Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target

Chadwick, Jessica; Hauck, J. Spencer; Lowe, Jeovanna; Shaw, Jeremiah J.; Guttridge, Denis C.; Gómez-Sánchez, Celso E.; Gómez-Sánchez, Elise P.; Rafael‐Fortney, Jill A.

doi:10.1096/fj.15-276782

Cited by 47 publications

(74 citation statements)

References 59 publications

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“…Snap frozen mouse tissues were pulverized and resuspended in cellular extract buffer as described previously [7]. Briefly, tissue homogenates were sonicated on ice, centrifuged, and total protein was quantified.…”

Section: Methodsmentioning

confidence: 99%

“…Surprisingly, a combination treatment with the angiotensin-converting enzyme inhibitor (ACEi) lisinopril and the mineralocorticoid receptor (MR) antagonist spironolactone, led to improved function and pathology not only in the heart, but also in skeletal muscles [6]. We then showed that mineralocorticoid receptors, not previously investigated in skeletal muscles, were present in limb and respiratory muscles from wild-type and dystrophic mice [7]. The endogenous mineralocorticoid receptor agonist aldosterone was able to induce a large number of gene expression changes in normal human differentiated myotubes, supporting MR functions as a steroid hormone receptor in skeletal muscles.…”

Section: Introductionmentioning

confidence: 99%

“…Both drugs are used at the same dosages interchangeably for cardiac disease, but typically not until late stage heart failure. Since MR was not previously identified in skeletal muscles, use of MR antagonists for skeletal myopathies has not been clinically investigated [7]. It is not known whether the functional benefit on dystrophic skeletal muscles is due to MR antagonism by spironolactone or from off-target effects on the other steroid hormone receptors that it can bind.…”

Section: Introductionmentioning

confidence: 99%

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Similar Efficacy from Specific and Non-Specific Mineralocorticoid Receptor Antagonist Treatment of Muscular Dystrophy Mice

Lowe

Floyd

Rastogi

et al. 2016

JND

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Background Combined treatment with an angiotensin-converting enzyme inhibitor and a mineralocorticoid receptor (MR) antagonist improved cardiac and skeletal muscle function and pathology in a mouse model of Duchenne muscular dystrophy. MR is present in limb and respiratory skeletal muscles and functions as a steroid hormone receptor. Objective The goals of the current study were to compare the efficacy of the specific MR antagonist eplerenone with the non-specific MR antagonist spironolactone, both in combination with the angiotensin-converting enzyme inhibitor lisinopril. Methods Three groups of n=18 dystrophin-deficient, utrophin-haploinsufficient male mice were given chow containing: lisinopril plus spironolactone, lisinopril plus eplerenone, or no drug, from four to 20 weeks-of-age. Eighteen C57BL/10 male mice were used as wild-type controls. In vivo measurements included cardiac magnetic resonance imaging, conscious electrocardiography, and grip strength. From each mouse in the study, diaphragm, extensor digitorum longus, and cardiac papillary muscle force was measured ex vivo, followed by histological quantification of muscle damage in heart, diaphragm, quadriceps, and abdominal muscles. MR protein levels were also verified in treated muscles. Results Treatment with specific and non-specific MR antagonists did not result in any adverse effects to dystrophic skeletal muscles or heart. Both treatments resulted in similar functional and pathological improvements across a wide array of parameters. MR protein levels were not reduced by treatment. Conclusions These data suggest that spironolactone and eplerenone show similar effects in dystrophic mice and support the clinical development of MR antagonists for treating skeletal muscles in Duchenne muscular dystrophy.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Similar Efficacy from Specific and Non-Specific Mineralocorticoid Receptor Antagonist Treatment of Muscular Dystrophy Mice

Lowe

Floyd

Rastogi

et al. 2016

JND

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“…The recent study shows the presence and the activity of the mineralocorticoid receptor (MR) in skeletal muscle [9]. MR and GR exhibit cross-reactivity with endogenous GCs, which have the same or even higher affinity to MR than GR (depending on the tissue).…”

Section: Introductionmentioning

confidence: 99%

“…MR and GR exhibit cross-reactivity with endogenous GCs, which have the same or even higher affinity to MR than GR (depending on the tissue). As a consequence of the high homology with GR, MR is activated by both mineralocorticoids (aldosterone, deoxycorticosterone) and GCs [9]. Data from the past several years have assigned a specific role for the MR in mediating oxidative stress development.…”

Section: Introductionmentioning

confidence: 99%

BST Stimulation Induces Atrophy and Changes in Aerobic Energy Metabolism in Rat Skeletal Muscles—The Biphasic Action of Endogenous Glucocorticoids

