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Mineralocorticoid Receptor Antagonists and Glucocorticoids Differentially Affect Skeletal Muscle Inflammation and Pathology in Muscular Dystrophy

ABSTRACT: Mineralocorticoid Receptor Antagonists and Glucocorticoids Differentially Affect Skeletal Muscle Inflammation and Pathology in Muscular Dystrophy

PROVIDER: PRJNA810878 | ENA |

REPOSITORIES: ENA

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

Project description:Mineralocorticoid receptor antagonists (MRAs) slow cardiomyopathy in patients with Duchenne muscular dystrophy (DMD) and improve skeletal muscle pathology and function in dystrophic mice. However, glucocorticoids, known antiinflammatory drugs, remain a standard of care for DMD, despite substantial side effects. Exact mechanisms underlying mineralocorticoid receptor (MR) signaling contribution to dystrophy are unknown. Whether MRAs affect inflammation in dystrophic muscles and how they compare with glucocorticoids is unclear. The MRA spironolactone and glucocorticoid prednisolone were each administered for 1 week to dystrophic mdx mice during peak skeletal muscle necrosis to compare effects on inflammation. Both drugs reduced cytokine levels in mdx quadriceps, but prednisolone elevated diaphragm cytokines. Spironolactone did not alter myeloid populations in mdx quadriceps or diaphragms, but prednisolone increased F4/80hi macrophages. Both spironolactone and prednisolone reduced inflammatory gene expression in myeloid cells sorted from mdx quadriceps, while prednisolone additionally perturbed cell cycle genes. Spironolactone also repressed myeloid expression of the gene encoding fibronectin, while prednisolone increased its expression. Overall, spironolactone exhibits antiinflammatory properties without altering leukocyte distribution within skeletal muscles, while prednisolone suppresses quadriceps cytokines but increases diaphragm cytokines and pathology. Antiinflammatory properties of MRAs and different limb and respiratory muscle responses to glucocorticoids should be considered when optimizing treatments for patients with DMD.

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Mineralocorticoid Receptor Antagonists and Glucocorticoids Differentially Affect Skeletal Muscle Inflammation and Pathology in Muscular Dystrophy

Project description:We report the RNA Sequencing of myleoid cells isolated from 4.5-week-old mdx mice that were administered spironolactone, prednisolone, or vehicle for 7 days. We find that both spironolactone and prednisolone downregulated expression of genes involved in inflammation and fibrosis, while prednisolone further perturbed cell cycle genes.

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Non-steroidal mineralocorticoid receptor antagonism by finerenone is sufficient to improve function in preclinical muscular dystrophy

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Mineralocorticoid receptor antagonists improve membrane integrity independent of muscle force in muscular dystrophy.

Project description:Mineralocorticoid receptor (MR) drugs have been used clinically for decades to treat cardiovascular diseases. MR antagonists not only show preclinical efficacy for heart in Duchenne muscular dystrophy (DMD) models but also improve skeletal muscle force and muscle membrane integrity. The mechanisms of action of MR antagonists in skeletal muscles are entirely unknown. Since MR are present in many cell types in the muscle microenvironment, it is critical to define cell-intrinsic functions in each cell type to ultimately optimize antagonist efficacy for use in the widest variety of diseases. We generated a new conditional knockout of MR in myofibers and quantified cell-intrinsic mechanistic effects on functional and histological parameters in a DMD mouse model. Skeletal muscle MR deficiency led to improved respiratory muscle force generation and less deleterious fibrosis but did not reproduce MR antagonist efficacy on membrane susceptibility to induced damage. Surprisingly, acute application of MR antagonist to muscles led to improvements in membrane integrity after injury independent of myofiber MR. These data demonstrate that MR antagonists are efficacious to dystrophic skeletal muscles through both myofiber intrinsic effects on muscle force and downstream fibrosis and extrinsic functions on membrane stability. MR antagonists may therefore be applicable for treating more general muscle weakness and possibly other conditions that result from cell injuries.

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Non-steroidal mineralocorticoid receptor antagonism by finerenone is sufficient to improve function in preclinical muscular dystrophy

Project description:Non-steroidal mineralocorticoid receptor antagonism by finerenone is sufficient to improve function in preclinical muscular dystrophy

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