Lipin1 Improves Dystrophic Pathology and Muscle Function
Abstract
Duchenne muscular dystrophy (DMD) is a severe disease that affects approximately 1 in 3,500 male births worldwide. In DMD, loss-of-function mutations in the gene encoding dystrophin trigger the instability of the plasma membrane in skeletal muscle, leading to muscle degeneration, progressive muscle weakness, and early mortality in affected teenagers. There is currently no cure for DMD. The gene therapy to restore dystrophin expression faces significant challenges due to the enormous size of the gene. Our recent findings suggest a critical role for lipin1 in maintaining muscle fiber stability by correcting altered skeletal muscle membrane composition and upregulating structural proteins. However, lipin1 expression levels are dramatically reduced in dystrophic muscles of both DMD patients and in the mdx mouse model of DMD. Strikingly, we found that increasing lipin1 levels via intramuscular gene delivery in mdx mice lessened muscle fiber degeneration, improved muscle mass, strengthened membrane integrity, and led to substantial gains in strength. In this project, we hypothesize that lipin1 can serve as a novel therapeutic agent to improve the dystrophic muscle membrane stability and inhibit muscle degeneration. We will utilize transgenic mice (in Aim 1) and systemic administration (in Aim 2) to examine the effectiveness of lipin1 gene delivery in ameliorating dystrophic disease and improving muscle function in mdx mice. In the short term, completion of this research will determine whether lipin1 upregulation can serve as a therapy to re-establish membrane stability and restore muscle function in mdx mice. In the long-term, these studies will aid in the development of lipin1 being used in combined DMD therapies (along with exon-skipping and micro-dystrophin gene therapies) as a means of combating necrosis and fibrosis associated with dystrophin-deficiency. Overall, discovering a therapeutic role for lipin1 upregulation is expected to have a sustained and transformative impact on the treatment of DMD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110679
Entities
People
- Hongmei Ren
Organizations
- United States Army
- Wright State University