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.

项目概要 使用异时联体共生的研究，这是一种建立双向交叉循环的外科手术干预措施 在年轻和年老动物之间，强烈表明存在调节血液传播的因素 骨骼肌和其他组织的再生和稳态，与年龄相关。工作自 我的实验室和其他人暗示循环蛋白生长分化因子 11 (GDF11) 和肌肉生长抑制素 （MSTN）作为负责肌肉衰老表型转位的候选老年因子 异时连接的小鼠。 GDF11 和 MSTN 是 TGFβ 超家族密切相关的配体，在 它们的受体结合域并表现出高度重叠的受体结合模式。然而尽管有这些 由于相似之处，已发表的报告表明这两种蛋白质可能对衰老的肌肉产生相反的影响。 特别是，我们表明，在老年小鼠中全身补充 GDF11 水平（通过注射 重组 GDF11 蛋白）可以显着逆转与年龄相关的肌肉修复能力缺陷， 重塑肌纤维超微结构，增强肌肉力量和耐力。 GDF11表达还有 在对多个物种的研究中，其与寿命呈正相关。相反，MSTN 缺陷的分析 动物表明 MSTN 的正常作用是限制肌肉生长并减缓受伤后的再生，并且 轻度抑制小鼠 MSTN 可能对寿命产生积极影响。重要的是，GDF11 的这些作用 和 MSTN 似乎都具有剂量和环境特异性，这引起了一些混乱和争议 关于它们各自对衰老和健康寿命的影响。 在这个提案中，我们的目标是克服先前的实验挑战，以产生清晰的分子遗传学 了解 GDF11 和 MSTN 在肌肉衰老中各自的作用及其与肌肉衰老的机制关系 彼此之间，以及它们作为具有治疗作用的老年蛋白的相关性。我们的研究将高度利用 特定的 LC-MS/MS 检测和小鼠遗传模型可追踪循环蛋白水平并进行操作 GDF11和MSTN在年轻、中年和老年小鼠以及年轻或老年伴侣中的表达 异时性联体共生，无论是在稳态还是对肌肉损伤的反应。这项工作的重要性在于 人体研究强调了 GDF11 和 MSTN 血清水平的差异与临床结果之间的联系 一些与衰老相关的疾病。因此，我们提出的工作对识别具有很大的潜在影响 以及未来开发有希望的目标来对抗与年龄相关的肌肉功能障碍，并直接 响应 RFA-AG-17-002：循环原老年和抗老年蛋白和肽的表征。