Voluntary wheel running mitigates disease in an Orai1 gain-of-function mouse model of tubular aggregate myopathy.
Voluntary wheel running mitigates disease in an Orai1 gain-of-function mouse model of tubular aggregate myopathy.
复制标题
自愿跑轮可减轻 Orai1 功能获得性小鼠管状聚集性肌病模型的疾病。
DOI：
10.1101/2023.09.29.559036
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Dirksen,RobertT
中科院分区：
文献类型：
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作者：
O'Connor,ThomasN;Zhao,Nan;Orciuoli,HaleyM;Brasile,Alice;Pietrangelo,Laura;He,Miao;Groom,Linda;Leigh,Jennifer;Mahamed,Zahra;Liang,Chen;Malik,Sundeep;Protasi,Feliciano;Dirksen,RobertT
管状聚集性肌病 (TAM) 是一种遗传性骨骼肌疾病，与进行性肌无力、痉挛和肌痛相关。管状聚集体 (TA) 是肌肉活检中高度有序且密集的 SR 直管的规则阵列； TA 的广泛存在是 TAM 患者中该疾病的一个关键组织病理学标志。 TAM 是由协调钙池操纵的 Ca2+ 进入 (SOCE) 的蛋白质的功能获得性突变引起的：肌浆网 (SR) 中的 STIM1 Ca2+ 传感器蛋白和表面膜中的 Ca2+ 渗透性 ORAI1 通道。我们之前已经证明，自愿轮跑（VWR）可以防止衰老小鼠 TA 的形成。在这里，我们基于 ORAI1 孔中的功能获得性突变，评估了耐力运动（以 VWR 的形式）在减轻 TAM 敲入小鼠模型（Orai1G100S/+ 或 GS 小鼠）的功能和结构改变方面的治疗潜力。 WT 和 GS 小鼠单独饲养六个月（2 至 8 个月大），使用自由旋转或锁定的低轮廓轮。六个月的 VWR 运动显着增加了 GS 小鼠的比目鱼肌峰值强直比力产生，使 FDB 纤维 Ca2+ 储存含量正常化，并显着降低了 GS 小鼠 EDL 肌肉中的 TA。六个月的 VWR 运动使线粒体蛋白的表达正常化，在久坐的 GS 小鼠中发现比目鱼肌中线粒体蛋白的表达发生了改变，并伴有蛋白质翻译和生物合成过程增加的特征。对久坐的 WT 和 GS 小鼠 EDL 肌肉进行的平行蛋白质组学分析揭示了参与超分子复合物形成的紧密通路网络的变化，这些变化在 VWR 六个月后也恢复正常。总之，持续的自愿耐力运动改善了慢肌功能，减少了快肌中 TA 的存在，并使 GS 小鼠的肌肉蛋白质组正常化，这与蛋白质稳态、线粒体结构/功能和超分子复合物形成的保护性适应一致。
Tubular aggregate myopathy (TAM) is an inherited skeletal muscle disease associated with progressive muscle weakness, cramps, and myalgia. Tubular aggregates (TAs) are regular arrays of highly ordered and densely packed SR straight-tubes in muscle biopsies; the extensive presence of TAs represent a key histopathological hallmark of this disease in TAM patients. TAM is caused by gain-of-function mutations in proteins that coordinate store-operated Ca2+ entry (SOCE): STIM1 Ca2+ sensor proteins in the sarcoplasmic reticulum (SR) and Ca2+-permeable ORAI1 channels in the surface membrane. We have previously shown that voluntary wheel running (VWR) prevents formation of TAs in aging mice. Here, we assessed the therapeutic potential of endurance exercise (in the form of VWR) in mitigating the functional and structural alterations in a knock-in mouse model of TAM (Orai1G100S/+ or GS mice) based on a gain-of-function mutation in the ORAI1 pore. WT and GS mice were singly-housed for six months (from two to eight months of age) with either free-spinning or locked low profile wheels. Six months of VWR exercise significantly increased soleus peak tetanic specific force production, normalized FDB fiber Ca2+ store content, and markedly reduced TAs in EDL muscle from GS mice. Six months of VWR exercise normalized the expression of mitochondrial proteins found to be altered in soleus muscle of sedentary GS mice in conjunction with a signature of increased protein translation and biosynthetic processes. Parallel proteomic analyses of EDL muscles from sedentary WT and GS mice revealed changes in a tight network of pathways involved in formation of supramolecular complexes, which were also normalized following six months of VWR. In summary, sustained voluntary endurance exercise improved slow twitch muscle function, reduced the presence of TAs in fast twitch muscle, and normalized the muscle proteome of GS mice consistent with protective adaptions in proteostasis, mitochondrial structure/function, and formation of supramolecular complexes.