Investigating GDF11 and MSTN as candidate circulating geronic factors

研究 GDF11 和 MSTN 作为候选循环老年因子

• 批准号: 9421907
• 负责人: AMY JO WAGERS
• 金额: $ 51.18万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9421907
• 关键词: Age; Aging; Animals; Biochemical; Biological; Biological Assay; Biological Process; Biophysics; Blood; Blood Circulation; C-terminal; Cells; Clinical; Confusion; Cross Circulation; Data; Development; Disease; Dose; Elderly; Employee Strikes; Endocrine; Exhibits; Fibrosis; Functional disorder; Future; GDF11 gene; GDF8 gene; Genetic; Genetic Models; Growth; Health; Heart; Homeostasis; Human; Injection of therapeutic agent; Injury; Intervention; Invertebrates; Life; Ligand Binding Domain; Ligands; Link; Longevity; Maintenance; Methods; Modeling; Molecular; Molecular Genetics; Mus; Muscle; Muscle function; Natural regeneration; Neuraxis; Operative Surgical Procedures; Orthologous Gene; Outcome; Parabiosis; Pathway interactions; Pattern; Peptides; Phenotype; Play; Population; Production; Proteins; Publishing; Receptor Signaling; Recombinants; Recovery; Regimen; Reporting; Role; Serum; Signal Transduction; Skeletal Muscle; Standardization; Structure; Supplementation; System; Testing; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Transgenic Organisms; Work; age related; aged; base; bone; combat; in vivo; juvenile animal; middle age; muscle aging; muscle strength; novel; receptor binding; regenerative; repaired; resilience; response

Project Summary Studies using heterochronic parabiosis, a surgical intervention that establishes bi-directional cross-circulation between young and old animals, strongly indicate the existence of blood-borne factors that regulate the regeneration and homeostasis of skeletal muscle, and other tissues, in an age-dependent manner. Work from my lab and others implicate the circulating proteins Growth Differentiation Factor 11 (GDF11) and Myostatin (MSTN) as candidate geronic factors responsible for the transposition of aging phenotypes in muscle in heterochronically joined mice. GDF11 and MSTN are closely related ligands of the TGFβ superfamily that share 89% sequence identity in their receptor-binding domains and exhibit highly overlapping patterns of receptor binding. Yet despite these similarities, published reports suggest that these two proteins may exert opposing influences on aging muscle. In particular, we showed that systemic supplementation of GDF11 levels in aged mice (by injection of recombinant GDF11 protein) can elicit a striking reversal of age-related deficits in muscle repair capacity, remodel myofiber ultrastructure, and enhance muscle strength and endurance. GDF11 expression also has been positively correlated with lifespan in studies of multiple species. Conversely, analyses of MSTN-deficient animals suggest that MSTN acts normally to limit muscle growth and slow regeneration after injury, and that mild suppression of MSTN in mice may have a positive impact on lifespan. Importantly, these effects of GDF11 and MSTN appear to be both dose- and context-specific, which has raised some confusion and controversy regarding their respective influences on aging and health span. In this proposal, we aim to overcome prior experimental challenges to generate a clear molecular genetic understanding of the respective roles of GDF11 and MSTN in muscle aging, their mechanistic relationship to one another, and their relevance as therapeutically actionable geronic proteins. Our studies will use highly specific LC-MS/MS assays and mouse genetic models to track circulating protein levels and manipulate GDF11 and MSTN expression in young, middle-aged and aged mice, and in the young or aged partners of heterochronic parabiosis, both in steady state and in response to muscle injury. The importance of this work is underscored by human studies linking differences in serum levels of GDF11 and MSTN with clinical outcomes in several aging-related diseases. As such, our proposed work has a high potential impact for the identification and future development of promising targets to combat age-related muscle dysfunction and is directly responsive to RFA-AG-17-002: Characterization of Circulating Pro- and Anti-Geronic Proteins and Peptides.

项目摘要 使用异核核酸副作用的研究，这是一种建立双向交叉循环的手术干预措施 在年轻动物和老年动物之间，强烈表明存在调节的血传播因素 骨骼肌和其他组织的再生和稳态，以年龄的依赖方式。工作 我的实验室和其他人实施了循环蛋白的生长分化因子11（GDF11）和肌生抑素 （MSTN）作为负责肌肉衰老表型转座的候选Geronic因素 杂体加入小鼠。 GDF11和MSTN是TGFβ超家族的密切相关的配体，在中具有89％的序列身份 它们的受体结合结构域和受体结合的高度重叠模式。但是目的地这些 相似之处，已发表的报告表明，这两种蛋白质可能对衰老肌肉产生相反的影响。 特别是，我们表明了年龄小鼠中GDF11水平的全身补充（通过注射 重组GDF11蛋白）可以引起与年龄相关的肌肉修复能力缺陷的显着逆转， 重塑肌纤维超微结构，并增强肌肉力量和耐力。 GDF11表达也有 在多种物种的研究中，与寿命呈正相关。相反，对MSTN缺陷的分析 动物表明，MSTN正常起作用肌肉生长和受伤后缓慢的再生，并且 小鼠中MSTN的轻度抑制可能会对寿命产生积极影响。重要的是，GDF11的这些影响 MSTN似乎既是剂量特定的，也引起了一些混乱和争议 关于它们各自对衰老和健康跨度的影响。 在此提案中，我们旨在克服先前的实验挑战，以产生清晰的分子遗传 了解GDF11和MSTN在肌肉衰老中的各自作用，其机械关系与 彼此之间，以及它们作为治疗性可起作用的香肠蛋白的相关性。我们的研究将高度使用 特定的LC-MS/MS分析和小鼠遗传模型以跟踪循环蛋白水平并操纵 年轻，中年和老年小鼠的GDF11和MSTN表达，以及年轻或老年伴侣 稳定状态和对肌肉损伤的反应，异性核心异常。这项工作的重要性是 由人类研究强调，将GDF11和MSTN血清水平差异与临床结局联系起来 在几种与衰老有关的疾病中。因此，我们提议的工作对识别具有很大的潜在影响 以及应许目标的未来发展，以打击与年龄相关的肌肉功能障碍，直接是 对RFA-AG-17-002的反应：循环促蛋白和抗蛋白质和肽的表征。