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Low dystrophin levels increase survival and improve muscle pathology and function in dystrophin/utrophin double‐knockout mice
Author(s) -
Putten Maaike,
Hulsker Margriet,
Young Courtney,
Nadarajah Vishna D.,
Heemskerk Hans,
Weerd Louise,
't Hoen Peter A. C.,
Ommen GertJan B.,
AartsmaRus Annemieke M.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-224170
Subject(s) - dystrophin , utrophin , duchenne muscular dystrophy , muscular dystrophy , mdx mouse , medicine , endocrinology , pathology , biology
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.—Van Putten, M., Hulsker, M., Young, C., Nadarajah, V. D., Heemskerk, H., van der Weerd, L., 't Hoen, P. A. C., van Ommen, G. J. B., Aartsma‐Rus, A. M. Low dystrophin levels increase survival and improve muscle pathology and function in dystrophin/utrophin double‐knockout mice. FASEB J. 27, 2484–2495 (2013). www.fasebj.org