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Effects of Myostatin Deficiency on Bone Strength

肌肉生长抑制素缺乏对骨强度的影响

基本信息

批准号：
7228603
负责人：
MARK W HAMRICK
金额：
$ 21.25万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7228603
关键词：
Activin Receptor Affect Age-Related Bone Loss Animals Biological Models Biomechanics Bone Density Cachexia Condition Deposition Development Differentiation and Growth Disease Distal Effectiveness Elderly Exercise Fatty acid glycerol esters Femur Figs - dietary Forelimb Fracture Gene Expression Growth Growth Factor Hindlimb Hyperplasia Hypertrophy Knockout Mice Left Life Measures Mechanics Modeling Morphology Mus Muscle Muscle Fibers Muscular Dystrophies Non-Insulin-Dependent Diabetes Mellitus Numbers Obesity Osteocalcin Osteogenesis Osteoporosis Osteoporosis prevention Pathway interactions Physical activity Property Puberty Public Health Purpose Rate Reaction Research Risk Rodent Skeletal Muscle Skeletal system Tail Tail Suspension Testing Therapeutic Tissues Transforming Growth Factors Weight Wild Type Mouse bone bone cell bone health bone loss bone strength bone stress growth-differentiation factor 8 improved in vivo inhibitor/antagonist loss of function member myostatin novel postnatal prevent receptor size ulna wasting

项目摘要

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年龄相关的骨丢失;然而，通过增加生命早期的峰值骨量，可以将骨丢失的潜在灾难性影响降至最低。拟议的研究评估了肌生长抑制素缺乏小鼠的肌肉量、骨量和身体活动之间的关系，以便更好地了解在生长期间增加骨强度并在成年期最大化骨量的机制。肌生长抑制素（GDF-8）是骨骼肌生长的负调节剂，与正常小鼠相比，肌生长抑制素缺失小鼠显示肌纤维大小和数量加倍。最近的研究表明，肌生长抑制素抑制剂具有减缓和/或预防肥胖、2型糖尿病和肌肉消耗性疾病如肌营养不良和恶病质的发展的潜力。本申请中呈现的初步结果表明，肌生长抑制素功能的丧失也显著增加骨形成、骨密度和骨强度。因此，肌生长抑制素抑制剂可作为预防骨质疏松症的一种新的治疗方法。本研究的目的是验证肌生长抑制素缺乏通过增加肌肉质量来增加出生后发育过程中骨形成和骨强度的假设。该项目旨在确定肌肉生长抑制素缺乏对骨强度的积极影响的机制，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引起的肌肉质量增加是否会增加骨矿物质密度和骨强度，而不依赖于总体重和脂肪量。具体目标2将确定肌肉生长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检查肌肉生长抑制素缺乏和剧烈运动对骨量和强度的影响。这项研究将严格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，并将以这种方式为预防骨质疏松症的新疗法的开发做出重大贡献。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Myostatin (GDF-8) as a key factor linking muscle mass and bone structure.

DOI：
发表时间：
2010-03
期刊：
Journal of musculoskeletal & neuronal interactions
影响因子：
1.9
作者：
M. Elkasrawy;M. Hamrick
通讯作者：
M. Elkasrawy;M. Hamrick

Myostatin (GDF-8) deficiency increases fracture callus size, Sox-5 expression, and callus bone volume.

Myostatin（GDF-8）缺乏会增加断裂的愈伤组织大小，SOX-5表达和愈伤组织骨体积。

DOI：
10.1016/j.bone.2008.08.126
发表时间：
2009-01
期刊：
BONE
影响因子：
4.1
作者：
Kellum, Ethan;Starr, Harlan;Arounleut, Phonepasong;Immel, David;Fulzele, Sadanand;Wenger, Karl;Hamrick, Mark W.
通讯作者：
Hamrick, Mark W.

Recombinant myostatin (GDF-8) propeptide enhances the repair and regeneration of both muscle and bone in a model of deep penetrant musculoskeletal injury.

DOI：
10.1097/ta.0b013e3181c451f4
发表时间：
2010-09
期刊：
The Journal of trauma
影响因子：
0
作者：
Hamrick MW;Arounleut P;Kellum E;Cain M;Immel D;Liang LF
通讯作者：
Liang LF

Role of muscle-derived growth factors in bone formation.

DOI：
发表时间：
2010-03
期刊：
Journal of musculoskeletal & neuronal interactions
影响因子：
1.9
作者：
Mark W. Hamrick;Paul L. McNeil;Stella L. Patterson
通讯作者：
Mark W. Hamrick;Paul L. McNeil;Stella L. Patterson

Muscle-bone interactions in dystrophin-deficient and myostatin-deficient mice.

DOI：
10.1002/ar.a.20224
发表时间：
2005-09
期刊：
The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology
影响因子：
0
作者：
E. Montgomery;C. Pennington;C. Isales;M. Hamrick
通讯作者：
E. Montgomery;C. Pennington;C. Isales;M. Hamrick