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- Title
Exploring lipin1 as a promising therapeutic target for the treatment of Duchenne muscular dystrophy.
- Authors
Jama, Abdulrahman; Alshudukhi, Abdullah A.; Burke, Steve; Dong, Lixin; Kamau, John Karanja; Morris, Brooklyn; Alkhomsi, Ibrahim A.; Finck, Brian N.; Voss, Andrew Alvin; Ren, Hongmei
- 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.
- Publication
Journal of Translational Medicine, 2024, Vol 22, Issue 1, p1
- ISSN
1479-5876
- Publication type
Article
- DOI
10.1186/s12967-024-05494-z