title: Dystrophin-deficient pigs provide new insights into the hierarchy of physiological derangements of dystrophic muscle.
abstract: Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked dystrophin (DMD) gene. The absence of dystrophin protein leads to progressive muscle weakness and wasting, disability and death. To establish a tailored large animal model of DMD, we deleted DMD exon 52 in male pig cells by gene targeting and generated offspring by nuclear transfer. DMD pigs exhibit absence of dystrophin in skeletal muscles, increased serum creatine kinase levels, progressive dystrophic changes of skeletal muscles, impaired mobility, muscle weakness and a maximum life span of 3 months due to respiratory impairment. Unlike human DMD patients, some DMD pigs die shortly after birth. To address the accelerated development of muscular dystrophy in DMD pigs when compared with human patients, we performed a genome-wide transcriptome study of biceps femoris muscle specimens from 2-day-old and 3-month-old DMD and age-matched wild-type pigs. The transcriptome changes in 3-month-old DMD pigs were in good concordance with gene expression profiles in human DMD, reflecting the processes of degeneration, regeneration, inflammation, fibrosis and impaired metabolic activity. In contrast, the transcriptome profile of 2-day-old DMD pigs showed similarities with transcriptome changes induced by acute exercise muscle injury. Our studies provide new insights into early changes associated with dystrophin deficiency in a clinically severe animal model of DMD.
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Klymiuk
authors.forename: Andreas
authors.initials: A
authors.lastname: Blutke
authors.forename: Alexander
authors.initials: A
authors.lastname: Graf
authors.forename: Sabine
authors.initials: S
authors.lastname: Krause
authors.forename: Katinka
authors.initials: K
authors.lastname: Burkhardt
authors.forename: Annegret
authors.initials: A
authors.lastname: Wuensch
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.forename: Barbara
authors.initials: B
authors.lastname: Kessler
authors.forename: Valeri
authors.initials: V
authors.lastname: Zakhartchenko
authors.forename: Mayuko
authors.initials: M
authors.lastname: Kurome
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kemter
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagashima
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.forename: Nadja
authors.initials: N
authors.lastname: Herbach
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Wanke
authors.forename: Annemieke
authors.initials: A
authors.lastname: Aartsma-Rus
authors.forename: Christian
authors.initials: C
authors.lastname: Thirion
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Maggie C
authors.initials: MC
authors.lastname: Walter
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
mesh_terms: D000375:Aging; D000818:Animals; D001724:Birth Weight; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005260:Female; D018390:Gene Targeting; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D053652:Nuclear Transfer Techniques; D010641:Phenotype; D017384:Sequence Deletion; D013314:Stress, Mechanical; D013552:Swine; D059467:Transcriptome
chemical_list: D016189:Dystrophin