Mutations in lamin A (LMNA) are responsible for a variety of human dystrophic and metabolic diseases. Here, we created a mouse model in which progerin, the lamin A mutant protein that causes Hutchinson–Gilford progeria syndrome (HGPS), can be inducibly overexpressed. Muscle‐specific overexpression of progerin was sufficient to induce muscular dystrophy and alter whole‐body energy expenditure, leading to premature death. Intriguingly, sarcolipin (Sln), an endoplasmic reticulum (ER)‐associated protein involved in heat production, is upregulated in progerin‐expressing and Lmna knockout (Lmna^−/−) skeletal muscle. The depletion of Sln accelerated the early death of Lmna^−/− mice. An examination at the molecular level revealed that progerin recruits Sln and Calnexin to the nuclear periphery. Furthermore, progerin‐expressing myoblasts presented enhanced store‐operated Ca²⁺ entry, as well as increased co‐localization of STIM1 and ORAI1. These findings suggest that progerin dysregulates calcium homeostasis through an interaction with a subset of ER‐associated proteins, resulting in thermogenic and metabolic abnormalities.

中文翻译：

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肌肉中的早搏蛋白通过受损的钙稳态而导致产热和代谢缺陷。

核纤层蛋白A（LMNA）突变是导致多种人类营养不良和代谢性疾病的原因。在这里，我们创建了一个小鼠模型，在其中可以诱导过表达早老蛋白，即导致Hutchinson-Gilford早衰综合征（HGPS）的核纤层蛋白A突变蛋白。早衰的肌肉特异性过表达足以诱发肌营养不良症并改变全身能量消耗，从而导致过早死亡。有趣的是，参与热量产生的内质网（ER）相关蛋白sarcolipin（Sln）在表达早老蛋白和Lmna基因敲除（Lmna ^-/-）骨骼肌中被上调。Sln的耗尽加速了Lmna的早期死亡^-/-老鼠。在分子水平上的检查表明，早老素将Sln和Calnexin募集到核外围。此外，表达早老蛋白的成肌细胞表现出增强的贮存操纵性Ca ²⁺进入，以及STIM1和ORAI1的共定位增加。这些发现表明，早老素通过与ER相关蛋白的子集相互作用而使钙稳态失调，从而导致生热和代谢异常。