BRCA1 is necessary for optimal skeletal muscle function

 描述(申请人提供)：BRCA1基因因其在癌症易感性中的作用而广为人知，部分原因是它对错义突变的高度敏感性。该基因编码一种大蛋白，调节细胞内的多种功能；然而，这些功能中的大多数只在乳腺组织中被描述过。通常被低估的是，BRCA1的表达模式超出了女性生殖组织的范围。例如，我们已经发现BRCA1在骨骼肌中表达，但目前BRCA1在骨骼肌中还没有明确的作用。在这里，我们的目标是使用一种综合的方法来描述BRCA1在骨骼肌中的调控机制。我们的初步数据表明，通过使用可诱导的基因消融方法，骨骼肌中BRCA1功能的丧失会导致肌肉虚弱、后凸、运动耐受性和线粒体功能降低。第一个具体目标将寻求确定BRCA1的表达是否对骨骼肌功能至关重要。第二个特定目标将寻求确定BRCA1的表达是否对骨骼肌的线粒体功能是必要的。第三个具体目标将寻求确定BRCA1基因已知的错义突变是否会导致骨骼肌功能下降。在这项提案中，我们将使用最先进的生理和分子 作为阐明BRCA1在骨骼肌中调节的生理机制的一种手段。由于BRCA1存在大量的遗传变异，了解BRCA1在骨骼肌中调节的机制有可能有助于预防骨骼肌减少和身体残疾等疾病。

 DESCRIPTION (provided by applicant): The BRCA1 gene is well known for its role in cancer susceptibility in part due to its high susceptibility to missense mutations. The gene encodes a large protein that regulates multiple functions within the cell; however the majority of these functions have only been described in mammary tissue. What is generally under-appreciated is the fact that BRCA1 expression patterns extend beyond female reproductive tissue. For example, we have found that BRCA1 is expressed in skeletal muscle, but at this time BRCA1 has no defined role in skeletal muscle. Here our goal is to use an integrative approach to delineate the mechanisms BRCA1 regulate in skeletal muscle. Our preliminary data demonstrate that loss of BRCA1 function in skeletal muscle through use of an inducible genetic ablation approach results in muscle weakness, kyphosis, exercise intolerance, and reduced mitochondrial function. The first specific aim will seek to determine if BRCA1 expression is critical for skeletal muscle function. The second specific aim will seek to determine if BRCA1 expression is necessary for mitochondrial function in skeletal muscle. The third specific aim will seek to determine if known missense mutations in the BRCA1 gene contribute to reduced skeletal muscle function. In this proposal we will use state-of-the-art physiological and molecular approaches as a means to elucidate the physiological mechanisms BRCA1 regulates in skeletal muscle. Since BRCA1 presents with a significant amount of genetic variation, understanding the mechanisms that BRCA1 regulates in skeletal muscle have the potential to aid in the prevention of conditions such as sarcopenia, physical disability, etc.