The glucocorticoid receptor acts locally to protect dystrophic muscle and heart during disease.

Absence of dystrophin results in muscular weakness, chronic inflammation and cardiomyopathy in Duchenne muscular dystrophy (DMD). Pharmacological corticosteroids are the DMD standard of care; however, they have harsh side effects and unclear molecular benefits. It is uncertain whether signaling by physiological corticosteroids and their receptors plays a modifying role in the natural etiology of DMD. Here, we knocked out the glucocorticoid receptor (GR, encoded by Nr3c1) specifically in myofibers and cardiomyocytes within wild-type and mdx52 mice to dissect its role in muscular dystrophy. Double-knockout mice showed significantly worse phenotypes than mdx52 littermate controls in measures of grip strength, hang time, inflammatory pathology and gene expression. In the heart, GR deletion acted additively with dystrophin loss to exacerbate cardiomyopathy, resulting in enlarged hearts, pathological gene expression and systolic dysfunction, consistent with imbalanced mineralocorticoid signaling. The results show that physiological GR functions provide a protective role during muscular dystrophy, directly contrasting its degenerative role in other disease states. These data provide new insights into corticosteroids in disease pathophysiology and establish a new model to investigate cell-autonomous roles of nuclear receptors and mechanisms of pharmacological corticosteroids.

Liver Androgen Receptor Knockout Improved High-fat Diet Induced Glucose Dysregulation in Female Mice But Not Male Mice.

Previous research has indicated that liver androgen receptors may play a role in modulating disease. This study aims to investigate the pathophysiology of high-fat diet (HFD) induced dysglycemia in male and female liver androgen receptor knockout (LivARKO) mice. We performed metabolic tests on LivARKO female and male mice fed a HFD or a control diet (from Research Diets Inc.) during months 1 or 2 after starting the diet. Additionally, we performed Western blot and quantitative real-time PCR analysis on the livers of the mice to examine intermediates in the insulin signaling pathway. LivARKO-HFD female mice displayed no difference in glucose tolerance compared to female LivARKO-Control (Con) mice, whereas in wild-type female mice, HFD impaired glucose tolerance (IGT). Our data suggests that starting at 1 month, LivARKO may be protecting female mice from HFD-induced metabolic dysfunction. LivARKO-HFD female mice displayed significantly worse insulin sensitivity at 15 minutes compared to LivARKO-Con female mice, but, strangely, LivARKO-HFD female mice had significantly better insulin sensitivity at 60 and 90 minutes compared to LivARKO-Con female mice. Despite protecting against IGT, LivARKO did not protect against HFD-induced hyperinsulinemia in female mice. In contrast to females, male LivARKO-HFD mice displayed impaired glucose tolerance compared to male LivARKO-Con mice. Thus, LivARKO is not protective against HFD-induced glucose metabolic dysfunction in male mice. Lastly, LivARKO-HFD female mice maintained hepatic insulin sensitivity whereas LivARKO-HFD male mice displayed hepatic insulin resistance. These findings suggest that LivARKO delayed the onset of HFD-induced dysglycemia in female mice.

Vamorolone improves Becker muscular dystrophy and increases dystrophin protein in bmx model mice.

There is no approved therapy for Becker muscular dystrophy (BMD), a genetic muscle disease caused by in-frame dystrophin deletions. We previously developed the dissociative corticosteroid vamorolone for treatment of the allelic, dystrophin-null disease Duchenne muscular dystrophy. We hypothesize vamorolone can treat BMD by safely reducing inflammatory signaling in muscle and through a novel mechanism of increasing dystrophin protein via suppression of dystrophin-targeting miRNAs. Here, we test this in the bmx mouse model of BMD. Daily oral treatment with vamorolone or prednisolone improves bmx grip strength and hang time phenotypes. Both drugs reduce myofiber size and decrease the percentage of centrally nucleated fibers. Vamorolone shows improved safety versus prednisolone by avoiding or reducing key side effects to behavior and growth. Intriguingly, vamorolone increases dystrophin protein in both heart and skeletal muscle. These data indicate that vamorolone, nearing approval for Duchenne, shows efficacy in bmx mice and therefore warrants clinical investigation in BMD.

Nonalcoholic Fatty Liver Disease in Women and Girls With Polycystic Ovary Syndrome.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of liver damage due to excessive hepatic lipid accumulation. Recent research has demonstrated a high prevalence of NAFLD in women with polycystic ovary syndrome (PCOS). RESULTS: Strong associations independent of body mass index (BMI) have been found between high androgen levels characteristic of PCOS, as well as insulin resistance, and the presence of NAFLD in these women, suggesting that these factors contribute to liver injury more significantly than obesity. Current studies indicate the occurrence of NAFLD in normal weight women with PCOS in addition to the commonly researched women who are overweight and obese. While the majority of studies address NAFLD in adult, premenopausal women (ages 25-40 years), the occurrence of NAFLD in young and adolescent women has gone largely unaddressed. Research in this field lacks diversity; a majority of studies either focus on populations of White women or are missing demographic information entirely. CONCLUSIONS: Future studies should include larger, more racially and ethnically inclusive populations and particular attention should be paid to how excess androgens and insulin resistance contribute to the increased risk of NAFLD seen in women with PCOS of varying weights, ages, and ethnicities. OBJECTIVE AND METHODS: Here, we review NAFLD in women with PCOS with subsections focused on the impact of hyperandrogenism, BMI, insulin resistance and age. Most notably, we present the most up-to-date racially and ethnically diverse worldwide prevalence of NAFLD in women with PCOS compared with women without PCOS (51.56% vs 29.64%, P < .001, respectively).