Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou 510080, China.
Oxid Med Cell Longev. 2023 Jan 18;2023:8408574. doi: 10.1155/2023/8408574. eCollection 2023.
Chronic muscle inflammation exacerbates the pathogenesis of Duchenne muscular dystrophy (DMD), which is characterized by progressive muscle degeneration and weakness. NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome plays a key role in the inflammatory process, and its abnormal activation leads to a variety of inflammatory or immune diseases. TRIM72 (MG53) is a protective myokine for tissue repair and regeneration. However, little is known about the potential impact of TRIM72 in the crosstalk between mitophagy and inflammatory process of DMD. Here, 10-week-old male mdx mice were injected intramuscularly with adeno-associated virus (AAV-TRIM72) to overexpress TRIM72 protein for 6 weeks. Then, skeletal muscle samples were collected, and relevant parameters were measured by histopathological analysis and molecular biology techniques. C2C12 cell line was transfected with lentivirus (LV-TRIM72) to overexpress or siRNA (si-TRIM72) to suppress the TRIM72 expression for the following experiment. Our data firstly showed that the TRIM72 expression was decreased in skeletal muscles of mdx mice. Then, we observed the increased NLRP3 inflammasome and impaired mitophagy in mdx mice compared with wild type mice. In mdx mice, administration of AAV-TRIM72 alleviated the accumulation of NLRP3 inflammasome and the consequent IL-18 and IL1 maturation by inducing autophagy, while this protective effect was reversed by chloroquine. Mitochondrial reactive oxygen species (mtROS), as a recognized activator for NLRP3 inflammasome, was attenuated by TRIM72 through the induction of mitophagy in C2C12 cells. Additionally, we proposed that the TRIM72 overexpression might promote mitophagy through both the early stage by PI3K-AKT pathway and the late stage by autolysosome fusion. In conclusion, the current study suggests that TRIM72 prevents DMD inflammation via decreasing NLRP3 inflammasomes and enhancing mitophagy. Collectively, our study provides insight into TRIM72 as a promising target for therapeutic intervention for DMD.
慢性肌肉炎症会加剧杜氏肌营养不良症（DMD）的发病机制，其特征是进行性肌肉退化和无力。NLRP3（核苷酸结合域和富含亮氨酸重复吡喃结构域包含 3）炎性小体在炎症过程中发挥关键作用，其异常激活导致多种炎症或免疫性疾病。TRIM72（MG53）是组织修复和再生的保护性肌因子。然而，TRIM72 在 DMD 中自噬和炎症过程的串扰中的潜在影响知之甚少。在这里，10 周龄雄性 mdx 小鼠肌肉内注射腺相关病毒（AAV-TRIM72）以过表达 TRIM72 蛋白 6 周。然后，收集骨骼肌样本，并通过组织病理学分析和分子生物学技术测量相关参数。C2C12 细胞系用慢病毒（LV-TRIM72）转染以过表达或 siRNA（si-TRIM72）以抑制 TRIM72 的表达进行以下实验。我们的数据首先表明，TRIM72 在 mdx 小鼠的骨骼肌中表达降低。然后，我们观察到与野生型小鼠相比，mdx 小鼠中 NLRP3 炎性小体增加和自噬受损。在 mdx 小鼠中，AAV-TRIM72 的给药通过诱导自噬缓解 NLRP3 炎性小体的积累和随后的 IL-18 和 IL1 成熟，而这种保护作用被氯喹逆转。线粒体活性氧（mtROS）作为 NLRP3 炎性小体的公认激活剂，通过 C2C12 细胞中自噬的诱导被 TRIM72 减弱。此外，我们提出，TRIM72 过表达可能通过 PI3K-AKT 通路的早期阶段和自噬体融合的晚期阶段来促进自噬。总之，本研究表明，TRIM72 通过降低 NLRP3 炎性小体和增强自噬来预防 DMD 炎症。总的来说，我们的研究表明 TRIM72 是治疗 DMD 的有希望的靶点。
