Poster abstracts
Poster number 94 submitted by Chetan Gomatam
The fibroblast response to direct mineralocorticoid receptor signaling in dystrophic skeletal muscle
Chetan K. Gomatam (Molecular, Cellular, and Developmental Biology Program, The Ohio State University), Swathy Krishna (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), Christoph Lepper (Department of Physiology and Cell Biology, College of Medicine, The Ohio State University), Jill A. Rafael-Fortney (Department of Physiology and Cell Biology and Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University)
Abstract:
Duchenne muscular dystrophy is a fatal X-linked disease resulting from the loss of dystrophin that causes chronic striated muscle injury and gradual muscle degeneration, leading to eventual loss of life in the mid-twenties. Asynchronous de- and regeneration cycles result in persistent injury, which leads to chronic inflammation and fibrosis. Fibroblasts are essential for temporarily stabilizing injury sites and maintaining organ structure by depositing extracellular matrix (ECM) components. However, overactivated fibroblasts in dystrophic muscles deposit excess ECM that replaces muscle tissue and causes pathogenic fibrosis. We have identified mineralocorticoid receptor (MR) antagonists as a potential therapy to alleviate fibrosis and inflammation in muscular dystrophies, and we have shown that in vivo MR signaling from other cell types in muscle indirectly affects fibroblasts. However, direct effects of MR signaling on fibroblasts are not known.
Via RNA sequencing of naïve wildtype fibroblasts treated in vitro with the MR agonist aldosterone, we show that MR signaling directly alters gene expression programs in fibroblasts. Notably, periostin and cilp were the only myofibroblast genes common to both in vivo myeloid MR knockout and direct fibroblast MR stimulation. We are currently exploring fibroblast responses to direct MR signaling and the role of fibroblast-specific MR using in vitro assays testing key aspects of fibroblast function, including proliferation, migration, and ECM production. Cultured muscle fibroblasts from neonatal dystrophin-deficient mdx and wildtype mice are more proliferative than their adult counterparts. Aldosterone treatment represses proliferation and migration in cultured muscle fibroblasts isolated from adult mdx mice. Further in vitro assays and genetic approaches will be used to decipher whether MR signaling has direct effects on fibroblast activation and ECM production.
Keywords: Muscular dystrophy, Fibrosis, Mineralocorticoid receptor