Klotho gene silencing promotes pathology in the mdx mouse model of Duchenne muscular dystrophy

Michelle Wehling-Henricks, Zhenzhi Li, Catherine Lindsey, Ying Wang, Steven S. Welc, Julian N. Ramos, Négar Khanlou, Makoto Kuro-O, James G. Tidball

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Duchenne muscular dystrophy (DMD) is a lethal muscle disease involving progressive loss of muscle regenerative capacity and increased fibrosis. We tested whether epigenetic silencing of the klotho gene occurs in the mdx mouse model of DMD and whether klotho silencing is an important feature of the disease. Our findings show that klotho undergoes muscle-specific silencing at the acute onset of mdx pathology. Klotho experiences increased methylation of CpG sites in its promoter region, which is associated with gene silencing, and increases in a repressive histone mark, H3K9me2. Expression of a klotho transgene in mdx mice restored their longevity, reduced muscle wasting, improved function and greatly increased the pool of muscle-resident stem cells required for regeneration. Reductions of fibrosis in late, progressive stages of the mdx pathology achieved by transgene expression were paralleled by reduced expression of Wnt target genes (axin-2), transforming growth factor-beta (TGF-β1) and collagens types 1 and 3, indicating that Klotho inhibition of the profibrotic Wnt/TGFβ axis underlies its anti-fibrotic effect in aging, dystrophic muscle. Thus, epigenetic silencing of klotho during muscular dystrophy contributes substantially to lost regenerative capacity and increased fibrosis of dystrophic muscle during late progressive stages of the disease.

Original languageEnglish (US)
Pages (from-to)2465-2482
Number of pages18
JournalHuman molecular genetics
Volume25
Issue number12
DOIs
StatePublished - Jun 15 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Wehling-Henricks, M., Li, Z., Lindsey, C., Wang, Y., Welc, S. S., Ramos, J. N., Khanlou, N., Kuro-O, M., & Tidball, J. G. (2016). Klotho gene silencing promotes pathology in the mdx mouse model of Duchenne muscular dystrophy. Human molecular genetics, 25(12), 2465-2482. https://doi.org/10.1093/hmg/ddw111