Skeletal muscle is susceptible to mechanical injury, and defects in sarcolemma repair cause muscular dystrophy and other abnormalities in muscular function. Recent research on plasma membrane repair has revealed a role for the lysosomal enzyme acid sphingomyelinase (ASM). In mammalian cell lines, upon plasma membrane wounding extracellular release of ASM induces the formation of endosomes, which appear to internalize lesions and promote cell resealing. ASM deficiency causes a serious human disease, Niemann-Pick Disease Type A (NPDA), which is characterized by neurodegeneration and early death. Another form of the disease, NPDB, is associated with longer survival, variable amounts of residual active ASM and a more complex and poorly characterized pathophysiology. So far, NPDA/B disease symptoms have only been attributed to indirect effects of the intracellular accumulation of sphingomyelin, the ASM substrate - with no consideration of the potential role of defective membrane repair. The central hypothesis to be tested in this project is that genetic deficiency in ASM directly impairs the sarcolemma repair capacity and consequent function of skeletal muscle. To this end, we will utilize a mouse model for NPDA/B to pursue two aims: 1) to investigate whether ASM deficiency impairs the ability of skeletal muscle to recover from injury in vivo; and 2) to develop a robust, population-based assay to assess the resealing capacity of isolated primary muscle fibers after injury, and examine the role of ASM and membrane traffic pathways in this process. Recognition of defective sarcolemma repair as a component of the pathology of NPDA/B disease would have a strong impact in the clinical management of NPDB patients, and also identify much needed endpoint measures to assess the efficacy of therapeutics for both forms of the disease. Furthermore, insights from this study will have a strong and sustained impact on our understanding of the mechanism of muscle fiber sarcolemma resealing, a fundamental process that is still poorly understood.
Niemann-Pick Disease Types A and B (NPDA/B) is caused by genetic deficiency in the lysosomal enzyme acid sphingomyelinase (ASM). This research will investigate the role of ASM in the repair of muscle fibers after injury using a mouse model that mimics human NPDA/B disease. These studies will provide insights for the clinical management of patients and for assessing the efficacy of therapeutics for this serious condition.
