title: Klotho gene silencing promotes pathology in the mdx mouse model of Duchenne muscular dystrophy.
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.
authors.affiliation: Department of Integrative Biology and Physiology.
authors.forename: Michelle
authors.initials: M
authors.lastname: Wehling-Henricks
authors.affiliation: Department of Integrative Biology and Physiology.
authors.forename: Zhenzhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Integrative Biology and Physiology.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lindsey
authors.affiliation: Molecular, Cellular & Integrative Physiology Program, University of California, Los Angeles, CA 90095-1606, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Integrative Biology and Physiology.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Welc
authors.affiliation: Department of Integrative Biology and Physiology.
authors.forename: Julian N
authors.initials: JN
authors.lastname: Ramos
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095-1732, USA.
authors.forename: Négar
authors.initials: N
authors.lastname: Khanlou
authors.affiliation: Division of Anti-Aging Medicine, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-O
authors.affiliation: Department of Integrative Biology and Physiology jtidball@physci.ucla.edu.|Molecular, Cellular & Integrative Physiology Program, University of California, Los Angeles, CA 90095-1606, USA.|Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095-1732, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Tidball
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000096:biosynthesis; D024042:Collagen Type I / Q000096:biosynthesis; D024061:Collagen Type III / Q000096:biosynthesis; D004195:Disease Models, Animal; D005355:Fibrosis / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D000090265:Klotho Proteins; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology; D012038:Regeneration / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; D024042:Collagen Type I; D024061:Collagen Type III; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D005966:Glucuronidase; D000090265:Klotho Proteins