Cell-type specific effects of mineralocorticoid receptor gene expression suggest intercellular communication regulating fibrosis in skeletal muscle disease

• DOI: 10.3389/fphys.2024.1322729
• Publication Date: 2024-04-26T05:02:41Z
• Authors: Chetan K. Gomatam; Pratham Ingale; Gabriel Rodriguez; Sarah Munger; Rachel Pomeranets; Swathy Krishna; Jeovanna Lowe; Zachary M. Howard; Jill A. Rafael-Fo...
• Keywords: Mineralocorticoid; Cell type

Introduction: Duchenne muscular dystrophy (DMD) is a fatal striated muscle degenerative disease. DMD caused by loss of dystrophin protein, which results in sarcolemmal instability and cycles myofiber degeneration regeneration. Pathology exacerbated overactivation infiltrating immune cells fibroblasts, leads to chronic inflammation fibrosis. Mineralocorticoid receptors (MR), type nuclear steroid hormone receptors, are potential therapeutic targets for DMD. MR antagonists show clinical efficacy on cardiomyopathy preclinical skeletal models. Methods: We have previously generated myeloid knockout mouse models dissect cell-specific functions within dystrophic muscles. Here, we compared gene expression from both knockouts further define cell-type specific signaling downstream MR. Results: Myeloid increased proinflammatory profibrotic signaling, including numerous myofibroblast signature genes. Tenascin C was the most highly upregulated fibrotic MR-knockout component fibrosis muscle. Surprisingly, lysyl oxidase (Lox), canonically collagen crosslinker, knockouts, but did not localize regions Lox localized myofibers, only region quadriceps Lysyl like 1 (Loxl1), another family member, specifically regions. Discussion: This study suggests that microenvironment involves communication between contributing cell types modulates inflammatory pathways