title: Dystrophic mdx mice develop severe cardiac and respiratory dysfunction following genetic ablation of the anti-inflammatory cytokine IL-10.
abstract: Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease that causes respiratory and cardiac failure. Inflammation is a key pathological characteristic of dystrophic muscle lesion formation, but its role and regulation in the disease time course has not been sufficiently examined. In the present study, we used IL-10(-/-)/mdx mice lacking both dystrophin and the anti-inflammatory cytokine, interleukin-10 (IL-10), to investigate whether a predisposition to inflammation affects the severity of DMD with advancing age. The IL-10 deficiency caused a profound DMD phenotype in the dystrophic heart such as muscle degeneration and extensive myofiber loss, but the limb muscle and diaphragm morphology of IL-10(-/) (-)/mdx mice was similar to that of mdx mice. Extensive infiltrates of pro-inflammatory M1 macrophages in regeneration of cardiotoxin-injured muscle, altered M1/M2 macrophage phenotype and increased pro-inflammatory cytokines/chemokines production were observed in the diaphragm and heart of IL-10(-/-)/mdx mice. We characterized the IL-10(-/-)/mdx mice as a dystrophic model with chronic inflammation and severe cardiorespiratory dysfunction, as evidenced by decreased percent fractional shortening (%FS) and ejection fraction percent (EF%) on echocardiography, reduced lower tidal volume on whole-body plethysmography. This study suggests that a predisposition to inflammation is an important indicator of DMD disease progression. Therefore, the development of anti-inflammatory strategies may help in slowing down the cardiorespiratory dysfunction on DMD.
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nitahara-Kasahara
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hayashita-Kinoh
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Chiyo
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Akiyo
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Okada
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan t-okada@ncnp.go.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada
mesh_terms: D000818:Animals; D054715:Cardiotoxins / Q000494:pharmacology; D003964:Diaphragm / Q000378:metabolism / Q000503:physiopathology*; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics*; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D012038:Regeneration; D012129:Respiratory Function Tests; D012720:Severity of Illness Index; D013318:Stroke Volume; D013990:Tidal Volume
chemical_list: D054715:Cardiotoxins; D016189:Dystrophin; C556062:IL10 protein, mouse; C085339:apo-dystrophin 1; D016753:Interleukin-10