Altered Ca2+ Homeostasis and Endoplasmic Reticulum Stress in Myotonic Dystrophy Type 1 Muscle Cells

Genes

Annalisa Botta³  Adriana Malena⁴  Emanuele Loro²  Giulia Del Moro⁴  Matteo Suman¹  Boris Pantic⁴  Gyorgy Szabadkai¹ 

[1] Department of Biomedical Sciences, University of Padua and CNR Neuroscience Institute, Padua 35100, Italy; E-Mails:;Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; E-Mail:;Department of Genetics, University “Tor Vergata”, Roma 00133, Italy; E-Mail:;Department of Neurosciences SNPSRR, University of Padova, Padova 35100, Italy; E-Mails:

关键词: myotonic dystrophy;    muscle cells;    Ca²⁺ homeostasis;    SERCA;    Ryr1;    Cav1.1;    ER stress;   

DOI  :  10.3390/genes4020275

来源: mdpi

【 摘 要 】

The pathogenesis of Myotonic Dystrophy type 1 (DM1) is linked to unstable CTG repeats in the DMPK gene which induce the mis-splicing to fetal/neonatal isoforms of many transcripts, including those involved in cellular Ca²⁺ homeostasis. Here we monitored the splicing of three genes encoding for Ca²⁺ transporters and channels (RyR1, SERCA1 and CACN1S) during maturation of primary DM1 muscle cells in parallel with the functionality of the Excitation-Contraction (EC) coupling machinery. At 15 days of differentiation, fetal isoforms of SERCA1 and CACN1S mRNA were significantly higher in DM1 myotubes compared to controls. Parallel functional studies showed that the cytosolic Ca²⁺ response to depolarization in DM1 myotubes did not increase during the progression of differentiation, in contrast to control myotubes. While we observed no differences in the size of intracellular Ca²⁺ stores, DM1 myotubes showed significantly reduced RyR1 protein levels, uncoupling between the segregated ER/SR Ca²⁺ store and the voltage-induced Ca²⁺ release machinery, parallel with induction of endoplasmic reticulum (ER) stress markers. In conclusion, our data suggest that perturbed Ca²⁺ homeostasis, via activation of ER stress, contributes to muscle degeneration in DM1 muscle cells likely representing a premature senescence phenotype.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.