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

Abstract

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.

Streptozotocin induces endoplasmic reticulum stress and apoptosis via disruption of calcium homeostasis in mouse pancreas

“…In cardiomyocytes, silencing CANX expression affects SERCA2a and RyR2, which are responsible for lumen ER calcium ion concentrations (Botta et al, 2013).…”

“…In addition to serving as the site of protein folding, the ER acts as a cellular calcium storage organelle (Lee, 2014) and controls cellular calcium levels by responding to hormones or various cytokines (Botta et al, 2013). Disruption of intracellular calcium homeostasis can trigger apoptosis.…”

Disbalance of calcium regulation-related genes in broiler hearts induced by selenium deficiency

“…Dysregulated Ca 2+ homeostasis is generally considered a key initiator of heart disease. In muscle cells, excitation-contraction coupling and regulation of intracellular Ca 2+ homeostasis are mediated by the coordinated action of a set of Ca 2+ channels and Ca-related genes, such as RyR and SERCA (Botta et al, 2013). In the current study, we aimed to investigate the effects of Se deficiency on Ca-related genes in the heart of broilers.…”

Stress response factors as hub‐regulators of microRNA biogenesis: implication to the diseased heart

“…It is often considered in the context of myotonic dystrophy, where being sequestered by CUG-enriched pathogenic mRNAs, MBNL1 becomes functionally inactive. 111,118,119,122,[124][125][126] At the same time, its role in other cardiac diseases is unclear. For example, although embryonic isoform of cardiac troponin-T re-expresses in the post-infarction failing heart, 127 the direct implication of MBNL1 was not shown.…”

“…It is often considered in the context of myotonic dystrophy, where being sequestered by CUG‐enriched pathogenic mRNAs, MBNL1 becomes functionally inactive . At the same time, its role in other cardiac diseases is unclear.…”