Project description:Molecular impacts in the pathogenesis of GNE myopathy in model mouse muscles were well described through expression profiling of a total of 34000 genes
Project description:Molecular impacts of 1% N-acetylcysteine treatment on GNE myopathy model mice were well described through expression profiling of a total of 34000 genes
Project description:Molecular impacts of 0.1% N-acetylcysteine treatment on GNE myopathy model mice were well described through expression profiling of a total of 34000 genes
Project description:Loss-of-function mutations in MEGF10 lead to a rare and understudied neuromuscular disorder known as MEGF10-related myopathy. There are no treatments for the progressive respiratory distress, motor impairment, and structural abnormalities in muscles caused by the loss of MEGF10 function. In this study, we asked whether mice lacking MEGF10 (MEGF10 KO) could be used as a model to generate preclinical insights to treat MEGF10-related myopathy. We deployed cellular and molecular assays to examine juvenile, young adult, and middle-aged Megf10 constitutive knockout (KO) mice. We found fewer muscle fibers in developing and adult Megf10 KO mice, supporting published studies that MEGF10 regulates myogenesis by affecting satellite cell differentiation. Interestingly, muscle fibers do not exhibit morphological hallmarks of atrophy in either young adult or middle-aged Megf10 KO mice. We next examined the neuromuscular junction (NMJ), in which MEGF10 has been shown to concentrate postnatally, using light and electron microscopy. We found early and progressive degenerative features at the NMJs of Megf10 KO mice. These include increased postsynaptic fragmentation, axon terminals failing to completely appose the postsynaptic region and perisynaptic Schwann cells intruding into the NMJ synaptic cleft. These findings strongly suggest that the NMJ is a site of postnatal pathology in MEGF10-related myopathy. We next sought to identify molecular mechanisms altered in muscles lacking Megf10 using RNA-seq. We discovered genes and pathways associated with myogenesis, skeletal muscle health, and NMJ stability dysregulated in Megf10 KO mice compared to wild-type mice. Altogether, these data support using MEGF10 KO mice to discover and test potential treatments for MEGF10-related myopathy.
Project description:We performed a genome-wide association study in pooled DNA samples from patients with severe statin myopathy and persistent symptoms post-therapy versus pooled DNAs from an age-adjusted statin-tolerant group. Affymetrix 100K SNP arrays were used according to the manufacturers instructions with two pools of 19 and 20 statin myopathy patients and two pools of 20 statin-tolerant controls.
Project description:We performed a genome-wide association study in pooled DNA samples from patients with severe statin myopathy and persistent symptoms post-therapy versus pooled DNAs from an age-adjusted statin-tolerant group.
Project description:The aim of this study was to investigate the molecular mechanisms implicated in this mouse model of nemaline myopathy, and to further compare the molecular disease response in different skeletal muscles. For this purpose, snap frozen skeletla muscle specimens from wild type and transgenic for alpha tropomyosin slow mice were studied. Five different muscle types were used (diaphragm, plantaris, extensor digitorum longus, tibialis anterior, gastrocnemus). Mice were sacrificed between 7 and 10 months. RNA pools from 3-5 animals were created and each pool was hybridized to a U74Av2 Affymetrix GeneChip. Datasets from 36 GeneChips were included in this study. Keywords: disease mouse model analysis