Long-Term Outcome of Interdisciplinary Management of Patients with Duchenne Muscular Dystrophy Receiving Daily Glucocorticoid Treatment

Wong, Brenda; Rybalsky, I.; Shellenbarger, K.; Tian, Chengming; McMahon, Mary; Rutter, Meilan M.; Sawnani, Hemant; Jefferies, John L.

doi:10.1016/j.jpeds.2016.11.078

“…Most of the clinical indications of GCs are related to their immune-modulating and anti-inflammatory effects 45,46 . However, glucocorticoids are highly pleiotropic molecules, affecting the physiology of practically any organ 47 and long term systemic administration is often accompanied by unwanted side effects 45,[48][49][50] . The molecular and physiological mechanisms underlying their mild beneficial effects on dystrophic patients, and adverse side effects, are poorly understood 51,52 .…”

Section: Discussionmentioning

confidence: 99%

Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

Perpetuini

¹

,

Giuliani

²

,

Reggio

³

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Muscle resident fibro-adipogenic progenitors (FAPs), support muscle regeneration by releasing cytokines that stimulate the differentiation of myogenic stem cells. However, in non-physiological contexts (myopathies, atrophy, aging) FAPs cause fibrotic and fat infiltrations that impair muscle function. We set out to perform a fluorescence microscopy-based screening to identify compounds that perturb the differentiation trajectories of these multipotent stem cells. From a primary screen of 1,120 FDA/EMA approved drugs, we identified 34 compounds as potential inhibitors of adipogenic differentiation of FAPs isolated from the murine model (mdx) of Duchenne muscular dystrophy (DMD). The hit list from this screen was surprisingly enriched with compounds from the glucocorticoid (GCs) chemical class, drugs that are known to promote adipogenesis in vitro and in vivo. To shed light on these data, three GCs identified in our screening efforts were characterized by different approaches. We found that like dexamethasone, budesonide inhibits adipogenesis induced by insulin in sub-confluent FAPs. However, both drugs have a pro-adipogenic impact when the adipogenic mix contains factors that increase the concentration of cAMP. Gene expression analysis demonstrated that treatment with glucocorticoids induces the transcription of Gilz/Tsc22d3, an inhibitor of the adipogenic master regulator PPARγ, only in anti-adipogenic conditions. Additionally, alongside their anti-adipogenic effect, GCs are shown to promote terminal differentiation of satellite cells. Both the anti-adipogenic and pro-myogenic effects are mediated by the glucocorticoid receptor and are not observed in the presence of receptor inhibitors. Steroid administration currently represents the standard treatment for DMD patients, the rationale being based on their anti-inflammatory effects. The findings presented here offer new insights on additional glucocorticoid effects on muscle stem cells that may affect muscle homeostasis and physiology.In muscular dystrophies the degeneration of muscle tissue is initially compensated by efficient regeneration that neutralize muscle loss 1 . However, over time, the regenerative potential in muscles of patients affected by myopathies is impaired and myofibers repair is curbed by the formation of fibrotic scars and fat infiltrations, ultimately leading to decreased muscle function 2 . Muscle fibro-adipogenic progenitors play an important role in these processes. FAPs are muscle mesenchymal stem cells residing in the muscle fibers interstitial space. FAPs express the SCA1, CD34 and PDGFRα (CD140a) antigens while they are negative for the hematopoietic and endothelial markers, CD45 and CD31, and for the satellite marker α7 integrin (ITGA7) 2-4 . FAPs contribute to muscle regeneration by secreting IGF-1 and IL-6 3 , by facilitating the clearance of necrotic debris 5 and by promoting the formation of extra-cellular matrix 6 . In addition to this pro-regenerative roles, FAPs are responsible for the formation of ectopic tissue infiltrations ...

show abstract

“…Only 6% of 16-year-old DMD patients had scoliosis. 25 Our results differed because in Dr Sardjito Hospital the patients did not receive adequate steroid therapy due to poor medication adherence, and delayed diagnosis, as our patients often presented at a later stage of disease.…”

Section: A Centers For Disease Control and Prevention Muscular Dystromentioning

confidence: 63%

Motor clinical progression in a series of pediatric Duchenne and Becker muscular dystrophy cases

