Gene expression effects of glucocorticoid and mineralocorticoid receptor agonists and antagonists on normal human skeletal muscle

Mineralocorticoid and glucocorticoid receptors are closely related steroid hormone receptors that regulate gene expression through many of the same hormone response elements. However, their transcriptional activities and effects in skeletal muscles are largely unknown. We recently identified mineralocorticoid receptors (MR) in skeletal muscles after finding that combined treatment with the angiotensin-converting enzyme inhibitor lisinopril and MR antagonist spironolactone was therapeutic in Duchenne muscular dystrophy mouse models. The glucocorticoid receptor (GR) agonist prednisolone is the current standard-of-care treatment for Duchenne muscular dystrophy because it prolongs ambulation, likely due to its anti-inflammatory effects. However, data on whether glucocorticoids have a beneficial or detrimental direct effect on skeletal muscle are controversial. Here, we begin to define the gene expression profiles in normal differentiated human skeletal muscle myotubes treated with MR and GR agonists and antagonists. The MR agonist aldosterone and GR agonist prednisolone had highly overlapping gene expression profiles, supporting the notion that prednisolone acts as both a GR and MR agonist that may have detrimental effects on skeletal muscles. Co-incubations with aldosterone plus either nonspecific or selective MR antagonists, spironolactone or eplerenone, resulted in similar numbers of gene expression changes, suggesting that both drugs can block MR activation to a similar extent. Eplerenone treatment alone decreased a number of important muscle-specific genes. This information may be used to develop biomarkers to monitor clinical efficacy of MR antagonists or GR agonists in muscular dystrophy, develop a temporally coordinated treatment with both drugs, or identify novel therapeutics with more specific downstream targets.

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Altered Gene Expression Profiles in Neural Stem Cells Derived from Duchenne Muscular Dystrophy Patients with Intellectual Disability

Experimental Neurobiology ◽

10.5607/en21008 ◽

2021 ◽

Vol 30 (4) ◽

pp. 263-274

Author(s):

Jahong Koo ◽

Subin Park ◽

Soo-Eun Sung ◽

Jeehun Lee ◽

Dae Soo Kim ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Intellectual Disability ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Neural Stem Cells ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Altered Gene Expression ◽

Altered Gene

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Gene expression profiling of skeletal muscles

10.1101/2021.02.17.431599 ◽

2021 ◽

Author(s):

Sarah I. Alto ◽

Chih-Ning Chang ◽

Kevin Brown ◽

Chrissa Kioussi ◽

Theresa M. Filtz

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Differentially Expressed Genes ◽

Tibialis Anterior ◽

Skeletal Muscles ◽

Expression Profiles ◽

Expression Patterns ◽

Gene Expression Profiles ◽

Differentially Expressed ◽

Analysis Tool

AbstractSoleus and tibialis anterior are two well-characterized skeletal muscles commonly utilized in skeletal muscle-related studies. Next-generation sequencing provides an opportunity for an in-depth biocomputational analysis to identify the gene expression patterns between soleus and tibialis anterior and analyze those genes’ functions based on past literature. This study acquired the gene expression profiles from soleus and tibialis anterior murine skeletal muscle biopsies via RNA-sequencing. Read counts were processed through edgeR’s differential gene expression analysis. Differentially expressed genes were filtered down using a false discovery rate less than 0.05c, a fold-change value larger than twenty, and an association with overrepresented pathways based on the Reactome pathway over-representation analysis tool. Most of the differentially expressed genes associated with soleus encoded for components of lipid metabolism and unique contractile elements. Differentially expressed genes associated with tibialis anterior encoded mostly for glucose and glycogen metabolic pathways’ regulatory enzymes and calcium-sensitive contractile components. These gene expression distinctions partly explain the genetic basis for muscle specialization and may help to explain skeletal muscle susceptibility to disease and drugs and refine tissue engineering approaches.

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Renin-angiotensin-aldosterone system inhibitors improve membrane stability and change gene-expression profiles in dystrophic skeletal muscles

AJP Cell Physiology ◽

10.1152/ajpcell.00269.2016 ◽

2017 ◽

Vol 312 (2) ◽

pp. C155-C168 ◽

Cited By ~ 8

Author(s):

