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Impaired regeneration in LGMD2A supported by increased PAX7-positive satellite cell content and muscle-specific microrna dysregulation

Authors

  • Xiomara Q. Rosales MD,

    1. Neuromuscular Center at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics and Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    3. The Ohio State University, Columbus, Ohio
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  • Vinod Malik PhD,

    1. Neuromuscular Center at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics and Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Amita Sneh PhD,

    1. Neuromuscular Center at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics and Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Lei Chen MS,

    1. Neuromuscular Center at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics and Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Sarah Lewis HT, ASCP,

    1. Neuromuscular Center at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics and Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Janaiah Kota PhD,

    1. Neuromuscular Center at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics and Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Julie M. Gastier-Foster PhD,

    1. The Ohio State University, Columbus, Ohio
    2. Department of Pathology and Laboratory Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Caroline Astbury PhD,

    1. The Ohio State University, Columbus, Ohio
    2. Department of Pathology and Laboratory Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Rob Pyatt PhD,

    1. The Ohio State University, Columbus, Ohio
    2. Department of Pathology and Laboratory Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Shalini Reshmi PhD,

    1. The Ohio State University, Columbus, Ohio
    2. Department of Pathology and Laboratory Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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  • Louise R. Rodino-Klapac PhD,

    1. Department of Pediatrics and Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. The Ohio State University, Columbus, Ohio
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  • K. Reed Clark PhD,

    1. Department of Pediatrics and Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. The Ohio State University, Columbus, Ohio
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  • Jerry R. Mendell MD,

    1. Neuromuscular Center at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. Department of Pediatrics and Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    3. The Ohio State University, Columbus, Ohio
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  • Zarife Sahenk MD, PhD

    Corresponding author
    1. Department of Pediatrics and Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    2. The Ohio State University, Columbus, Ohio
    3. Department of Pathology and Laboratory Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
    • Neuromuscular Center at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
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Correspondence to: Z. Sahenk; e-mail: zarife.sahenk@nationwidechildrens.org

Abstract

Introduction: Recent in vitro studies suggest that CAPN3 deficiency leads initially to accelerated myofiber formation followed by depletion of satellite cells (SC). In normal muscle, up-regulation of miR-1 and miR-206 facilitates transition from proliferating SCs to differentiating myogenic progenitors. Methods: We examined the histopathological stages, Pax7 SC content, and muscle-specific microRNA expression in biopsy specimens from well-characterized LGMD 2A patients to gain insight into disease pathogenesis. Results: Three distinct stages of pathological changes were identified that represented the continuum of the dystrophic process from prominent inflammation with necrosis and regeneration to prominent fibrosis, which correlated with age and disease duration. Pax7-positive SCs were highest in the fibrotic group and correlated with down-regulation of miR-1, miR-133a, and miR-206. Conclusions: These observations, and other published reports, are consistent with microRNA dysregulation leading to inability of Pax7-positive SCs to transit from proliferation to differentiation. This results in impaired regeneration and fibrosis. Muscle Nerve 47: 731–739, 2013

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