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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE197553 | GEO | 2022/11/23

REPOSITORIES: GEO

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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.

| S-EPMC9675571 | biostudies-literature

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

Project description:Mineralocorticoid Receptor Antagonists and Glucocorticoids Differentially Affect Skeletal Muscle Inflammation and Pathology in 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:The objective of this study was to test the novel non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone as a monotherapy in a preclinical Duchenne muscular dystrophy (DMD) model. Microarray was used to detail gene expression differences in ventricular heart tissue from finerenone-treated dystrophin-deficient, utrophin-haploinsufficient Het (utrn+/−; mdx) mice versus untreated Het mice.

2020-08-10 | GSE150302 | GEO

miR-206 modulates the pathogenesis of muscular dystrophy of mdx mice

Project description:In response to skeletal muscle injury, adult myogenic stem cells, known as satellite cells, are activated and undergo proliferation and differentiation to regenerate new muscle fibers. The skeletal muscle-specific microRNA, miR-206, is up-regulated in satellite cells following muscle injury, but its role in muscle regeneration has not been defined. Here we show that skeletal muscle regeneration in response to cardiotoxin injury is impaired in mice lacking miR-206. Loss of miR-206 also accelerates and exacerbates the dystrophic phenotype of mdx mice, a model for Duchenne muscular dystrophy. MiR-206 promotes satellite cell differentiation and fusion to form multinucleated myofibers by suppressing a collection of negative regulators of myogenesis. Our findings reveal an essential role for miR-206 in satellite cell differentiation during skeletal muscle regeneration and as a modulator of Duchenne muscular dystrophy. total RNA obtained from TA muscle of mdx and 3 miR-206 KO; mdx mice at 3 months of age.

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Inactivation of Sirt6 ameliorates muscular dystrophy in mdx mice by releasing suppression of utrophin expression

Project description:In this study, Pax7-Cre mediated inactivation of Sirt6 in mdx mice resulted in profound improvement of the mdx phenotype at the functional level. To study the underlying molecular mechanisms and identify specific Sirt6 targets irrespectively to mdx mutation, we performed RNA-seq of freshly isolated muscle stem cells from control and Sirt6mKO mice.

2022-05-12 | GSE199487 | GEO

Expression data from quadriceps of utrn+/-;mdx mice treated with spironolactone plus lisinopril, eplerenone plus lisinopril or prednisolone compared to untreated

Project description:To identify the gene expression differences in skeletal muscles resulting from treatment of dystrophic mice with spironolactone plus lisinopril, eplerenone plus lisinopril or prednisolone.

2017-03-07 | GSE84876 | GEO

Transcriptomic analysis of mdx mouse muscles reveals a signature of early human Duchenne muscular dystrophy

Project description:The mdx mouse (C57BL/10ScSn-DMDmdx/J), like Duchenne muscular dystrophy (DMD) patients, lacks the protein dystrophin. However, the mdx mouse has a normal lifespan and mild pathology while DMD remains a severe, fatal disease. New mouse models have been developed that are more severely affected but they have not replaced the mdx mouse in DMD research. A few years ago RNA-sequencing (RNA-seq) results of biopsies from DMD and normal human muscle were published but we could not find equivalent data for the mouse. We now report RNA-sequencing of three wild-type and mdx mouse muscles: the flexor digitorum brevis (FDB), the extensor digitorum longus (EDL), and the soleus (SOL). The FDB, a plantar foot muscle is often used for in vivo and ex vivo experiments but may be less affected by the lack of dystrophy than the hindlimb muscles. We compared muscles from 2- and 5-month old mice to investigate the time-course of the mdx pathology. The results show a muscle- and age-dependent parallel between mdx and DMD muscles. Although the FDB is less affected than EDL and SOL at 2 months, the three muscles show, at both ages, activation of close to 100 genes from 7 pathways that are affected in presymptomatic DMD patients and have been called "DMD disease signature".

2021-06-22 | GSE162455 | GEO

The microRNA, miR-133b, functions to slow Duchenne muscular dystrophy pathogenesis

Project description:Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle degeneration. No treatments are currently available to prevent the disease. While the muscle enriched microRNA, miR-133b, has been implicated in muscle biogenesis, its role in DMD remains unknown. To assess miR-133b function in DMD-affected skeletal muscles, we genetically ablated miR-133b in the mdx mouse model of DMD. In the absence of miR-133b, the tibialis anterior muscle of juvenile and adult mdx mice is populated by small muscle fibers and exhibits increased fibrosis, characterized by thickened interstitial space. Additional analysis revealed that loss of miR-133b exacerbates DMD-pathogenesis partly by altering satellite cell numbers and through widespread transcriptomic changes. These include known miR-133b targets as well as genes involved in cell proliferation and fibrosis. Altogether, our data demonstrate that skeletal muscles utilize miR-133b to mitigate the deleterious effects of DMD.

2020-08-15 | GSE156267 | GEO

Recent advances of glucocorticoids in the treatment of Duchenne muscular dystrophy (Review).

Project description:Duchenne muscular dystrophy (DMD) is the most common degenerative neuromuscular disease. The incidence of DMD in live births is 1/3,600-1/6,000. Although glucocorticoid-dependent medication is the mainstay treatment option for DMD, a standard treatment regimen has yet to be determined. The present review discusses the literature on the timing, methods and courses of glucocorticoid treatment for DMD. The review highlights the importance of the immediate commencement of glucocorticoid treatment following the diagnosis of DMD, with weekend-only administration being advantageous. Adherence to long-term single-glucocorticoid therapy can delay the loss of ambulation ability, and the side effects of the treatment are controllable. However, the standard medication for patients of different ages and stages of disease development, and the use of combination therapy require further investigation.

| S-EPMC7967797 | biostudies-literature

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