In dystrophic <i>mdx</i> hindlimb muscles where fibrosis is limited, versican haploinsufficiency transiently improves contractile function without reducing inflammation

Versican is increased with inflammation and fibrosis, and is upregulated in Duchenne muscular dystrophy. In fibrotic diaphragm muscles from dystrophic <i>mdx</i> mice, genetic reduction of versican attenuated macrophage infiltration and improved contractile function. Versican is also implicated in myogenesis. Here, we investigated whether versican modulated <i>mdx</i> 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 (α-methylprednisolone) modify versican expression. To genetically reduce versican, female <i>mdx</i> and male versican haploinsufficient (hdf) mice were bred resulting in male <i>mdx</i>-hdf and <i>mdx</i> (control) pups. Versican expression, contractile function, and pathology were evaluated in hindlimb muscles. Versican immunoreactivity was greater in slow versus fast hindlimb muscles. <i>Versican</i> mRNA transcripts were reduced by α-methylprednisolone in soleus, but not in fast extensor digitorum longus, muscles. In juvenile (6-wk-old) <i>mdx</i>-hdf mice, versican expression was most robustly decreased in soleus muscles leading to improved 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 <i>mdx</i>-hdf mice and <i>mdx</i> littermates. Improvements in soleus contractile function were not retained in adult (20-wk-old) <i>mdx</i>-hdf mice. In conclusion, soleus muscles from juvenile <i>mdx</i> mice were most responsive to pharmacological or genetic approaches targeting versican; however, the benefits of versican reduction were limited due to low fibrosis. Preclinical matrix research in dystrophy should account for muscle phenotype (including age) and the interdependence between inflammation and fibrosis. <b>NEW & NOTEWORTHY</b> The proteoglycan versican is upregulated in muscular dystrophy. In fibrotic diaphragm muscles from <i>mdx</i> mice, versican reduction attenuated macrophage infiltration and improved performance. Here, in hindlimb muscles from 6- and 20-wk-old <i>mdx</i> mice, where pathology is mild, versican reduction did not decrease inflammation and contractile function improvements were limited to juvenile mice. In dystrophic <i>mdx</i> muscles, the association between versican and inflammation is mediated by fibrosis, demonstrating interdependence between the immune system and extracellular matrix.