Department of Molecular Biology, University of Cantabria, 39011 Santander, Spain.
Health Research Institute Valdecilla (IDIVAL), 39011 Santander, Spain.
Int J Mol Sci. 2024 Nov 19;25(22):12415. doi: 10.3390/ijms252212415.
Spinal muscular atrophy (SMA) is caused by a deficiency of the ubiquitously expressed survival motor neuron (SMN) protein. The main pathological hallmark of SMA is the degeneration of lower motor neurons (MNs) with subsequent denervation and atrophy of skeletal muscle. However, increasing evidence indicates that low SMN levels not only are detrimental to the central nervous system (CNS) but also directly affect other peripheral tissues and organs, including skeletal muscle. To better understand the potential primary impact of SMN deficiency in muscle, we explored the cellular, ultrastructural, and molecular basis of SMA myopathy in the SMNΔ7 mouse model of severe SMA at an early postnatal period (P0-7) prior to muscle denervation and MN loss (preneurodegenerative [PND] stage). This period contrasts with the neurodegenerative (ND) stage (P8-14), in which MN loss and muscle atrophy occur. At the PND stage, we found that SMN∆7 mice displayed early signs of motor dysfunction with overt myofiber alterations in the absence of atrophy. We provide essential new ultrastructural data on focal and segmental lesions in the myofibrillar contractile apparatus. These lesions were observed in association with specific myonuclear domains and included abnormal accumulations of actin-thin myofilaments, sarcomere disruption, and the formation of minisarcomeres. The sarcoplasmic reticulum and triads also exhibited ultrastructural alterations, suggesting decoupling during the excitation-contraction process. Finally, changes in intermyofibrillar mitochondrial organization and dynamics, indicative of mitochondrial biogenesis overactivation, were also found. Overall, our results demonstrated that SMN deficiency induces early and MN loss-independent alterations in myofibers that essentially contribute to SMA myopathy. This strongly supports the growing body of evidence indicating the existence of intrinsic alterations in the skeletal muscle in SMA and further reinforces the relevance of this peripheral tissue as a key therapeutic target for the disease.
脊髓性肌萎缩症（SMA）是由广泛表达的生存运动神经元（SMN）蛋白缺乏引起的。SMA 的主要病理学特征是运动神经元（MNs）的退化，随后出现神经支配丧失和骨骼肌萎缩。然而，越来越多的证据表明，低 SMN 水平不仅对中枢神经系统（CNS）有害，而且直接影响其他外周组织和器官，包括骨骼肌。为了更好地理解 SMN 缺乏对肌肉的潜在原发性影响，我们在严重 SMA 的 SMNΔ7 小鼠模型中探索了 SMA 肌病的细胞、超微结构和分子基础，该模型在肌肉失神经支配和 MN 丧失（神经前退行性 [PND] 阶段）之前的出生后早期（P0-7）。这一时期与神经退行性（ND）阶段（P8-14）形成对比，在该阶段 MN 丧失和肌肉萎缩发生。在 PND 阶段，我们发现 SMN∆7 小鼠表现出运动功能障碍的早期迹象，尽管没有萎缩，但肌纤维发生明显改变。我们提供了关于肌原纤维收缩装置局灶性和节段性病变的重要新超微结构数据。这些病变与特定的肌核域相关联，包括肌动蛋白-薄肌丝的异常积聚、肌节破坏和小肌节的形成。肌浆网和三联体也表现出超微结构改变，表明在兴奋-收缩过程中发生解耦。最后，还发现了肌纤维间线粒体组织和动力学的变化，表明线粒体生物发生过度激活。总之，我们的结果表明，SMN 缺乏会导致肌纤维发生早期且与 MN 丧失无关的改变，这些改变是 SMA 肌病的主要原因。这强烈支持越来越多的证据表明 SMA 中存在骨骼肌的内在改变，并进一步强化了这种外周组织作为疾病关键治疗靶点的相关性。
