Poster abstracts
Poster number 104 submitted by Chetan Gomatam
Dissecting the role of mineralocorticoid receptor signaling on fibrosis in dystrophic skeletal muscle
Chetan K. Gomatam (Molecular, Cellular, and Developmental Biology Program, The Ohio State University), Zachary M. Howard (Department of Physiology and Cell Biology, College of Medicine, The Ohio State University), Pratham Ingale (Department of Physiology and Cell Biology, College of Medicine, The Ohio State University), Jeovanna Lowe (Department of Physiology and Cell Biology, College of Medicine, The Ohio State University), Shyam S. Bansal (Department of Physiology and Cell Biology and Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University), Jill A. Rafael-Fortney (Department of Physiology and Cell Biology, College of Medicine, The Ohio State University)
Abstract:
Duchenne muscular dystrophy (DMD) is a fatal X-linked disease resulting from loss of dystrophin that causes chronic striated muscle injury and degeneration, leading to loss of life in the mid-twenties. Muscle degeneration and regeneration cycles lead to overactive fibroblasts. Fibroblasts are crucial for tissue maintenance and wound healing because they stabilize injuries by depositing matrix (ECM). However, overactivation in DMD leads to excess ECM deposition and pathogenic fibrosis. We have shown efficacy of mineralocorticoid receptor (MR) antagonists (MRAs), drugs used to treat heart failure, on dystrophic skeletal muscle and heart. We have shown MRAs to have benefits on all steps in DMD pathogenesis. Although MR signaling has been demonstrated on kidney and heart fibroblasts, its role on DMD skeletal muscle fibroblasts is unknown.
Using fluorescence activated cell sorting and gene expression analyses in MRA-treated dystrophic mdx mice and in mdx mice with cell-specific MR conditional knockouts (MRcko), we are exploring fibroblast responses to MR signaling in skeletal muscle and the role of fibroblast-specific MR. Our gene expression microarray of whole muscles from MRcko-mdx mice and RNA-seq of mdx myeloid immune cells suggest that crosstalk between immune cells, fibroblasts, and myofibers in DMD modulates fibrosis. Many genes involved in ECM regulation and fibrosis development were significantly upregulated in myeloid cell MRcko-mdx mice vs. myofiber MRcko-mdx mice, such as fibronectin and tenascin. We have also begun querying the effects of aldosterone, the canonical MR ligand, on fibroblasts in vitro. Preliminary data suggest that aldosterone may play a role in activating skeletal muscle fibroblasts. Further in vivo, in vitro, and gene expression assays will be used to clarify indirect and direct effects of MR signaling on fibroblast proliferation, migration and activity, and if MR signaling differs between muscle groups and between chronic and acute injury.
References:
Buechler MB et al. Cross-tissue organization of the fibroblast lineage. Nature 593: 575-579, 2021.
Keywords: Muscular dystrophy, Fibrosis, Mineralocorticoid receptor