Mineralocorticoid receptor antagonists reduce inflammatory signaling independent of myofiber mineralocorticoid receptor.

Chronic inflammation is a feature of Duchenne muscular dystrophy (DMD), a degenerative striated muscle disease. Mineralocorticoid receptor (MR) antagonists (MRAs) have demonstrated clinical benefit on later onset DMD cardiomyopathy, and preclinical studies in mouse models have demonstrated efficacy on multiple steps of skeletal muscle pathology. MRA treatment of the mdx mouse model reduces pro-inflammatory gene expression from skeletal muscle myeloid immune cells and represses muscle cytokine signaling and fibrosis. Myofiber-specific knockout of MR in mdx mice improves muscle force and reduces fibrosis, but inflammation in this model had not been investigated. In this study we investigated muscle inflammation at the cellular level using flow cytometry and at the protein signaling level using an unbiased cytokine assay. Numbers and proportions of myeloid cells were the same in mdx mice and those lacking myofiber MR, similar to the absence of cell type differences previously observed with either MRA treatment or myeloid MR knockout. MRA treatment, but not myofiber MR deletion alone, led to reductions in numerous cytokines and chemokines also previously observed in mdx mice. These data suggest that the beneficial reduction of inflammatory signaling from MRAs is largely independent of myofiber MR and occurs through another mechanism.