Myeloid mineralocorticoid receptors contribute to skeletal muscle repair in muscular dystrophy and acute muscle injury

Abstract

Suppressing mineralocorticoid receptor (MR) activity with MR antagonists is therapeutic for chronic skeletal muscle pathology in Duchenne Muscular Dystrophy (DMD) mouse models. Although mechanisms underlying clinical MR antagonist efficacy for DMD cardiomyopathy and other cardiac diseases are defined, mechanisms on skeletal muscles are not fully elucidated. Myofiber MR knockout improves skeletal muscle force and a subset of dystrophic pathology. However, MR signaling in myeloid cells is known to be a major contributor to cardiac efficacy. To define contributions of myeloid MR in skeletal muscle function and disease, we performed parallel assessments of muscle pathology, cytokine levels and myeloid cell populations resulting from myeloid MR genetic knockout in muscular dystrophy and in acute muscle injury. Myeloid MR knockout led to lower levels of immunosuppressive macrophages resulting in sustained myofiber damage and slowed regeneration and muscle repair after acute injury of normal muscle. In acute injury, myeloid MR knockout also led to increased local muscle levels of the enzyme that produces the endogenous MR agonist aldosterone, further supporting important contributions of MR signaling in normal muscle repair. In muscular dystrophy, myeloid MR knockout altered cytokine levels differentially between quadriceps and diaphragm muscles, which contain different myeloid populations. Myeloid MR knockout led to higher levels of fibrosis in dystrophic diaphragm where pro-inflammatory macrophages are more prevalent than in quadriceps. These results support important contributions of myeloid MR signaling to skeletal muscle repair in acute and chronic injuries and highlight the useful information gained from cell-specific genetic knockouts to delineate mechanisms of pharmacological efficacy.

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury

“…Interestingly, myeloid MR knockout in mdx and injured wild-type skeletal muscles worsened pathology and prolonged damage, respectively ( Howard et al, 2022 ). Numerous chemokines and cytokines are increased with myeloid MR knockout in mdx quadriceps, but are decreased in the diaphragm.…”

“…Macrophages displaying C-C motif chemokine receptor 2 (CCR2) are reduced in injured myeloid MR knockout wild-type muscles, which correlates with an increase in ongoing myofiber damage. In addition, CYP11B2 is upregulated in myofibers post-injury, emphasizing a role for aldosterone-mediated MR signaling within the myeloid cells to facilitate muscle repair ( Howard et al, 2022 ).…”

A 1.1 Mb duplication CNV on chromosome 17 contributes to skeletal muscle development in Boer goats

“…Nuclear receptor subfamily 3 group C member 2 ( NR3C2 ) is a key component of hypothalamic-pituitary-adrenal neuroendocrine axis regulation, and variants in this gene are associated with muscle glycogen content and meat quality traits in male Nellore cattle ( Poleti et al, 2015 ). NR3C2 also contributes to muscular dystrophy relief and skeletal muscle repair in acute muscle injury ( Howard et al, 2022 ). Endothelin receptor type A ( EDNRA ) is involved in various physiological functions, including smooth muscle contraction and fetal muscle development ( Kobayashi et al, 2016 ; Sato et al, 2008 ).…”

Mineralocorticoid receptor antagonists and glucocorticoids differentially affect skeletal muscle inflammation and pathology in muscular dystrophy

“…Long-term MRA treatment leads to improved diaphragm and limb muscle function and reduced pathology in dystrophic mice ( 30 , 33 , 36 ). However, a complete KO of myeloid MR on an mdx background leads to higher cytokine and chemokine levels in quadriceps and increased diaphragm fibrosis, suggesting crosstalk between inflammatory cells and other cell types within the dystrophic skeletal muscle microenvironment ( 70 ). Inflammatory cells play a known role in promoting regeneration and repair; therefore, complete abrogation of their injury response can lead to long-term deleterious consequences that may underlie the observed side effects by prednisolone.…”