Karnia

Myślińska

Dzik

et al. 2020

IJMS

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(1) The primary involvement in stress-induced disturbances in skeletal muscles is assigned to the release of glucocorticoids (GCs). The current study aims to investigate the impact of the biphasic action of the chronic stress response (CSR) induced by the electrical stimulation of the bed nucleus of the stria terminalis (BST) effects on muscle atrophy and aerobic energy metabolism in soleus (SOL) and extensor digitorum longus (EDL) muscles. (2) Male Wistar rats (n = 17) were used. The rats were divided randomly into three groups: the BST two weeks (ST2), four weeks (ST4), and the sham (SHM) electrically stimulated group. The plasma corticosterone (CORT) and irisin concentration were measured. Glucocorticoid and mineralocorticoid receptors (GR and MR), 11β-hydroxysteroid dehydrogenase type 1 and 2 (HSD11B1 and HSD11B2), atrogin-1, and insulin-like growth factor-1 (IGF-1) level were determined in SOL and EDL muscles. Citrate synthase (CS) activity was measured in both muscles. (3) We found elevated plasma concentration of CORT and irisin, raised the level of GR in SOL muscle, and the higher level of MR in both muscles in the ST4 group. The level of HSD11B1 was also higher in the ST4 group compared to the SHM group. Moreover, we observed increased activity of CS in SOL. (4) We suggest that biphasic action of the glucocorticoid induced by the CSR occurs and causes dysregulation of proteins involved in muscle atrophy and aerobic energy metabolism. Our findings potentially contribute to a better understanding of the mechanisms by which GCs and the CSR may regulate muscle atrophy and energy preservation of the red muscle.

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Mineralocorticoid receptor antagonism by finerenone is sufficient to improve function in preclinical muscular dystrophy

et al. 2020

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Aims Duchenne muscular dystrophy (DMD) is an X-linked inherited disease due to dystrophin deficiency causing skeletal and cardiac muscle dysfunction. Affected patients lose ambulation by age 12 and usually die in the second to third decades of life from cardiac and respiratory failure. Symptomatic treatment includes the use of anti-inflammatory corticosteroids, which are associated with side effects including weight gain, osteoporosis, and increased risk of cardiovascular disease. Novel treatment options include blockade of the renin-angiotensin-aldosterone system, because angiotensin as well as aldosterone contribute to persistent inflammation and fibrosis, and aldosterone blockade represents an efficacious anti-fibrotic approach in cardiac failure. Recent preclinical findings enabled successful clinical testing of a combination of steroidal mineralocorticoid receptor antagonists (MRAs) and angiotensin converting enzyme inhibitors in DMD boys. The efficacy of MRAs alone on dystrophic skeletal muscle and heart has not been investigated. Here, we tested efficacy of the novel non-steroidal MRA finerenone as a monotherapy in a preclinical DMD model. Methods and results The dystrophin-deficient, utrophin haploinsufficient mouse model of DMD was treated with finerenone and compared with untreated dystrophic and wild-type controls. Grip strength, electrocardiography, cardiac magnetic resonance imaging, muscle force measurements, histological quantification, and gene expression studies were performed. Finerenone treatment alone resulted in significant improvements in clinically relevant functional parameters in both skeletal muscle and heart. Normalized grip strength in rested dystrophic mice treated with finerenone (40.3 ± 1.0 mN/g) was significantly higher (P = 0.0182) compared with untreated dystrophic mice (35.2 ± 1.5 mN/g). Fatigued finerenone-treated dystrophic mice showed an even greater relative improvement (P = 0.0003) in normalized grip strength (37.5 ± 1.1 mN/g) compared with untreated mice (29.7 ± 1.1 mN/g). Finerenone treatment also led to significantly lower (P = 0.0075) susceptibility to limb muscle damage characteristic of DMD measured during a contraction-induced injury protocol. Normalized limb muscle force after five lengthening contractions resulted in retention of 71 ± 7% of baseline force in finerenone-treated compared with only 51 ± 4% in untreated dystrophic mice. Finerenone treatment also prevented significant reductions in myocardial strain rate (P = 0.0409), the earliest sign of DMD cardiomyopathy. Moreover, treatment with finerenone led to very specific cardiac gene expression changes in clock genes that might modify cardiac pathophysiology in this DMD model. Conclusions Finerenone administered as a monotherapy is disease modifying for both skeletal muscle and heart in a preclinical DMD model. These findings support further evaluation of finerenone in DMD clinical trials.

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Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target

Cited by 47 publications

References 59 publications

Similar Efficacy from Specific and Non-Specific Mineralocorticoid Receptor Antagonist Treatment of Muscular Dystrophy Mice

Similar Efficacy from Specific and Non-Specific Mineralocorticoid Receptor Antagonist Treatment of Muscular Dystrophy Mice

BST Stimulation Induces Atrophy and Changes in Aerobic Energy Metabolism in Rat Skeletal Muscles—The Biphasic Action of Endogenous Glucocorticoids

Mineralocorticoid receptor antagonism by finerenone is sufficient to improve function in preclinical muscular dystrophy

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