A scalable, clinically severe pig model for Duchenne muscular dystrophy

Stirm, Michael; Fonteyne, Lina Marie; Shashikadze, Bachuki; Lindner, Magdalena; Chirivi, Maila; Lange, Andreas; Kaufhold, Clara; Mayer, Christian; Medugorac, Ivica; Kessler, Barbara; Kurome, Mayuko; Zakhartchenko, Valeri; Hinrichs, Arne; Kemter, Elisabeth; Krause, Sabine; Wanke, Rüdiger; Arnold, Georg J.; Wess, Gerhard; Nagashima, Hiroshi; de Angelis, Marin Hrabe; Flenkenthaler, Florian; Kobelke, Levin Arne; Bearzi, Claudia; Rizzi, Roberto; Bähr, Andreas; Reese, Sven ; Matiasek, Kaspar; Walter, Maggie C.; Kupatt, Christian; Ziegler, Sibylle; Bartenstein, Peter; Fröhlich, Thomas; Klymiuk, Nikolai; Blutke, Andreas and Wolf, Eckhard (19. November 2021): A scalable, clinically severe pig model for Duchenne muscular dystrophy. In: Disease Models & Mechanisms, Vol. 14, No. 12

Abstract

Large animal models for Duchenne muscular dystrophy (DMD) are crucial for evaluation of diagnostic procedures and treatment strategies. Pigs cloned from male cells lacking DMD exon 52 (DMDΔ52) resemble molecular, clinical and pathological hallmarks of DMD, but die before sexual maturity and cannot be propagated by breeding. Therefore, we generated female DMD+/- carriers. A single founder animal had 11 litters with 29 DMDY/-, 34 DMD+/- as well as 36 male and 29 female wild-type offspring. Breeding with F1 and F2 DMD+/- carriers resulted in additional 114 DMDY/- piglets. With intensive neonatal management, the majority survived for 3-4 months, providing statistically relevant cohorts for experimental studies. Pathological investigations and proteome studies of skeletal muscles and myocardium confirmed the resemblance of human disease mechanisms. Importantly, DMDY/- pigs reveal progressive myocardial fibrosis and increased expression of connexin-43, associated with significantly reduced left ventricular ejection fraction already at age 3 months. Furthermore, behavioral tests provided evidence for impaired cognitive ability. Our breeding cohort of DMDΔ52 pigs and standardized tissue repositories provide important resources for studying DMD disease mechanisms and for testing novel treatment strategies.

• Item Type: Journal article
• EU Funded Grant Agreement Number: 812660
• EU Projects: Horizon 2020; Horizon 2020 > Marie Skłodowska Curie Actions
• Form of publication: Publisher's Version
• Keywords: Duchenne muscular dystrophy; Pig model; Pathology; Proteomics; Biobank; Carrier
• Faculties: Veterinary Medicine > Department of Veterinary Medicine > Lehrstuhl für Molekulare Tierzucht und Biotechnologie; Veterinary Medicine > Centre for Clinical Veterinary Medicine; Veterinary Medicine > Centre for Clinical Veterinary Medicine > Institut für Tierpathologie
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1754-8403
• Annotation: This project was supported by the ForTra gGmbH für Forschungstransfer der Else Kröner-Fresenius-Stiftung (2018_T20). In addition, the project received funding from the European Union's H2020 Marie Skłodowska-Curie Actions (812660, DohART-NET; 760986, iNanoBIT). Open Access funding provided by the Ludwig-Maximilians-Universität München. Deposited in PMC for immediate release.
• Language: English