Antagonistic functions of LMNA isoforms in energy expenditure and lifespan
Antagonistic functions of LMNA isoforms in energy expenditure and lifespan
复制标题
DOI：
10.1002/embr.201338126
复制
发表时间：
2014-05-01
期刊：
影响因子：
7.7
通讯作者：
Tazi, Jamal
中科院分区：
文献类型：
--
作者：
Lopez-Mejia, Isabel C.;de Toledo, Marion;Tazi, Jamal
LMNA前mrna的选择性RNA加工产生三种主要的蛋白质亚型，即层合蛋白A、progerin和lamin c。有利于progerin在层合蛋白A上表达的新生突变导致Hutchinson-Gilford早衰综合征（HGPS），为LMNA加工参与病感性衰老提供了支持。Lamin C的表达与Lamin A和progerin亚型的剪接相互排斥，并通过选择性聚腺苷化发生。在这里，我们研究了lamin C在衰老和代谢中的功能，使用仅表达该亚型的小鼠。有趣的是，这些老鼠寿命更长，能量代谢下降，体重增加，呼吸减少。相反，表达progerin的小鼠表现出能量代谢增加和脂肪营养不良。在hgps样小鼠的脂肪组织中发现线粒体生物发生增加，而只有纤层蛋白c的小鼠线粒体较少。与此一致的是，对HGPS和纯纤层蛋白c小鼠脂肪组织的转录组分析显示，能量消耗的关键调节因子，包括Pgc1a和strp5的表达呈负相关。我们的研究结果表明，LMNA编码功能不同的异构体，对哺乳动物的能量代谢和寿命有相反的影响。
Alternative RNA processing of LMNA pre-mRNA produces three main protein isoforms, that is, lamin A, progerin, and lamin C. De novo mutations that favor the expression of progerin over lamin A lead to Hutchinson-Gilford progeria syndrome (HGPS), providing support for the involvement of LMNA processing in pathological aging. Lamin C expression is mutually exclusive with the splicing of lamin A and progerin isoforms and occurs by alternative polyadenylation. Here, we investigate the function of lamin C in aging and metabolism using mice that express only this isoform. Intriguingly, these mice live longer, have decreased energy metabolism, increased weight gain, and reduced respiration. In contrast, progerin-expressing mice show increased energy metabolism and are lipodystrophic. Increased mitochondrial biogenesis is found in adipose tissue from HGPS-like mice, whereas lamin C-only mice have fewer mitochondria. Consistently, transcriptome analyses of adipose tissues from HGPS and lamin C-only mice reveal inversely correlated expression of key regulators of energy expenditure, including Pgc1a and Sfrp5. Our results demonstrate that LMNA encodes functionally distinct isoforms that have opposing effects on energy metabolism and lifespan in mammals.