Alternative splicing alterations of Ca2+ handling genes are associated with Ca2+ signal dysregulation in myotonic dystrophy type 1 (DM1) and type 2 (DM2) myotubes. Issue 4 (June 2014)

• Record Type: Journal Article
• Authors: Santoro, Massimo; Piacentini, Roberto; Masciullo, Marcella; Bianchi, Maria Laura Ester; Modoni, Anna; Podda, Maria Vittoria; Ricci, Enzo; Silvestri, Gabriella; Grassi, Claudio
• Is Part Of: Neuropathology & applied neurobiology. Volume 40:Issue 4(2014)
• Page Start: 464
• Page End: 476
• Publication Date: 2014-06
• Subjects: Nervous system -- Diseases -- Pathology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/nan.12076
• Languages: English
• ISSNs: 0305-1846

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="nan12076-sec-0001" sec-type="section"> <title>Aims</title> <p>The pathogenesis of myotonic dystrophy type 1 (DM1) and type 2 (DM2) has been related to the aberrant splicing of several genes, including those encoding for ryanodine receptor 1 (<italic>RYR1</italic>), sarcoplasmatic/endoplasmatic Ca<sup>2+</sup>‐ATPase (<italic>SERCA</italic>) and α<sub>1S</sub> subunit of voltage‐gated Ca<sup>2+</sup> channels (<italic>Ca<sub>v</sub>1.1</italic>). The aim of this study is to determine whether alterations of these genes are associated with changes in the regulation of intracellular Ca<sup>2+</sup> homeostasis and signalling.</p> </sec> <sec id="nan12076-sec-0002" sec-type="section"> <title>Methods</title> <p>We analysed the expression of <italic>RYR1</italic>, <italic>SERCA</italic> and <italic>Ca<sub>v</sub>1.1</italic> and the intracellular Ca<sup>2+</sup> handling in cultured myotubes isolated from DM1, DM2 and control muscle biopsies by semiquantitative RT‐PCR and confocal Ca<sup>2+</sup> imaging respectively.</p> </sec> <sec id="nan12076-sec-0003" sec-type="section"> <title>Results</title> <p>(i) The alternative splicing of <italic>RYR1</italic>, <italic>SERCA</italic> and <italic>Ca<sub>v</sub>1.1</italic> was more severely affected in DM1 than in DM2 myotubes; (ii) DM1 myotubes exhibited higher resting intracellular Ca<sup>2+</sup> levels than DM2; (iii) the amplitude of intracellular Ca<sup>2+</sup> transients induced by sustained membrane depolarization was higher in DM1 myotubes than in controls, whereas DM2 showed opposite behaviour; and (iv) in both DM myotubes, Ca<sup>2+</sup> release from sarcoplasmic reticulum through RYR1 was lower than in controls.</p> </sec> <sec id="nan12076-sec-0004" sec-type="section"> <title>Conclusion</title> <p>The aberrant splicing of <italic>RYR1</italic>, <italic>SERCA1</italic> and <italic>Ca<sub>v</sub>1.1</italic> may alter intracellular Ca<sup>2+</sup> signalling in DM1 and DM2 myotubes. The differing dysregulation of intracellular Ca<sup>2+</sup> handling in DM1 and DM2 may explain their distinct sarcolemmal hyperexcitabilities.</p> </sec> </abstract>