Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy

49 human patient mRNA profiles was generated using HG-U133 Plus 2.0 microarrays. Procesed in Affymetrix Expression console using Plier normalization method and later processed in Partek Genomics Suite. The clustering figure was generated using HCE clustering software. We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor β-centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are observed in bouts separated by 4 d, whereas a chronic profibrotic state was seen in bouts separated by 10 d. Treatment of asynchronously remodeling WT muscle with either prednisone or VBP15 mitigated the molecular phenotype. Our asynchronous regeneration model for pathological fibrosis and muscle wasting in the muscular dystrophies is likely generalizable to tissue failure in chronic inflammatory states in other regenerative tissues. These datasets contained profiles from 6 normal controls, 17 DMD (absence of dystrophin), 11 BMD (present but abnormal dystrophin), 7 LGMD2I (FKRP deficiency, a glycosylation defect), and 8 LGMD2B (DYSF). Patients had a broad range of ages, clinical severity of their disease, and histopathological findings, although all neuromuscular disease patients showed evidence of a dystrophic process (degeneration/regeneration of muscle fibers)