Abstract

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by mutations in the dystrophin gene. To examine the influence of muscle structure on the pathogenesis of DMD we generated mdx4cv:desmin double knockout (dko) mice. The dko male mice died of apparent cardiorespiratory failure at a median age of 76 days compared to 609 days for the desmin−/− mice. An ∼2.5 fold increase in utrophin expression in the dko skeletal muscles prevented necrosis in ∼91% of 1a, 2a and 2d/x fiber-types. In contrast, utrophin expression was reduced in the extrasynaptic sarcolemma of the dko fast 2b fibers leading to increased membrane fragility and dystrophic pathology. Despite lacking extrasynaptic utrophin, the dko fast 2b fibers were less dystrophic than the mdx4cv fast 2b fibers suggesting utrophin-independent mechanisms were also contributing to the reduced dystrophic pathology. We found no overt change in the regenerative capacity of muscle stem cells when comparing the wild-type, desmin−/−, mdx4cv and dko gastrocnemius muscles injured with notexin. Utrophin could form costameric striations with α-sarcomeric actin in the dko to maintain the integrity of the membrane, but the lack of restoration of the NODS (nNOS, α-dystrobrevin 1 and 2, α1-syntrophin) complex and desmin coincided with profound changes to the sarcomere alignment in the diaphragm, deposition of collagen between the myofibers, and impaired diaphragm function. We conclude that the dko mice may provide new insights into the structural mechanisms that influence endogenous utrophin expression that are pertinent for developing a therapy for DMD.

Highlights

  • Duchenne muscular dystrophy (DMD) is an X-linked muscle disorder that affects approximately 1:4000 boys [1]

  • Increased expression of utrophin prevented necrosis of dko skeletal muscle fibers We examined whether the dystrophic pathology in the dko muscles was improved by an increase in utrophin expression

  • In conclusion, we report a significant increase in utrophin expression in dko skeletal muscles that prevented necrosis in a fiber-type specific manner

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Summary

Introduction

Duchenne muscular dystrophy (DMD) is an X-linked muscle disorder that affects approximately 1:4000 boys [1]. Skeletal muscle necrosis in the mdx mouse model of DMD is prevented by the expression of a full-length utrophin transgene when expressed at twice the levels of the endogenous utrophin [26]. Utrophin expression in DMD patients correlates with the severity of disease and time to wheelchair demonstrating the therapeutic potential of utrophin in humans [25,27,28,29,30,31]. An utrophin therapy would benefit all DMD patients and circumvent a potential T-cell mediated immune response that could impair the long-term benefit of prospective dystrophin replacement strategies [32,33,34]. While promising utrophin-mediated therapies are being tested in clinical trials [33,35], the mechanisms that influence utrophin expression are not fully understood

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