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Abstract
Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder resulting from mutations in the dystrophin gene. The mdx/utrn−/− mouse, lacking in both dystrophin and its autosomal homologue utrophin, is commonly used to model the clinical symptoms of DMD. Interestingly, these mice are infertile but the mechanisms underlying this phenomenon remain unclear. Using dystrophin deficient mdx mouse and utrophin haplodeficient mdx/utrn+/− mouse models, we demonstrate the contribution of Dp427 (full-length dystrophin) and utrophin to testis and epididymis development, as well as spermatogenesis. We show that Dp427 deficiency disturbed the balance between proliferation and apoptosis of germ cells during spermatogenesis, which was further disrupted with utrophin haplodeficiency, deciphering a compensatory role of utrophin for dystrophin in the male reproductive system. In the spermatozoa, we have found a compensatory response of utrophin to dystrophin deficiency - namely the upregulation and relocation of utrophin to the flagellar midpiece. This study demonstrates the contribution of Dp427 and utrophin in male fertility, suggesting a potential pathology in DMD patients.
Highlights
Lack of the protein dystrophin results in Duchenne muscular dystrophy (DMD), a devastating hereditary childhood disease
The results suggest the involvement of dystrophin and utrophin during the development of male reproductive organs, the contribution of utrophin in mdx/utrn+/− mouse infertility needs further investigation
In DMD patients, the level of utrophin negatively correlates with the disease severity[11, 17]
Summary
Lack of the protein dystrophin results in Duchenne muscular dystrophy (DMD), a devastating hereditary childhood disease. Dystrophin is a rod-shaped cytoskeletal protein linking extracellular laminin and intracellular F-actin in muscles to mediate force transmission and signal transduction[4,5,6]. In addition to this mechanical role, dystrophin regulates asymmetric division of satellite cells by regulating the polarity of a microtubule kinase MARK27. Sarcolemma recruitment and upregulation of utrophin in the skeletal muscle of mdx mice, the most common animal model of DMD, with a nonsense mutation in exon 23, implies that utrophin plays a role to compensate for the loss of dystrophin[14,15,16]. We used mdx and mdx/utrn+/− mice to unravel the role played by dystrophin and utrophin in the male reproductive system
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