Brown Alexandra, Morris Brooklyn, Kamau John Karanja, Rakoczy Ryan J, Finck Brian N, Wyatt Christopher N, Ren Hongmei
Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH, United States.
Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH, United States.
Front Physiol. 2024 Nov 12;15:1477976. doi: 10.3389/fphys.2024.1477976. eCollection 2024.
In Duchenne muscular dystrophy (DMD), diaphragm muscle dysfunction results in respiratory insufficiency which is a leading cause of death in patients. Mutations to the dystrophin gene result in myocyte membrane instability, contributing to the structural deterioration of the diaphragm muscle tissues. With previous works suggesting the importance of lipin1 for maintaining skeletal muscle membrane integrity, we explored the roles of lipin1 in the dystrophic diaphragm. We found that the protein expression levels of lipin1 were reduced by 60% in the dystrophic diaphragm. While further knockdown of lipin1 in the dystrophic diaphragm leads to increased necroptosis, restoration of lipin1 in the dystrophic diaphragm results in reduced inflammation and fibrosis, decreased myofiber death, and improved respiratory function. Our results demonstrated that lipin1 restoration improved respiratory function by enhancing membrane integrity and suggested that lipin1 could be a potential therapeutic target for preventing respiratory insufficiency and respiratory failure in DMD. Continued investigation is required to better understand the mechanisms behind these findings, and to determine the role of lipin1 in maintaining muscle membrane stability.
在杜兴氏肌营养不良症（DMD）中，膈肌功能障碍会导致呼吸功能不全，这是患者死亡的主要原因。肌营养不良蛋白基因突变会导致肌细胞膜不稳定，促使膈肌组织发生结构恶化。鉴于先前的研究表明脂联素1对维持骨骼肌膜完整性具有重要作用，我们探究了脂联素1在营养不良性膈肌中的作用。我们发现，在营养不良性膈肌中，脂联素1的蛋白表达水平降低了60%。在营养不良性膈肌中进一步敲低脂联素1会导致坏死性凋亡增加，而在营养不良性膈肌中恢复脂联素1则会减少炎症和纤维化，降低肌纤维死亡，并改善呼吸功能。我们的结果表明，恢复脂联素1可通过增强膜完整性来改善呼吸功能，并提示脂联素1可能是预防DMD患者呼吸功能不全和呼吸衰竭的潜在治疗靶点。需要持续进行研究，以更好地理解这些发现背后的机制，并确定脂联素1在维持肌膜稳定性中的作用。