Jessica A. Chadwick ◽

Sayak Bhattacharya ◽

Jeovanna Lowe ◽

Noah Weisleder ◽

Jill A. Rafael-Fortney

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Skeletal Muscles ◽

Expression Profiles ◽

Membrane Integrity ◽

Gene Expression Profiles ◽

Renin Angiotensin Aldosterone System ◽

Raas Inhibitors ◽

Dystrophic Mice ◽

Inhibitor Treatment

Angiotensin-converting enzyme inhibitors (ACEi) and mineralocorticoid receptor (MR) antagonists are FDA-approved drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) and are used to treat heart failure. Combined treatment with the ACEi lisinopril and the nonspecific MR antagonist spironolactone surprisingly improves skeletal muscle, in addition to heart function and pathology in a Duchenne muscular dystrophy (DMD) mouse model. We recently demonstrated that MR is present in all limb and respiratory muscles and functions as a steroid hormone receptor in differentiated normal human skeletal muscle fibers. The goals of the current study were to begin to define cellular and molecular mechanisms mediating the skeletal muscle efficacy of RAAS inhibitor treatment. We also compared molecular changes resulting from RAAS inhibition with those resulting from the current DMD standard-of-care glucocorticoid treatment. Direct assessment of muscle membrane integrity demonstrated improvement in dystrophic mice treated with lisinopril and spironolactone compared with untreated mice. Short-term treatments of dystrophic mice with specific and nonspecific MR antagonists combined with lisinopril led to overlapping gene-expression profiles with beneficial regulation of metabolic processes and decreased inflammatory gene expression. Glucocorticoids increased apoptotic, proteolytic, and chemokine gene expression that was not changed by RAAS inhibitors in dystrophic mice. Microarray data identified potential genes that may underlie RAAS inhibitor treatment efficacy and the side effects of glucocorticoids. Direct effects of RAAS inhibitors on membrane integrity also contribute to improved pathology of dystrophic muscles. Together, these data will inform clinical development of MR antagonists for treating skeletal muscles in DMD.

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The Duchenne muscular dystrophy gene product is localized in sarcolemma of human skeletal muscle

Nature ◽

10.1038/333466a0 ◽

1988 ◽

Vol 333 (6172) ◽

pp. 466-469 ◽

Cited By ~ 464

Author(s):

Elizabeth E. Zubrzycka-Gaarn ◽

Dennis E. Bulman ◽

George Karpati ◽

Arthur H. M. Burghes ◽

Bonnie Belfall ◽

...

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Gene Product ◽

Human Skeletal Muscle ◽

Duchenne Muscular Dystrophy Gene

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PSIV-6 Differential gene expression of fibro/adipogenic progenitors between Wagyu and Brahman cattle: A possible contribution to their different meat quality

Journal of Animal Science ◽

10.1093/jas/skab235.553 ◽

2021 ◽

Vol 99 (Supplement_3) ◽

pp. 301-301

Author(s):

Chaoyang Li ◽

Qianglin Liu ◽

Matt Welborn ◽

Leshan Wang ◽

Yuxia Li ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Meat Quality ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cattle Breed ◽

Intramuscular Fat ◽

Brahman Cattle ◽

Differential Gene ◽

The Difference

Abstract The amount of intramuscular fat directly influences the meat quality. However, significant differences in the ability to accumulate intramuscular fat are present among different beef cattle breeds. While Wagyu, a cattle breed that originated from Japan, is renowned for abundant intramuscular fat, Brahman cattle generally have very little intramuscular fat accumulation and produce tougher meat. We identified that bovine intramuscular fat is derived from a group of bipotent progenitor cells named fibro/adipogenic progenitors (FAPs) which also give rise to fibroblasts. Thus, the variation in intramuscular fat development between Wagyu and Brahman is likely attributed to the difference in FAPs between these two breeds. In order to understand the gene expression difference between FAPs of the two breeds, single-cell RNA-seq was performed using total single-nucleated cells isolated from the longissimus muscle of young purebred Wagyu, purebred Brahman, and Wagyu-Brahman cross cattle. FAPs constitute the largest single-nucleated cell population in both Wagyu and Brahman skeletal muscle. Multiple subpopulations of FAPs with different gene expression profiles were identified, suggesting that FAP is a heterogeneous population. A unique FAP cluster expressing lower levels of fibrillar collagen and extracellular remodeling enzyme genes but higher levels of select proadipogenic genes was identified exclusively in Wagyu skeletal muscle, which likely contributes to the robust intramuscular adipogenic efficiency of Wagyu FAPs. In conclusion, the difference in the cellular composition and gene expression of FAPs between Wagyu and Brahman cattle likely contribute to their distinct meat quality.

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Analysis of gene expression profiles in insulin-sensitive tissues from pre-diabetic and diabetic Zucker diabetic fatty rats

Journal of Molecular Endocrinology ◽

10.1677/jme.1.01679 ◽

2005 ◽

Vol 34 (2) ◽

pp. 299-315 ◽

Cited By ~ 42

Author(s):

Young Ho Suh ◽

Younyoung Kim ◽

Jeong Hyun Bang ◽

Kyoung Suk Choi ◽

June Woo Lee ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Zucker Diabetic Fatty Rats ◽

