Abstract
Duchenne muscular dystrophy (DMD) is a lethal, X-linked muscle-wasting disease caused by lack of the cytoskeletal protein dystrophin. Constitutive utrophin expression, a structural and functional paralogue of dystrophin, can successfully prevent the dystrophic pathology in the dystrophin-deficient mdx mouse model. In dystrophic muscles, utrophin is increased as part of the repair process and localized at the sarcolemma of regenerating myofibers. The presence of developmental myosin such as embryonic myosin (MyHC-emb) and neonatal represents a useful marker of muscle regeneration and a meaningful indicator of muscle damage, which correlates with the clinical severity of milder Becker muscular dystrophy and DMD patients. In the present study, we demonstrate that MyHC-emb is a robust marker of regeneration at different ages and in different skeletal muscles. We also evaluate the correlation between utrophin, dystrophin and MyHC-emb in wild-type (wt) and regenerating dystrophic muscles. Restoration of dystrophin significantly reduced MyHC-emb levels. Similarly, overexpression of utrophin in the transgenic mdx-Fiona mice reduced the number of MyHC-emb positive fibers to wt level, prevented the regenerative process and rescued the muscle function. In contrast, the absence of utrophin in the dystrophin-deficient double-knockout mice resulted in a higher MyHC-emb content and in a more severe dystrophic pathophysiology than in mdx mice. These data illustrate the importance of monitoring utrophin and MyHC-emb levels in the preclinical evaluation of therapies and provide translational support for the use of developmental myosin as a disease biomarker in DMD clinical trials.
Highlights
Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disease affecting 1 in 5000 newborn males [1,2]
We investigated the expression of MyHCemb, a well-established marker of regeneration [50] in correlation with dystrophin and utrophin levels in diverse murine skeletal muscles at different ages in order to assess its utility in monitoring muscle health in preclinical studies
In the dystrophic muscles described, recurrent myofiber damage elicits a constant need for skeletal muscle regeneration and the chronic cycles of myofiber necrosis and repair are a hallmark of the disease [1]
Summary
Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disease affecting 1 in 5000 newborn males [1,2]. This disorder is caused by mutations in the DMD gene (OMIM 300377, Xp21.2-p21.1) [3,4], presenting one of the highest rates in new mutations, which are predominantly deletions of the gene [5]. DMD patients manifest the first onset of symptoms such as walking abnormalities, abnormal gait, proximal muscle weakness and calf muscle pseudo-hypertrophy in their early infancy These symptoms progress relentlessly to loss of ambulation generally by the age of 12 years [9] and patients develop respiratory and cardiac failure leading to premature death by their early 30s [10]
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