Effects of Myostatin Deficiency on Bone Strength

描述(申请人提供)：导致骨质疏松症发病的主要因素是与年龄相关的骨丢失；然而，通过在生命早期增加峰值骨量可以最大限度地减少骨丢失的潜在灾难性影响。这项拟议的研究评估了肌肉抑制素缺陷小鼠的肌肉质量、骨量和体力活动之间的关系，以更好地了解在生长过程中增加骨强度和在成年后最大限度地增加骨量的机制。肌肉生长抑制素(GDF-8)是骨骼肌生长的负调控因子，与正常小鼠相比，肌肉抑制素基因缺失的小鼠的肌肉纤维大小和数量增加了一倍。最近的研究表明，肌肉生长抑制素有可能减缓和/或预防肥胖、2型糖尿病和肌肉萎缩障碍(如肌营养不良和恶病质)的发展。这项应用的初步结果表明，肌肉抑制素功能的丧失也显著增加了骨形成、骨密度和骨强度。因此，肌肉生长抑素抑制剂可能成为预防骨质疏松症的一种新疗法。本研究的目的是验证肌肉抑制素缺乏通过增加肌肉质量来增加出生后发育过程中的骨形成和骨强度的假设。本项目旨在确定肌肉生长抑素缺乏对骨强度产生积极影响的机制，具体目标如下：具体目标1将确定由于肌肉生长抑制素缺乏导致的肌肉质量增加是否会增加骨密度和骨强度，而不依赖于全身质量和脂肪质量。具体目标2将确定肌肉抑制素缺乏是否通过机械转导途径增加骨形成。具体目标3研究肌肉生长抑素缺乏和剧烈运动对骨量和强度的影响。这项研究将对靶向肌肉质量作为改善骨骼健康的治疗策略的有效性进行批判性评估，并将以此方式为预防骨质疏松症的新疗法的开发做出重大贡献。

DESCRIPTION (provided by applicant): The primary factor leading to the onset of osteoporosis is age related bone loss; however, the potentially disastrous affects of bone loss may be minimized by increasing peak bone mass early in life. The proposed research evaluates relationships among muscle mass, bone mass, and physical activity in myostatin-deficient mice in order to better understand the mechanisms that increase bone strength during growth and maximize bone mass at adulthood. Myostatin (GDF-8) is a negative regulator of skeletal muscle growth and myostatin null mice show a doubling of muscle fiber size and number compared to normal mice. Recent studies have shown that myostatin inhibitors have the potential to slow and/or prevent the development of obesity, type 2 diabetes, and muscle wasting disorders such as muscular dystrophy and cachexia. Preliminary results presented in this application indicate that loss of myostatin function also significantly increases bone formation, bone density, and bone strength. Myostatin inhibitors may therefore serve as a novel treatment for the prevention of osteoporosis. The purpose of this study is to test the hypothesis that myostatin deficiency increases bone formation and bone strength during postnatal development by increasing muscle mass. This project seeks to define the mechanisms underlying the positive effects of myostatin deficiency on bone strength with the following Specific Aims: Specific Aim 1 will determine if increased muscle mass due to myostatin deficiency increases bone mineral density and bone strength independent of total body mass and fat mass. Specific Aim 2 will determine if myostatin deficiency increases bone formation through a mechanotransduction pathway. Specific Aim 3 examines the effects of myostatin deficiency and intense exercise on bone mass and strength. This research will critically evaluate the effectiveness of targeting muscle mass as a therapeutic strategy for improving bone health, and will in this way contribute significantly to the development of novel treatments for the prevention of osteoporosis.