title: Low dystrophin levels increase survival and improve muscle pathology and function in dystrophin/utrophin double-knockout mice.
abstract: Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder caused by the lack of functional dystrophin. There is no cure, but several clinical trials aimed to restore the synthesis of functional dystrophin are underway. The dystrophin levels needed for improvement of muscle pathology, function, and overall vitality are not known. Here, we describe the mdx/utrn(-/-)/Xist(Δhs) mouse model, which expresses a range of low dystrophin levels, depending on the degree of skewing of X inactivation in a utrophin-negative background. Mdx/utrn(-/-) mice develop severe muscle weakness, kyphosis, respiratory and heart failure, and premature death closely resembling DMD pathology. We show that at dystrophin levels < 4%, survival and motor function in these animals are greatly improved. In mice expressing >4% dystrophin, histopathology is ameliorated, as well. These findings suggest that the dystrophin levels needed to benefit vitality and functioning of patients with DMD might be lower than those needed for full protection against muscle damage.
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Maaike
authors: M
authors: van Putten
authors: Margriet
authors: M
authors: Hulsker
authors: Courtney
authors: C
authors: Young
authors: Vishna D
authors: VD
authors: Nadarajah
authors: Hans
authors: H
authors: Heemskerk
authors: Louise
authors: L
authors: van der Weerd
authors: Peter A C
authors: PA
authors: 't Hoen
authors: Gert-Jan B
authors: GJ
authors: van Ommen
authors: Annemieke M
authors: AM
authors: Aartsma-Rus
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D053580:Muscle Strength / Q000235:genetics / Q000502:physiology; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000473:pathology* / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000473:pathology* / Q000503:physiopathology*; D010641:Phenotype; D049411:Utrophin / Q000172:deficiency* / Q000235:genetics
chemical_list: D015415:Biomarkers; D016189:Dystrophin; D049411:Utrophin
keywords: Becker muscular dystrophy; Duchenne muscular dystrophy; biomarkers; cardiomyopathy; mouse models