Why the study?
Nemaline myopathy is a skeletal muscle disorder caused by thin filament mutations, but many pathogenic aspects of the disease remain largely unclear.
Impairments in muscle contractility in nemaline myopathy lead to secondary nuclear and cytoskeletal defects, which can be rescued by enhancing force production.
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Nuclear defects in NM may aid diagnosis; leaves open mechanistic role and therapeutic potential.
Nemaline myopathy (NM) is a skeletal muscle disorder caused by mutations in genes that are generally involved in muscle contraction, in particular those related to the structure and/or regulation of the thin filament. Many pathogenic aspects of this disease remain largely unclear. Here, we report novel pathological defects in skeletal muscle fibres of mouse models and patients with NM: irregular spacing and morphology of nuclei; disrupted nuclear envelope; altered chromatin arrangement; and disorganisation of the cortical cytoskeleton. Impairments in contractility are the primary cause of these nuclear defects. We also establish the role of microtubule organisation in determining nuclear morphology, a phenomenon which is likely to contribute to nuclear alterations in this disease. Our results overlap with findings in diseases caused directly by mutations in nuclear envelope or cytoskeletal proteins. Given the important role of nuclear shape and envelope in regulating gene expression, and the cytoskeleton in maintaining muscle fibre integrity, our findings are likely to explain some of the hallmarks of NM, including contractile filament disarray, altered mechanical properties and broad transcriptional alterations.
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Ross et al. (2019) studied this question.
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