Journal of Translational Medicine (Jul 2024)

Exploring lipin1 as a promising therapeutic target for the treatment of Duchenne muscular dystrophy

  • Abdulrahman Jama,
  • Abdullah A. Alshudukhi,
  • Steve Burke,
  • Lixin Dong,
  • John Karanja Kamau,
  • Brooklyn Morris,
  • Ibrahim A. Alkhomsi,
  • Brian N. Finck,
  • Andrew Alvin Voss,
  • Hongmei Ren

DOI
https://doi.org/10.1186/s12967-024-05494-z
Journal volume & issue
Vol. 22, no. 1
pp. 1 – 18

Abstract

Read online

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.

Keywords