Istianah¹,

Sunartini

²

,

Nugroho

³

2019

PI

0

View full text Add to dashboard Cite

M uscular dystrophy is a neuromuscular disorder that begins with muscle weakness and impaired motor function. Duchenne muscular dystrophy (DMD) is more severe and destructive than Becker muscular dystrophy (BMD), and both are progressive in nature. These 2 types of muscular dystrophy are caused by mutations in related to X-chromosome genes. 1 The mutations that occur in DMD are nonsense mutations. Deletion is present in 60% of DMD cases, while duplication occurs in 10% of DMD cases, resulting in loss of dystrophin protein. Mutations in BMD are missense mutations, so dystrophin is still formed, but in decreased amounts and quality. 2,3 The prevalence of DMD was reported to be three times greater than that of BMD, with a prevalence of 1.02 per 10,000 male births vs. 0.36 per 10,000 male infants, respectiveley. 4 Anatomical pathology examination revealed loss of dystrophin in the examination of muscle biopsy without the presence of evidence leading to other neuromuscular diseases. Clinical DMD symptoms begin to appear at the age of 2-4 years. The child is observed to fall often and has difficulty climbing stairs. Muscle weakness worsens, especially in the upper limbs, continuing with heart and respiratory problems. The main causes of death in DMD are respiratory failure and heart failure. 5 The BMD has varied clinical symptoms, beginning with the appearance of myalgia, muscle cramps, and arm weakness progressing towards myopathy. Some patients are asymptomatic until the age of 15, but 50% of patients show symptoms at age 10, and almost all by age 20. 6 [Paediatr Indones. 2019;59:104-12; doi: http://dx.

show abstract

“…Most of the clinical indications of GCs are related to their immune-modulating and anti-inflammatory effects 48,49 . However, glucocorticoids are highly pleiotropic molecules, affecting the physiology of practically any organ 50 and long term systemic administration is often accompanied by unwanted side effects 48,[51][52][53] . The molecular and physiological mechanisms underlying their mild beneficial effects on dystrophic patients, and adverse side effects, are poorly understood 54,55 .…”

Section: Discussionmentioning

confidence: 99%

Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

Perpetuini

¹

,

Reggio

²

,

Cerretani

³

et al. 2019

Preprint

View full text Add to dashboard Cite

Muscle resident fibro-adipogenic progenitors (FAPs), support muscle regeneration by releasing cytokines that stimulate the differentiation of myogenic stem cells. However, in non-physiological contexts (myopathies, atrophy and aging) FAPs cause fibrotic and fat infiltrations that impair muscle function. We set out to perform a fluorescence microscopy-based screening to identify compounds that perturb the differentiation trajectories of these multipotent stem cells. From a primary screening of 1120 FDA/EMA approved drugs, we identified 34 compounds as potential inhibitors of adipogenic differentiation of FAPs isolated from the murine model (mdx) of Duchenne muscular dystrophy (DMD). To our surprise we found the hit list enriched for the glucocorticoid chemical class (GCs). Glucorticoids are often described as drugs that promote adipogenesis in vitro and in vivo. To shed light on conflicting reports we further characterized by different approaches three GCs identified in our screening focusing on budesonide a potent inhibitor of adipogenesis. We found that, similarly to dexamethasone, budesonide inhibits adipogenesis induced by insulin on subconfuent FAPs. However, both drugs have a proadipogenic impact when the adipogenic mix contains factors that increase the concentration of cAMP. By gene expression analysis we observed that treatment with glucocorticoids induces the transcription of Gilz/Tsc22d3, an inhibitor of the adipogenic master regulator PPARγ, only in antiadipogenic conditions. Finally, we noticed that alongside their anti-adipogenic effect, GCs promote terminal differentiation of satellite cells. Both the pro-adipogenic and pro-myogenic effects are mediated by the glucocorticoid receptor as they are not observed in the presence of receptor inhibitor. Steroid administration currently represents the standard treatment of DMD patients, the rationale being based on their antiinflammatory effects. The findings presented here offer new insights on additional glucocorticoid effects on muscle stem cells that may affect muscle homeostasis and physiology.

show abstract

Long-Term Outcome of Interdisciplinary Management of Patients with Duchenne Muscular Dystrophy Receiving Daily Glucocorticoid Treatment

Cited by 56 publications

References 29 publications

Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

Motor clinical progression in a series of pediatric Duchenne and Becker muscular dystrophy cases

Janus effect of glucocorticoids on differentiation of muscle fibro/adipogenic progenitors

Contact Info

Product

Resources

About