷的翻译起始信号传导和可能的自分泌生长因子信号传导调节非反应器肌管中钝化的蛋白质合成反应。具体目标2。我们将确定非反应肌管的肥大是否与细胞能量产生的能力受损有关。无法维持足够的能源生产来蛋白质合成可能是无响应肌管中减毒肥大的主要原因。完全期望这些实验能够促进我们对负责表型的机制的理解。从这些实验中获得的知识对于开发辅助疗法以增强RT诱导的肌肉减少症老年人的肌肉再生非常有价值。