Healthy Aging and Myostatin Antagonsits

描述（由申请人提供）：老年人不成比例地受到各种慢性疾病的影响，通常与虚弱和代谢综合征有关。这两种疾病都无法治愈，但可以通过改变生活方式来延缓。例如，运动可以增加肌肉量，提高胰岛素敏感性，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，为了延缓与年龄相关的身体和代谢功能障碍，发展分子方法来模拟运动对健康的益处尤为重要。这项工作的目的是测试肌生长抑制素阻断是否可以被视为一种有用的运动模拟物。我们假设在中年晚期阻断肌肉生长抑制素（一种内源性肌肉发育抑制剂）会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对幼龄动物肌肉生长抑制素敲除和抑制剂的广泛研究的支持，但缺乏衰老背景下的概念证明。这项工作的结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初步发现，我们提出了第二个假设，即肝脏可能是肌生长抑制素阻断的直接靶点。这解释了先前肌肉生长抑制素敲除小鼠肝功能改善的发现，以及我们的初步数据显示，肌肉生长抑制素抑制前肽治疗小鼠饮食诱导的肝骨化症减少。支持这一假设的确凿证据将在这项工作中收集，将把肌肉生长抑制素研究的范式从仅仅关注肌肉转移到包括肝脏和可能的其他器官。这可能为基于肌生成抑制素的代谢疾病治疗发展带来新的机遇。我们将使用中年晚期的野生型小鼠模型来验证我们的假设，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）来实现肌生长抑制素阻断。动物将与标准低脂饮食和等热量高脂肪饮食同时进行测试，有两个具体目标。Aim-1将侧重于在体内评估衰老不同阶段的代谢和功能表现，包括呼吸、胰岛素敏感性、力量和耐力，以及中位和最长寿命的测量。Aim-2将专注于肌肉和肝脏特异性信号，线粒体活性，蛋白质合成和脂质代谢。

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.