Healthy Aging and Myostatin Antagonsits

健康衰老和肌肉生长抑制素拮抗剂

• 批准号: 8108812
• 负责人: WEN GUO
• 金额: $ 20.79万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8108812
• 关键词: Adverse effects; Affect; Age; Aging; Animals; Atherosclerosis; Attenuated; C57BL/6 Mouse; Cell Culture Techniques; Chronic Disease; Clinical; Corn Oil; Data; Dependovirus; Development; Diet; Elderly; Energy Metabolism; Exercise; Fatty acid glycerol esters; Functional disorder; Gene Transfer; Glucose tolerance test; Goals; Health; Health Benefit; Hepatocyte; Histology; Housing; Human; Individual; Infiltration; Injection of therapeutic agent; Insulin Resistance; Intervention; Knock-out; Knockout Mice; Knowledge; Life; Life Style; Lipids; Liver; Longevity; Measurement; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Mission; Mitochondria; Molecular; Monitor; Mus; Muscle; Muscle Development; Obesity; Organ; Pathway interactions; Performance; Pharmaceutical Preparations; Physical Function; Plasma; Population; Protein Biosynthesis; Research; Resistance; Respiration; Role; Signal Transduction; Skeletal Muscle; Solid; Staging; Starch; System; Testing; Time; Tissues; United States National Institutes of Health; Variant; Wild Type Mouse; Work; age related; aged; base; burden of illness; cohort; density; disability; effective intervention; frailty; functional decline; functional outcomes; grasp; healthy aging; human FRAP1 protein; improved; in vivo; inhibitor/antagonist; insulin sensitivity; insulin sensitizing drugs; insulin tolerance; juvenile animal; lipid metabolism; liver function; mature animal; middle age; mimetics; mouse model; muscle form; muscle hypertrophy; mutant; myogenesis; myostatin; novel; retinal rods; sarcopenia; therapeutic development

DESCRIPTION (provided by applicant): Older people are disproportionally affected by various chronic illnesses, typically related to frailty and metabolic syndrome. Both conditions cannot be cured but may be delayed by lifestyle changes. For instance, exercise increases muscle mass, enhances insulin sensitivity, and improves median survival. However, exercise is not always feasible for aged individuals. Hence, development of molecular approaches to mimic the health benefit of exercise can be especially important in order to delay age-related physical and metabolic dysfunction. The goal of this work is to test whether myostatin blockade can be viewed as such a useful exercise mimetic. We hypothesize that blocking myostatin, an endogenous inhibitor for muscle development, at late middle age will increase muscle mass and delay sarcopenia. While this hypothesis is supported by extensive previous studies with myostatin knockout and inhibitors in young animals, proof-of-concept within the context of aging is missing. This knowledge gap will be filled by the results from this work. In addition, based on our novel preliminary findings of interactions between myostatin and hepatocytes in cell culture, we propose a second hypothesis that liver can be a direct target of myostatin blockade. This explains the prior findings of improved liver function in myostatin knockout mice and our preliminary data showing decreased diet-induced hepatosteatosis in mice treated with myostatin inhibitory propeptide. Solid evidence to support this hypothesis, as will be collected in this work, will shift the paradigm of myostatin studies from exclusively muscle-focused to include liver and possibly other organs. This may bring novel opportunities for myostatin-based therapeutic developments to treat metabolic diseases. We will test our hypothesis using a wild-type mouse model beginning at late middle age, with myostatin blockade achieved by one-time injection of adeno-associated virus (AAV) encoding a myostatin-specific inhibitor, the propeptide mutant. Animals will be tested in parallel with standard low-fat and isocaloric high-fat diets, following two specific aims. Aim-1 will focus on in vivo assessment of metabolic and functional performance at different points of aging, including measurement of respiration, insulin sensitivity, strength and endurance, as well as median and maximum lifespan. Aim-2 will focus on muscle- and liver-specific signaling, mitochondrial activity, protein synthesis, and lipid metabolism. PUBLIC HEALTH RELEVANCE: The proposed research will determine if and how blocking myostatin, a muscle-secreted negative regulator for muscle development, will delay age-associated metabolic and functional decline. This work is directly relevant to the mission of NIH to pursue knowledge to extend healthy life and reduce burdens of illness and disability.

描述（由申请人提供）：老年人受到各种慢性疾病的影响，通常与虚弱和代谢综合征有关。这两种情况都无法治愈，但可能会因生活方式的改变而延迟。例如，运动增加肌肉质量，增强胰岛素敏感性，提高中位生存率。然而，锻炼对于老年人来说并不总是可行的。因此，开发分子方法来模拟运动的健康益处对于延缓与年龄相关的身体和代谢功能障碍尤为重要。这项工作的目标是测试肌肉生长抑制素阻断是否可以被视为这样一个有用的运动模拟。我们假设，在中年晚期阻断肌肉生长抑制素（一种肌肉发育的内源性抑制剂）将增加肌肉质量并延缓肌肉减少症。虽然这一假设得到了先前在年轻动物中进行的大量肌肉生长抑制素敲除和抑制剂研究的支持，但缺乏衰老背景下的概念验证。这项工作的成果将填补这一知识空白。此外，基于我们在细胞培养中肌生长抑制素和肝细胞之间相互作用的新的初步发现，我们提出了第二个假设，即肝脏可以是肌生长抑制素阻断的直接靶点。这解释了先前在肌肉生长抑制素敲除小鼠中改善肝功能的发现，以及我们的初步数据显示用肌肉生长抑制素抑制性前肽治疗的小鼠中饮食诱导的脂肪肝减少。支持这一假设的确凿证据，将在这项工作中收集，将改变肌生长抑制素研究的范式，从专门的肌肉集中，包括肝脏和可能的其他器官。这可能为基于肌肉生长抑制素的治疗发展带来新的机会，以治疗代谢性疾病。我们将使用野生型小鼠模型从中年晚期开始测试我们的假设，通过一次性注射编码肌生长抑制素特异性抑制剂（前肽突变体）的腺相关病毒（AAV）实现肌生长抑制素阻断。按照两个特定目标，将对动物进行标准低脂和等热量高脂饮食平行试验。Aim-1将专注于在不同年龄点的代谢和功能表现的体内评估，包括呼吸，胰岛素敏感性，力量和耐力，以及中位数和最长寿命的测量。Aim-2将专注于肌肉和肝脏特异性信号传导，线粒体活性，蛋白质合成和脂质代谢。 公共卫生相关性：这项拟议中的研究将确定是否以及如何阻断肌肉生长抑制素（一种肌肉分泌的肌肉发育负调节剂）将延缓与年龄相关的代谢和功能衰退。这项工作与NIH的使命直接相关，即追求知识，以延长健康的生命，减少疾病和残疾的负担。