Poster abstracts
Poster number 87 submitted by Chetan Gomatam
Mineralocorticoid receptor signaling in the microenvironment of dystrophic skeletal muscles
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 disease resulting from the absence of dystrophin that causes chronic striated muscle injury and gradual muscle degeneration, leading to destruction of muscle and loss of life in the mid-twenties. Chronic injury occurs due to cycles of muscle degeneration and regeneration, which leads to overactivation of fibroblasts. Fibroblasts are normally essential for organ structure and wound healing via their ability to temporarily stabilize injury sites by depositing extracellular matrix (ECM) components. However, fibroblasts cause pathogenic fibrosis when overactivated due to excess ECM deposition that replaces muscle tissue in DMD. We have identified mineralocorticoid receptor (MR) antagonists as a potential therapy to alleviate fibrosis and inflammation in muscular dystrophies. However, effects of MR signaling on fibroblasts and the role of MR in fibroblasts are not known.
Using fluorescence activated cell sorting and gene expression analyses in MR antagonist-treated dystrophic mdx mice and in mdx mice with cell-specific MR conditional knockouts (MRcko), we have begun exploring the fibroblast response to MR signaling in dystrophic muscle and the role of fibroblast-specific MR. Our recent gene expression microarray of MRcko-mdx mice and RNA sequencing of mdx myeloid immune cells from dystrophic muscles suggest that there is significant crosstalk between immune cells, fibroblasts, and myofibers in DMD. Several genes involved in regulation of ECM and development of fibrosis were significantly upregulated in myeloid cell-specific MRcko-mdx mice versus myofiber-specific MRcko-mdx mice, including fibronectin, tenascin, and lysyl oxidase. In vivo and in vitro assays combined with genetic approaches will be used to decipher whether MR signaling in the muscle microenvironment has indirect and direct effects on fibroblast activation and function, and whether MR signaling differs between muscle groups and between chronic and acute injury.
Keywords: Muscular dystrophy, Fibrosis, Mineralocorticoid receptor