Stupka, N. | bioRxiv Science

bioRxiv2024

Moderate-term dimethyl fumarate treatment reduces pathology of dystrophic skeletal and cardiac muscle in a mouse model

In Duchenne muscular dystrophy (DMD), corticosteroids significantly slow disease progression and have been used as a standard of care tool for more than 30 years. However, corticosteroids also impart side effects severe enough to preclude use in some patients. There remains an unmet need for new therapeutics that target the flow-on pathogenic mechanisms of DMD with a more favourable side-effect profile. We have previously demonstrated that short-term treatment with dual-purpose anti-inflammatory, anti-oxidative dimethyl fumarate (DMF), a drug with indication and established safety data in Multiple Sclerosis, more selectively modulates Duchenne (mdx) immunology than the frequently used corticosteroid, prednisone (PRED). Here, we assess the effect of moderate-term DMF treatment over 5 weeks in the typically mild mdx mouse model that we aggravated using exercise. We show that like PRED, DMF maintains anti-inflammatory action but with additional anti-fibrotic and anti-lipogenic effects on muscle with moderate-term use. This study supports our previous work highlighting DMF as a possible repurposing candidate for DMD, especially for patients who cannot tolerate chronic corticosteroid treatment.

pathology↗

bioRxiv2024

In dystrophic mdx hindlimb muscles where fibrosis is limited versican haploinsufficiency transiently improves contractile function without decreasing inflammation

The provisional matrix protein versican is upregulated in Duchenne muscular dystrophy. Versican heightens inflammation in fibrotic diseases and is involved in myogenesis. In fibrotic diaphragm muscles from dystrophic mdx mice, versican reduction attenuated macrophage infiltration and improved contractile function. We investigated the association between versican and mdx hindlimb muscle pathology, where inflammation and regeneration are increased but fibrosis is minimal. Immunohistochemistry and qRT-PCR were used to assess how fiber type and glucocorticoids (-methylprednisolone) modulate versican expression. Female mdx and male versican haploinsufficient (hdf) mice were bred resulting in male mdx-hdf and mdx (control) pups. Versican expression, contractile function, and pathology were evaluated in fast extensor digitorum longus (EDL) and slow soleus muscles, excised under medetomidine-midazolam- fentanyl anesthesia. Versican immunoreactivity was highest in soleus muscles. Versican mRNA transcripts were reduced by -methylprednisolone in soleus, but not EDL, muscles. Versican expression was decreased in soleus muscles from 6-week-old mdx-hdf mice leading to increased force output and a modest reduction in fatiguability. These functional benefits were not accompanied by decreased inflammation; muscle architecture, regeneration markers, and fiber type also did not differ between genotypes. Improvements in soleus function were lost in adult (20-week-old) mdx-hdf mice with no significant effect of versican haploinsufficiency on macrophage infiltration and regeneration markers. Soleus muscles from juvenile mdx mice were most responsive to pharmacological or genetic approaches targeting versican; however, the benefits of versican reduction were limited due to low fibrosis. Pre-clinical matrix research in dystrophy should account for muscle phenotype and the interdependence between the fibrosis and inflammation. NEW & NOTEWORTHYThe proteoglycan versican is upregulated in muscular dystrophy. In fibrotic diaphragm muscles from mdx mice, versican reduction attenuated macrophage infiltration and improved performance. Here, in hindlimb muscles from 6- and 20-week-old mdx mice, where pathology is mild, versican reduction did not decrease inflammation and contractile function improvements were limited to juvenile mice. In dystrophic mdx muscles, the association between versican and inflammation is mediated by fibrosis, demonstrating interdependence between the immune system and extracellular matrix.

physiology↗