PDF(Pubmed)
Abstract：
BACKGROUND: Duchenne muscular dystrophy (DMD) is a progressive and devastating muscle disease, resulting from the absence of dystrophin. This leads to cell membrane instability, susceptibility to contraction-induced muscle damage, subsequent muscle degeneration, and eventually disability and early death of patients. Currently, there is no cure for DMD. Our recent studies identified that lipin1 plays a critical role in maintaining myofiber stability and integrity. However, lipin1 gene expression levels are dramatically reduced in the skeletal muscles of DMD patients and mdx mice.
METHODS: To identify whether increased lipin1 expression could prevent dystrophic pathology, we employed unique muscle-specific mdx:lipin1 transgenic (mdx:lipin1Tg/0) mice in which lipin1 was restored in the dystrophic muscle of mdx mice, intramuscular gene delivery, as well as cell culture system.
RESULTS: We found that increased lipin1 expression suppressed muscle degeneration and inflammation, reduced fibrosis, strengthened membrane integrity, and resulted in improved muscle contractile and lengthening force, and muscle performance in mdx:lipin1Tg/0 compared to mdx mice. To confirm the role of lipin1 in dystrophic muscle, we then administered AAV1-lipin1 via intramuscular injection in mdx mice. Consistently, lipin1 restoration inhibited myofiber necroptosis and lessened muscle degeneration. Using a cell culture system, we further found that differentiated primary mdx myoblasts had elevated expression levels of necroptotic markers and medium creatine kinase (CK), which could be a result of sarcolemmal damage. Most importantly, increased lipin1 expression levels in differentiated myoblasts from mdx:lipin1Tg/0 mice substantially inhibited the elevation of necroptotic markers and medium CK levels.
CONCLUSIONS: Overall, our data suggest that lipin1 is a promising therapeutic target for the treatment of dystrophic muscles.
METHODS: To identify whether increased lipin1 expression could prevent dystrophic pathology, we employed unique muscle-specific mdx:lipin1 transgenic (mdx:lipin1Tg/0) mice in which lipin1 was restored in the dystrophic muscle of mdx mice, intramuscular gene delivery, as well as cell culture system.
RESULTS: We found that increased lipin1 expression suppressed muscle degeneration and inflammation, reduced fibrosis, strengthened membrane integrity, and resulted in improved muscle contractile and lengthening force, and muscle performance in mdx:lipin1Tg/0 compared to mdx mice. To confirm the role of lipin1 in dystrophic muscle, we then administered AAV1-lipin1 via intramuscular injection in mdx mice. Consistently, lipin1 restoration inhibited myofiber necroptosis and lessened muscle degeneration. Using a cell culture system, we further found that differentiated primary mdx myoblasts had elevated expression levels of necroptotic markers and medium creatine kinase (CK), which could be a result of sarcolemmal damage. Most importantly, increased lipin1 expression levels in differentiated myoblasts from mdx:lipin1Tg/0 mice substantially inhibited the elevation of necroptotic markers and medium CK levels.
CONCLUSIONS: Overall, our data suggest that lipin1 is a promising therapeutic target for the treatment of dystrophic muscles.
摘要：
背景：杜氏肌营养不良症（DMD）是一种进行性和破坏性的肌肉疾病，由于缺乏肌营养不良蛋白。这导致细胞膜不稳定，对收缩引起的肌肉损伤的敏感性，随后的肌肉变性，最终导致患者残疾和早逝。目前,没有治疗DMD的方法。我们最近的研究表明，lipin1在维持肌纤维的稳定性和完整性方面起着关键作用。然而,lipin1基因表达水平在DMD患者和mdx小鼠的骨骼肌中显著降低。
方法：为了确定增加的lipin1表达是否可以预防营养不良病理，我们采用了独特的肌肉特异性mdx：lipin1转基因（mdx：lipin1Tg/0）小鼠，其中lipin1在mdx小鼠的营养不良肌肉中恢复，肌内基因递送，以及细胞培养系统。
结果：我们发现增加的lipin1表达抑制了肌肉变性和炎症，减少纤维化，加强膜的完整性，并改善了肌肉收缩力和伸长力，与mdx小鼠相比，mdx:lipin1Tg/0的肌肉表现。为了证实lipin1在营养不良肌肉中的作用，然后，我们通过肌肉注射给mdx小鼠施用AAV1-lipin1。始终如一，lipin1修复抑制肌纤维坏死并减轻肌肉变性。使用细胞培养系统，我们进一步发现分化的原代mdx成肌细胞的坏死标志物和中等肌酸激酶（CK）的表达水平升高，这可能是肌膜损伤的结果.最重要的是,mdx：lipin1Tg/0小鼠分化成肌细胞中lipin1表达水平的增加基本上抑制了坏死标志物和中等CK水平的升高。
结论：总体而言，我们的数据表明,lipin1是治疗营养不良性肌肉的一个有前景的治疗靶点.
方法：为了确定增加的lipin1表达是否可以预防营养不良病理，我们采用了独特的肌肉特异性mdx：lipin1转基因（mdx：lipin1Tg/0）小鼠，其中lipin1在mdx小鼠的营养不良肌肉中恢复，肌内基因递送，以及细胞培养系统。
结果：我们发现增加的lipin1表达抑制了肌肉变性和炎症，减少纤维化，加强膜的完整性，并改善了肌肉收缩力和伸长力，与mdx小鼠相比，mdx:lipin1Tg/0的肌肉表现。为了证实lipin1在营养不良肌肉中的作用，然后，我们通过肌肉注射给mdx小鼠施用AAV1-lipin1。始终如一，lipin1修复抑制肌纤维坏死并减轻肌肉变性。使用细胞培养系统，我们进一步发现分化的原代mdx成肌细胞的坏死标志物和中等肌酸激酶（CK）的表达水平升高，这可能是肌膜损伤的结果.最重要的是,mdx：lipin1Tg/0小鼠分化成肌细胞中lipin1表达水平的增加基本上抑制了坏死标志物和中等CK水平的升高。
结论：总体而言，我们的数据表明,lipin1是治疗营养不良性肌肉的一个有前景的治疗靶点.
