Lipid composition and organization helps plasma membrane repair and offers novel therapeutic target to treat degenerative muscle disease

Abstract

The plasma membrane of all cells is routinely injured, with considerable investigative effort focused on understanding how proteins help repair this injury. Despite being the most abundant component of the plasma membrane, the role of lipids in repairing injured mammalian cells has remained unexplored. Through systematic live cell imaging we have examined the involvement of lipids in plasma membrane repair following injury. This shows that change in composition and localization of plasma membrane lipids is crucial for repair. Specifically, we find that cell injury results in a rapid change in local cholesterol and sphingomyelin content, and failure of which increases membrane fluidity and compromises membrane repair. Plasma membrane injury also alters the local composition of phospholipids including PIP2 and diacylglycerol (DAG), which is required for the repair of the injured plasma membrane. Failure of these lipid changes in muscle fibers injured by mechanical or other activity, results in myofiber death and Limb Girdle Muscular Dystrophy (LGMD2B). To target this deficit we developed a gene therapy approach to exogenously modify the plasma membrane lipid composition in a mouse model of LGMD2B. This approach improved the repair of the dystrophic muscle, attenuated myofiber death and improved muscle strength and histopathology. These findings provide direct evidence of the diverse roles of lipids in not only maintaining the integrity of the plasma membrane, but also in re‐establishing its integrity following injury. Here, we establish the clinical relevance of the structural and signaling roles of lipids in cell repair, and identify therapeutic approaches that address these deficits in muscle diseases.Support or Funding InformationThis work is supported by R01AR055686 from NIH/NIAMS.