Lipin1 Improves Dystrophic Pathology and Muscle Function
Abstract
In Duchenne muscular dystrophy (DMD), loss-of-function mutations in the gene encoding dystrophin trigger skeletal muscle sarcolemma instability, causing membrane damage during muscle contraction. This leads to progressive muscle weakness and dramatic muscle degeneration that results in early mortality in affected teenagers. Most of the patients die from respiratory failure and heart failure. A primary strategy in treating DMD is to reverse the instability of muscle membranes by increasing dystrophin levels. However, there is a major obstacle in that the dystrophin gene is too large to be packaged into current gene therapy vectors. Lipin1 is a phosphatidic acid (PA) phosphatase (PAP) that catalyzes the conversion of PA to diacylglycerol, a critical step in the synthesis of glycerophospholipids. We found that using our unique muscle-specific mdx:lipin transgenic (mdx:lipin1Tg) mice, increasing lipin1 expression levels attenuated inflammation infiltration, fibrosis, and necrosis in gastrocnemius of mdx mice. It also strengthened membrane integrity and resulted in markedly improved gastrocnemius muscle contractile and eccentric force. In addition, AAV-mediated lipin1 gene delivery also attenuated gastrocnemius pathology in mdx mice. These data suggest that lipin1 could be a potential therapeutic target for the treatment of DMD.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2023
- Accession Number
- AD1209665
Entities
People
- Hongmei Ren
Organizations
- Wright State University