Healthy Aging and Myostatin Antagonsits

描述(申请人提供)：老年人不成比例地受到各种慢性病的影响，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，锻炼可以增加肌肉质量，增强胰岛素敏感性，提高中位存活率。然而，锻炼对老年人来说并不总是可行的。因此，开发模拟运动对健康有益的分子方法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抑制素阻断是否可以被视为一种有用的运动模拟物。我们假设，在中年后期阻断肌肉生长抑制素(一种肌肉发育的内源性抑制物)会增加肌肉质量并延缓骨骼肌减少。虽然这一假说得到了先前对年轻动物中的肌肉生长抑制素基因敲除和抑制剂的广泛研究的支持，但在衰老的背景下缺乏概念验证。这一知识空白将被这项工作的结果所填补。此外，基于我们在细胞培养中肌肉抑制素与肝细胞相互作用的新的初步发现，我们提出了第二个假设，即肝脏可以成为肌肉生长抑素阻断的直接靶点。这解释了先前在myostatin基因敲除小鼠中改善肝功能的发现，以及我们的初步数据显示，在使用myostatin抑制前肽治疗的小鼠中，饮食诱导的肝骨病减少。在这项工作中收集的支持这一假说的确凿证据将改变肌肉抑制素研究的范式，从完全集中于肌肉转向包括肝脏和可能的其他器官。这可能为基于肌肉生长抑素的治疗发展带来新的机会来治疗代谢性疾病。我们将使用野生型小鼠模型来验证我们的假设，该模型始于中年后期，通过一次性注射腺相关病毒(AAV)来实现肌肉生长抑制素阻断，该病毒编码一种肌肉生长抑制素特异性抑制物，即前肽突变体。动物将接受与标准低脂肪和等卡路里高脂肪饮食平行的测试，遵循两个具体目标。AIM-1将集中在体内评估不同衰老阶段的代谢和功能表现，包括测量呼吸、胰岛素敏感性、强度和耐力，以及中位寿命和最长寿命。AIM-2将专注于肌肉和肝脏特有的信号、线粒体活性、蛋白质合成和脂肪代谢。 与公共健康相关：拟议的研究将确定阻断肌肉分泌的肌肉生长抑制素是否以及如何延缓与年龄相关的代谢和功能衰退。肌肉生长抑制素是肌肉发育的一种负调控因子。这项工作直接关系到NIH追求知识以延长健康寿命和减少疾病和残疾负担的使命。

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.