Abstract

ABSTRACTDystrophin, encoded by the DMD gene on the X chromosome, stabilizes the sarcolemma by linking the actin cytoskeleton with the dystrophin-glycoprotein complex (DGC). In-frame mutations in DMD cause a milder form of X-linked muscular dystrophy, called Becker muscular dystrophy (BMD), characterized by the reduced expression of truncated dystrophin. So far, no animal model with in-frame mutations in Dmd has been established. As a result, the effect of in-frame mutations on the dystrophin expression profile and disease progression of BMD remains unclear. In this study, we established a novel rat model carrying in-frame Dmd gene mutations (IF rats) and evaluated the pathology. We found that IF rats exhibited reduced expression of truncated dystrophin in a proteasome-independent manner. This abnormal dystrophin expression caused dystrophic changes in muscle tissues but did not lead to functional deficiency. We also found that the expression of additional dystrophin named dpX, which forms the DGC in the sarcolemma, was associated with the appearance of truncated dystrophin. In conclusion, the outcomes of this study contribute to the further understanding of BMD pathology and help elucidate the efficiency of dystrophin recovery treatments in Duchenne muscular dystrophy, a more severe form of X-linked muscular dystrophy.

Highlights

  • Dystrophin, a 427 kDa protein crucial for sarcolemma integrity, is encoded by the dystrophin gene (DMD gene) on the X chromosome (Hoffman et al, 1987)

  • In-frame mutations in Duchenne muscular dystrophy (DMD) cause a milder form of X-linked muscular dystrophy, called Becker muscular dystrophy (BMD), characterized by the reduced expression of truncated dystrophin

  • We found that the expression of additional dystrophin named dpX, which forms the dystrophin-glycoprotein complex (DGC) in the sarcolemma, is associated with the appearance of truncated dystrophin

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Summary

Introduction

Dystrophin (dp427), a 427 kDa protein crucial for sarcolemma integrity, is encoded by the dystrophin gene (DMD gene) on the X chromosome (Hoffman et al, 1987). Dystrophin functions as a sarcolemma-supporting protein during muscle contraction by linking the intracellular actin cytoskeleton to transmembrane components of the dystrophinassociated glycoprotein complex (DGC). The function of dystrophin requires its N-terminal and C-terminal sequences, which are essential for binding with the cytoskeletal actin filament and with βdystroglycan (βDG), respectively, in DGC (Campbell and Kahl, 1989; Rybakova et al, 1996). Becker muscular dystrophy (BMD) is a form of X-linked muscular dystrophy caused by in-frame mutations in DMD. In BMD muscle tissues, a truncated form of dystrophin (tdp427) is expressed, based on the missing genomic sequence. The pathology of this disease is generally milder than that of Duchenne muscular dystrophy (DMD), known as a more severe form of X-linked muscular dystrophy caused by the complete loss of the dystrophin protein. The clinical severity of BMD varies among individuals, from asymptomatic to as severe as DMD (Koenig et al, 1989)

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