Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA.
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Cell Rep. 2018 Sep 11;24(11):2919-2931. doi: 10.1016/j.celrep.2018.08.036.
The major objective of this study was to understand the molecular basis of how sarcolipin uncoupling of SERCA regulates muscle oxidative metabolism. Using genetically engineered sarcolipin (SLN) mouse models and primary muscle cells, we demonstrate that SLN plays a crucial role in mitochondrial biogenesis and oxidative metabolism in muscle. Loss of SLN severely compromised muscle oxidative capacity without affecting fiber-type composition. Mice overexpressing SLN in fast-twitch glycolytic muscle reprogrammed mitochondrial phenotype, increasing fat utilization and protecting against high-fat diet-induced lipotoxicity. We show that SLN affects cytosolic Ca transients and activates the Ca/calmodulin-dependent protein kinase II (CamKII) and PGC1α axis to increase mitochondrial biogenesis and oxidative metabolism. These studies provide a fundamental framework for understanding the role of sarcoplasmic reticulum (SR)-Ca cycling as an important factor in mitochondrial health and muscle metabolism. We propose that SLN can be targeted to enhance energy expenditure in muscle and prevent metabolic disease.
本研究的主要目的是了解肌浆网蛋白解偶联 SERCA 调节肌肉氧化代谢的分子基础。我们利用基因工程肌浆网蛋白（SLN）小鼠模型和原代肌肉细胞，证明 SLN 在肌肉中线粒体生物发生和氧化代谢中起着关键作用。SLN 的缺失严重损害了肌肉的氧化能力，而不影响纤维类型组成。在快速抽搐糖酵解肌肉中过表达 SLN 的小鼠重新编程了线粒体表型，增加了脂肪的利用，并防止了高脂肪饮食诱导的脂毒性。我们表明，SLN 影响细胞质 Ca 瞬变，并激活 Ca/钙调蛋白依赖性蛋白激酶 II（CamKII）和 PGC1α 轴，以增加线粒体生物发生和氧化代谢。这些研究为理解肌浆网（SR）-Ca 循环作为线粒体健康和肌肉代谢的重要因素的作用提供了一个基本框架。我们提出，SLN 可以作为靶点，以增加肌肉的能量消耗并预防代谢疾病。
