Fujita Kyohei, Desmond Patrick, Blondelle Jordan, Soták Matúš, Rajan Meenu Rohini, Clark Madison, Estève Éric, Chan Yunghang, Gu Yusu, Actis Dato Virginia, Marrocco Valeria, Dalton Nancy D, Ghassemian Majid, Do Aryanne, Klos Matthew, Peterson Kirk L, Sheikh Farah, Cho Yoshitake, Börgeson Emma, Lange Stephan
Division of Cardiovascular Medicine, School of Medicine (K.F., P.D., J.B., M.C., E.E., Y. Chan, Y.G., V.A.D., V.M., N.D.D., A.D., M.K., K.L.P., F.S., Y. Cho, S.L.), University of California San Diego, La Jolla.
Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Japan (K.F.).
Circ Heart Fail. 2025 Apr;18(4):e011867. doi: 10.1161/CIRCHEARTFAILURE.124.011867. Epub 2025 Mar 11.
Muscle proteins of the obscurin protein family play important roles in sarcomere organization and sarcoplasmic reticulum and T-tubule architecture and function. However, their precise molecular functions and redundancies between protein family members as well as their involvement in cardiac diseases remain to be fully understood.
To investigate the functional roles of Obsc (obscurin) and its close homolog Obsl1 (obscurin-like 1) in the heart, we generated and analyzed knockout mice for , , as well as double knockouts.
We show that double-knockout mice are viable but show postnatal deficits in cardiac muscle sarcoplasmic reticulum and mitochondrial architecture and function at the microscopic, biochemical, and cellular levels. Altered sarcoplasmic reticulum structure resulted in perturbed calcium cycling, whereas mitochondrial ultrastructure deficits were linked to decreased levels of Chchd3 (coiled-coil-helix-coiled-coil-helix domain containing 3), a Micos (mitochondrial contact site and cristae organizing system) complex protein. Hearts of double-knockout mice also show altered levels of Atg4 proteins, novel Obsl1 interactors, resulting in abnormal mitophagy, and increased unfolded protein response. At the physiological level, loss of obscurin and Obsl1 resulted in a profound delay of cardiac relaxation, associated with metabolic signs of heart failure.
Taken together, our data suggest that Obsc and Obsl1 play crucial roles in cardiac sarcoplasmic reticulum structure, calcium cycling, mitochondrial function, turnover, and metabolism.
obscurin蛋白家族的肌肉蛋白在肌节组织、肌浆网以及T小管的结构和功能中发挥重要作用。然而，它们精确的分子功能、蛋白家族成员之间的冗余性以及它们在心脏疾病中的作用仍有待充分了解。
为了研究Obsc（ obscurin）及其紧密同源物Obsl1（ obscurin样蛋白1）在心脏中的功能作用，我们构建并分析了Obsc、Obsl1基因敲除小鼠以及Obsc和Obsl1双基因敲除小鼠。
我们发现双基因敲除小鼠能够存活，但在出生后，其心肌肌浆网、线粒体的结构和功能在微观、生化和细胞水平上出现缺陷。肌浆网结构改变导致钙循环紊乱，而线粒体超微结构缺陷与Chchd3（含卷曲螺旋-螺旋-卷曲螺旋结构域3）水平降低有关，Chchd3是一种线粒体接触位点和嵴组织系统（Micos）复合物蛋白。双基因敲除小鼠的心脏还显示Atg4蛋白水平改变，Atg4蛋白是新型的Obsl1相互作用蛋白，可导致异常的线粒体自噬，并增加未折叠蛋白反应。在生理水平上，obscurin和Obsl1的缺失导致心脏舒张严重延迟，并伴有心力衰竭的代谢迹象。
综上所述，我们的数据表明Obsc和Obsl1在心脏肌浆网结构、钙循环、线粒体功能、更新和代谢中起关键作用。
