Effects of Myostatin Deficiency on Bone Strength

肌肉生长抑制素缺乏对骨强度的影响

• 批准号: 6827153
• 负责人: MARK W HAMRICK
• 金额: $ 22.77万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827153
• 关键词: biomechanics; body composition; bone density; bone development; densitometry; exercise; laboratory mouse; mechanical pressure; muscle; myostatin; normal ossification; osteoporosis

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.

描述（由申请人提供）：导致骨质疏松症发作的主要因素是与年龄相关的骨质流失；但是，通过在生命的早期增加峰值骨骼质量，可以最大程度地减少骨质流失的灾难性影响。拟议的研究评估了肌抑制素缺陷型小鼠的肌肉质量，骨骼质量和体育活动之间的关系，以便更好地了解增加生长过程中骨骼强度并在成年期最大化骨骼质量的机制。与正常小鼠相比，肌生抑素（GDF-8）是骨骼肌生长的负调节剂，肌抑制素无效小鼠的肌肉纤维大小和数量增加了一倍。最近的研究表明，肌抑制素抑制剂有可能减慢和/或防止肥胖，2型糖尿病以及肌肉浪费障碍（如肌肉营养不良和卡氏病）的发展。本应用中提出的初步结果表明，肌抑素功能的丧失还显着增加了骨骼的形成，骨密度和骨骼强度。因此，肌抑制剂可以作为预防骨质疏松症的新型治疗方法。这项研究的目的是检验以下假设：肌抑制素缺乏通过增加肌肉质量在产后发育过程中增加骨形成和骨强度。该项目旨在定义肌抑素缺乏症对骨强度的积极作用的基础机制，其特定目的是：特定目标1将确定由于肌抑制素缺乏而增加的肌肉质量是否增加了骨矿物质的密度和骨骼强度，而骨骼强度与总体重和脂肪质量无关。特定的目标2将确定肌抑制素缺乏是否通过机械转移途径增加骨形成。特定目标3检查了肌抑制素缺乏症和强烈运动对骨骼质量和力量的影响。这项研究将批判性地评估靶向肌肉质量作为改善骨骼健康的治疗策略的有效性，并以这种方式对预防骨质疏松症的新型治疗产生产生重大贡献。