#apaperaday: Mineralocorticoid receptor antagonists and glucocorticoids differentially affect skeletal muscle inflammation and pathology in muscular dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Mineralocorticoid receptor antagonists and glucocorticoids differentially affect skeletal muscle inflammation and pathology in muscular dystrophy

Today’s pick from Howard et al in Journal of Clinical Investigation Insight on glucocorticoid and mineral receptors (GR and MR) in mdx mice doi 10.1172/jci.insight.159875

Duchenne is characterized by chronic muscle damage, which results in chronic inflammation. Normally synchronized steps occur during muscle damage: inflammation (remove debris), deposition of connective tissue and muscle regeneration. Chronic inflammation messes things up.

It increases fibrosis deposition & inhibits muscle regeneration. glucocorticosteroids (GC) can inhibit disease pathology for Duchenne – likely by inhibition of inflammatory response. However, GC do more than this (don’t forget that while this paper focuses only on inflammation).

GC are antagonists of the GR, but can also activate the MR – this is thought to lead to most of the side effects of chronic steroid use. MR antagonists (blockers) can also have anti-inflammatory properties and that would be expected to lead to less side effects.

here authors study the effect on inflammatory cells in quadriceps and diaphragm of mdx mice after treatment with GC (prednisone) and an MR antagonist (spironolactone). The dose of spironolactone used appears to be very high compared to what is used in human.

37.5 mg/kg is used, while in Duchenne trials 50 mg was used (for patients weighing >50 kg probably so 1 mg/kg) https://pubmed.ncbi.nlm.nih.gov/31549577/. For prednisone 1 mg/kg was used, which is slightly higher than what is used in the clinic (0.75 mg/kg).

Authors checked the effect on inflammation by measuring factors produced by inflammatory cells: chemokines and cytokines. Both prednisone and spironolactone reduced production of these factors in quadriceps. In diaphragm however prednisone increased production for some factors.

Authors then studied the inflammatory cells present in the muscles. No impact was seen of spironolactone treatment on the cell types, while prednisone treatment increased the amount of a specific macrophage (F4/80(hi) for the initiated – which I am not).

Finally, authors isolated RNA from the inflammatory cells to study their gene expression. Prednisone changed expression of 686 genes, spironolactone of 263 genes. Only altered 53 genes were shared between prednisone and spironolactone.

Authors zoom in on one transcript: fibronectine, a protein leading to fibrosis. This was higher in prednisone treated mice. Authors performed a short term treatment showing that more fibronectine is produced in diaphragms of prednisone treated mice.

Authors provide a long discussion which focuses on the different immunological pathways and how steroid treatment and spironolactone treatment can have influenced this. However, they do not discuss limitations much. 

1. This was very short term treatment (2 weeks). Duchenne patients will receive treatment chronically.
2. These were mdx mice during the active regeneration phase (3-6 weeks old), which is not comparable with the human situation of impaired regeneration. So things are only partially translatable
3. I am not sure about the dose used for spirononlactone. It seems to be much higher than what can be used in humans…so how relevant is this comparison?
4. Authors did not study function of the muscle and focus only on one pathway while more is happening when dystrophin is lost
5. Authors do not mention vamorolone. This is a dissociative steroid tested in Duchenne patients currently. I understand they cannot do a head to head to head comparison, but authors should at least mention it.
6. We know that only blocking inflammation in Duchenne does not lead to a significant effect on disease progression. So prednisone/GC do more in Duchenne patients to slow progression. Knowing this, I’m not sure the focus on inflammatory response is the most relevant.

I’m not saying the paper is not good – just would have liked it more if the authors had put it in a broader context than only inflammation.