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Alternative splicing alterations of Ca2+ handling genes are associated with Ca2+ signal dysregulation in myotonic dystrophy type 1 ( DM1) and type 2 ( DM2) myotubes.
- Source :
- Neuropathology & Applied Neurobiology; Jun2014, Vol. 40 Issue 4, p464-476, 13p
- Publication Year :
- 2014
-
Abstract
- Aims 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 ( RYR1), sarcoplasmatic/endoplasmatic Ca<superscript>2+</superscript>- ATPase ( SERCA) and α<subscript>1S</subscript> subunit of voltage-gated Ca<superscript>2+</superscript> channels ( Ca<subscript>v</subscript>1.1). The aim of this study is to determine whether alterations of these genes are associated with changes in the regulation of intracellular Ca<superscript>2+</superscript> homeostasis and signalling. Methods We analysed the expression of RYR1, SERCA and Ca<subscript>v</subscript>1.1 and the intracellular Ca<superscript>2+</superscript> handling in cultured myotubes isolated from DM1, DM2 and control muscle biopsies by semiquantitative RT-PCR and confocal Ca<superscript>2+</superscript> imaging respectively. Results (i) The alternative splicing of RYR1, SERCA and Ca<subscript>v</subscript>1.1 was more severely affected in DM1 than in DM2 myotubes; (ii) DM1 myotubes exhibited higher resting intracellular Ca<superscript>2+</superscript> levels than DM2; (iii) the amplitude of intracellular Ca<superscript>2+</superscript> 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<superscript>2+</superscript> release from sarcoplasmic reticulum through RYR1 was lower than in controls. Conclusion The aberrant splicing of RYR1, SERCA1 and Ca<subscript>v</subscript>1.1 may alter intracellular Ca<superscript>2+</superscript> signalling in DM1 and DM2 myotubes. The differing dysregulation of intracellular Ca<superscript>2+</superscript> handling in DM1 and DM2 may explain their distinct sarcolemmal hyperexcitabilities. [ABSTRACT FROM AUTHOR]
- Subjects :
- GENES
RYANODINE
PHYSIOLOGICAL control systems
BIOPSY
CLINICAL pathology
Subjects
Details
- Language :
- English
- ISSN :
- 03051846
- Volume :
- 40
- Issue :
- 4
- Database :
- Complementary Index
- Journal :
- Neuropathology & Applied Neurobiology
- Publication Type :
- Academic Journal
- Accession number :
- 95662769
- Full Text :
- https://doi.org/10.1111/nan.12076