Impaired regeneration in LGMD2A supported by increased PAX7‐positive satellite cell content and muscle‐specific microrna dysregulation |
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| Authors: | Xiomara Q. Rosales MD Vinod Malik PhD Amita Sneh PhD Lei Chen MS Sarah Lewis HT ASCP Janaiah Kota PhD Julie M. Gastier‐Foster PhD Caroline Astbury PhD Rob Pyatt PhD Shalini Reshmi PhD Louise R. Rodino‐Klapac PhD K. Reed Clark PhD Jerry R. Mendell MD Zarife Sahenk MD PhD |
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| Affiliation: | 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, 43205;3. The Ohio State University, , Columbus, Ohio;4. Department of Pathology and Laboratory Medicine, The Research Institute at Nationwide Children's Hospital, , Columbus, Ohio |
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| 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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| Keywords: | fibrosis LGMD2A microRNA muscle regeneration Pax |
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