Jackson Kathryn C, Gidlund Eva-Karin, Norrbom Jessica, Valencia Ana P, Thomson David M, Schuh Rosemary A, Neufer P Darrell, Spangenburg Espen E
Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD.
J Lipid Res. 2014 Apr;55(4):668-80. doi: 10.1194/jlr.M043851. Epub 2014 Feb 24.
Breast cancer type 1 (BRCA1) susceptibility protein is expressed across multiple tissues including skeletal muscle. The overall objective of this investigation was to define a functional role for BRCA1 in skeletal muscle using a translational approach. For the first time in both mice and humans, we identified the presence of multiple isoforms of BRCA1 in skeletal muscle. In response to an acute bout of exercise, we found increases in the interaction between the native forms of BRCA1 and the phosphorylated form of acetyl-CoA carboxylase. Decreasing BRCA1 content using a shRNA approach in cultured primary human myotubes resulted in decreased oxygen consumption by the mitochondria and increased reactive oxygen species production. The decreased BRCA1 content also resulted in increased storage of intracellular lipid and reduced insulin signaling. These results indicate that BRCA1 plays a critical role in the regulation of metabolic function in skeletal muscle. Collectively, these data reveal BRCA1 as a novel target to consider in our understanding of metabolic function and risk for development of metabolic-based diseases.
乳腺癌1型（BRCA1）易感蛋白在包括骨骼肌在内的多种组织中表达。本研究的总体目标是采用转化研究方法确定BRCA1在骨骼肌中的功能作用。在小鼠和人类中，我们首次在骨骼肌中鉴定出BRCA1的多种异构体。在一次急性运动后，我们发现BRCA1天然形式与乙酰辅酶A羧化酶磷酸化形式之间的相互作用增加。在培养的原代人肌管中使用shRNA方法降低BRCA1含量，导致线粒体耗氧量减少，活性氧生成增加。BRCA1含量降低还导致细胞内脂质储存增加和胰岛素信号传导减少。这些结果表明，BRCA1在骨骼肌代谢功能调节中起关键作用。总体而言，这些数据揭示BRCA1是我们理解代谢功能和代谢性疾病发生风险时需要考虑的一个新靶点。
