Transcriptomic analysis of mdx mouse muscles reveals a signature of early human Duchenne muscular dystrophy

Abstract

The mdx mouse (C57BL/10ScSn-DMDmdx/J) is the oldest model of Duchenne muscular dystrophy (DMD). Mdx remains popular and has not been replaced by newer mouse models, despite criticisms that mdx has a nearly normal lifespan and mild pathology while DMD remains a severe, fatal disease. At some point we noticed that the absence of mdx RNA-seq data limited our ability to assess the results of physiological work on the mouse model and to compare these results to human genetic data [1]. We carried out RNA-seq analysis of wild-type and mdx mice of 2 and 5 months of age, using three hindlimb muscles per mouse: the flexor digitorum brevis (FDB), the extensor digitorum longus (EDL) and the soleus (SOL), with a total of 55 samples. We then mined the data and found that each of the three muscles is a valid experimental model for DMD-related mouse work, even the FDB, despite a delayed pathology development. We also show that the mdx mouse muscles are enriched in metabolic, developmental, regenerational and structural pathways that have been found to be the "disease signature" of DMD in young and presymptomatic subjects [38, 39]. Additionally, we show that healthy human muscle fiber microtubules present the grid-like organization found in control rodents but perturbed in the mdx mouse. We conclude that the mdx mouse appropriately mimics the early stages of DMD, with its microtubule defects signaling fiber regeneration [35]. We hope that these results may contribute to a better understanding of the failure of regeneration as DMD progresses.