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J Cell Biol. 2014 Oct 13;207(1):139-58. doi: 10.1083/jcb.201402079.

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

Author information

1
Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010.
2
The Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA 24061.
3
Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 ehoffman@childrensnational.org.

Abstract

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.

PMID:
25313409
PMCID:
PMC4195829
DOI:
10.1083/jcb.201402079
[Indexed for MEDLINE]
Free PMC Article

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