Zdf Rats

Insulin resistance occurs early in the disease process, preceding the development of type 2 diabetes. Therefore, the identification of molecules that contribute to insulin resistance and leading up to type 2 diabetes is important to elucidate the molecular pathogenesis of the disease. To this end, we characterized gene expression profiles from insulin-sensitive tissues, including adipose tissue, skeletal muscle, and liver tissue of Zucker diabetic fatty (ZDF) rats, a well characterized type 2 diabetes animal model. Gene expression profiles from ZDF rats at 6 weeks (pre-diabetes), 12 weeks (diabetes), and 20 weeks (late-stage diabetes) were compared with age- and sex-matched Zucker lean control (ZLC) rats using 5000 cDNA chips. Differentially regulated genes demonstrating > 1.3-fold change at age were identified and categorized through hierarchical clustering analysis. Our results showed that while expression of lipolytic genes was elevated in adipose tissue of diabetic ZDF rats at 12 weeks of age, expression of lipogenic genes was decreased in liver but increased in skeletal muscle of 12 week old diabetic ZDF rats. These results suggest that impairment of hepatic lipogenesis accompanied with the reduced lipogenesis of adipose tissue may contribute to development of diabetes in ZDF rats by increasing lipogenesis in skeletal muscle. Moreover, expression of antioxidant defense genes was decreased in the liver of 12-week old diabetic ZDF rats as well as in the adipose tissue of ZDF rats both at 6 and 12 weeks of age. Cytochrome P450 (CYP) genes were also significantly reduced in 12 week old diabetic liver of ZDF rats. Genes involved in glucose utilization were downregulated in skeletal muscle of diabetic ZDF rats, and the hepatic gluconeogenic gene was upregulated in diabetic ZDF rats. Genes commonly expressed in all three tissue types were also observed. These profilings might provide better fundamental understanding of insulin resistance and development of type 2 diabetes.

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Exploring the Mechanism of Skeletal Muscle in a Tacrolimus-Induced Posttransplantation Diabetes Mellitus Model on Gene Expression Profiles

Journal of Diabetes Research ◽

10.1155/2020/6542346 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Chenlei Zheng ◽

Cheng Wang ◽

Tan Zhang ◽

Ding Li ◽

Xiao-feng Ni ◽

...

Keyword(s):

Gene Expression ◽

Diabetes Mellitus ◽

Skeletal Muscle ◽

Muscle Development ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Enrichment Analysis ◽

Quadriceps Muscle ◽

Control Group ◽

Bioinformatics Analyses

Objective. Posttransplantation diabetes mellitus (PTDM) is a known complication of transplantation that affects the prognosis. Tacrolimus (Tac or FK506) is a widely used immunosuppressant that has been reported to be a risk factor for PTDM and to further induce complications in heart and skeletal muscles, but the mechanism is still largely unknown. In our preliminary experiments, we found that after Tac treatment, blood glucose increased, and the weight of skeletal muscle declined. Here, we hypothesize that tacrolimus can induce PTDM and influence the atrophy of skeletal muscle. Methods. We designed preliminary experiments to establish a tacrolimus-induced PTDM model. Gene expression profiles in quadriceps muscle from this rat model were characterized by oligonucleotide microarrays. Then, differences in gene expression profiles in muscle from PTDM rats that received tacrolimus and control subjects were analyzed by using GeneSpring GX 11.0 software (Agilent). Functional annotation and enrichment analysis of differentially expressed genes (DEGs) helped us identify clues for the side effects of tacrolimus. Results. Our experiments found that the quadriceps in tacrolimus-induced PTDM group were smaller than those in the control group. The study identified 275 DEGs that may be responsible for insulin resistance and the progression of PTDM, including 86 upregulated genes and 199 downregulated genes. GO and KEGG functional analysis of the DEGs showed a significant correlation between PTDM and muscle development. PPI network analysis screened eight hub genes and found that they were related to troponin and tropomyosin. Conclusions. This study explored the molecular mechanism of muscle atrophy in a tacrolimus-induced PTDM model by bioinformatics analyses. We identified 275 DEGs and identified significant biomarkers for predicting the development and progression of tacrolimus-induced PTDM.

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Characterisation of dystrophin during development of human skeletal muscle

Development ◽

10.1242/dev.114.2.395 ◽

1992 ◽

Vol 114 (2) ◽

pp. 395-402 ◽

Cited By ~ 5

Author(s):

A. Clerk ◽

P.N. Strong ◽

C.A. Sewry

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Human Skeletal Muscle ◽

Gradual Increase ◽

Differential Staining ◽

Relative Molecular Mass ◽

Adult Tissue ◽

Dmd Gene

Dystrophin, the 427 × 10(3) Mr product of the Duchenne muscular dystrophy (DMD) gene, was studied in human foetal skeletal muscle from 9 to 26 weeks of gestation. Dystrophin could be detected from at least 9 weeks of gestation at the sarcolemmal membrane of most myotubes, though there was differential staining with antibodies raised to various regions of the protein. Dystrophin immunostaining increased and became more uniform with age and by 26 weeks of gestation there was intense sarcolemmal staining of all myotubes. On a Western blot, a doublet of smaller relative molecular mass than that seen in adult tissue was detected in all foetuses studied. There was a gradual increase in abundance of the upper band from 9 to 26 weeks, and the lower band, although present in low amounts in young foetuses, increased significantly between 20 and 26 weeks of gestation. These data indicate that there are several specific isoforms of dystrophin present in developing skeletal muscle, though the role of these is unknown.

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