Dystrophin-deficient pigs provide new insights into the hierarchy of physiological derangements of dystrophic muscle

Nikolai Klymiuk, Andreas Blutke, Alexander Graf, Sabine Krause, Katinka Burkhardt, Annegret Wuensch, Stefan Krebs, Barbara Kessler, Valeri Zakhartchenko, Mayuko Kurome, Elisabeth Kemter, Hiroshi Nagashima, Benedikt Schoser, Nadja Herbach, Helmut Blum, Rü diger Wanke, Annemieke Aartsma-Rus, Christian Thirion, Hanns Lochmü ller, Maggie C. WalterEckhard Wolf

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

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. DMDpigs 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-oldand3-month-oldDMDandage-matched wild-type pigs. Thetranscriptomechanges in3-month-oldDMDpigs were ingoodconcordance withgene expression profiles inhumanDMD, 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.

Original languageEnglish
Article numberddt287
Pages (from-to)4368-4382
Number of pages15
JournalHuman Molecular Genetics
Volume22
Issue number21
DOIs
StatePublished - Nov 2013
Externally publishedYes

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