scholarly journals Identification of ER/SR resident proteins as biomarkers for ER/SR calcium depletion in skeletal muscle cells

2021 ◽  
Author(s):  
Lacey K. Greer ◽  
Katherine G. Meilleur ◽  
Brandon K. Harvey ◽  
Emily S. Wires
Keyword(s):  
Skeletal Muscle ◽  
Calcium Homeostasis ◽  
Plasma Levels ◽  
Calcium Release ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Calcium Handling ◽  
Calcium Depletion ◽  
Calcium Release Channel ◽  
Potential Biomarker

Aberrations to endoplasmic/sarcoplasmic reticulum (ER/SR) calcium concentration can result in the departure of endogenous proteins in a phenomenon termed exodosis. Redistribution of the ER/SR proteome can have deleterious effects to cell function and cell viability, often contributing to disease pathogenesis. Many proteins prone to exodosis reside in the ER/SR via an ER retention/retrieval sequence (ERS) and are involved in protein folding, protein modification, and protein trafficking. While the consequences of their extracellular presence have yet to be fully delineated, the proteins that have undergone exodosis may be useful for biomarker development. Skeletal muscle cells rely upon tightly coordinated ER/SR calcium release for muscle contractions, and perturbations to calcium homeostasis can result in myopathies. Ryanodine receptor type-1 (RYR1) is a calcium release channel located in the SR. Mutations to the RYR1 gene can compromise calcium homeostasis leading to a vast range of clinical phenotypes encompassing hypotonia, myalgia, respiratory insufficiency, ophthalmoplegia, fatigue and malignant hyperthermia (MH). There are currently no FDA approved treatments for RYR1-related myopathies (RYR1-RM). Here we examine the exodosis profile of skeletal muscle cells following ER/SR calcium depletion. Proteomic analysis identified 4,465 extracellular proteins following ER/SR calcium depletion with 1280 proteins significantly different than vehicle. A total of 54 ERS proteins were identified and 33 ERS proteins significantly increased following ER/SR calcium depletion. Specifically, ERS protein, mesencephalic astrocyte-derived neurotrophic factor (MANF), was elevated following calcium depletion, making it a potential biomarker candidate for human samples. Despite no significant elevation of MANF in plasma levels among healthy volunteers and RYR1-RM individuals, MANF plasma levels positively correlated with age in RYR1-RM individuals, presenting a potential biomarker of disease progression. Selenoprotein N (SEPN1) was also detected only in extracellular samples following ER/SR calcium depletion. This protein is integral to calcium handling and SEPN1 variants have a causal role in SEPN1-related myopathies (SEPN1-RM). Extracellular presence of ER/SR membrane proteins may provide new insight into proteomic alterations extending beyond ERS proteins. Pre-treatment of skeletal muscle cells with bromocriptine, an FDA approved drug recently found to have anti-exodosis effects, curbed exodosis of ER/SR resident proteins. Changes to the extracellular content caused by intracellular calcium dysregulation presents an opportunity for biomarker development and drug discovery.

NF-κB activation by depolarization of skeletal muscle cells depends on ryanodine and IP3 receptor-mediated calcium signals

2007 ◽  
Vol 292 (5) ◽  
pp. C1960-C1970 ◽  
Author(s):  
Juan Antonio Valdés ◽  
Jorge Hidalgo ◽  
José Luis Galaz ◽  
Natalia Puentes ◽  
Mónica Silva ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Calcium Release ◽  
Ryanodine Receptors ◽  
Field Potential ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Ip3 Receptor ◽  
Pharmacological Agents ◽  
Calcium Dependent ◽  
Element Binding Protein

Depolarization of skeletal muscle cells by either high external K+ or repetitive extracellular field potential pulses induces calcium release from internal stores. The two components of this release are mediated by either ryanodine receptors or inositol 1,4,5-trisphosphate (IP3) receptors and show differences in kinetics, amplitude, and subcellular localization. We have reported that the transcriptional regulators including ERKs, cAMP/Ca2+-response element binding protein, c- fos, c- jun, and egr-1 are activated by K+-induced depolarization and that their activation requires IP3-dependent calcium release. We presently describe the activation of the nuclear transcription factor NF-κB in response to depolarization by either high K+ (chronic) or electrical pulses (fluctuating). Calcium transients of relative short duration activate an NF-κB reporter gene to an intermediate level, whereas long-lasting calcium increases obtained by prolonged electrical stimulation protocols of various frequencies induce maximal activation of NF-κB. This activation is independent of extracellular calcium, whereas calcium release mediated by either ryanodine or IP3 receptors contribute in all conditions tested. NF-κB activation is mediated by IκBα degradation and p65 translocation to the nucleus. Partial blockade by N-acetyl-l-cysteine, a general antioxidant, suggests the participation of reactive oxygen species. Calcium-dependent signaling pathways such as those linked to calcineurin and PKC also contribute to NF-κB activation by depolarization, as assessed by blockade through pharmacological agents. These results suggest that NF-κB activation in skeletal muscle cells is linked to membrane depolarization and depends on the duration of elevated intracellular calcium. It can be regulated by sequential activation of calcium release mediated by the ryanodine and by IP3 receptors.

scholarly journals Atf-6 regulates lifespan through ER-mitochondrial calcium homeostasis

2020 ◽  
Author(s):  
Kristopher Burkewitz ◽  
Sneha Dutta ◽  
Charlotte A. Kelley ◽  
Michael Steinbaugh ◽  
Erin J. Cram ◽  
...  
Keyword(s):  
Calcium Homeostasis ◽  
Calcium Release ◽  
Calcium Handling ◽  
Mitochondrial Calcium ◽  
Calcium Release Channel ◽  
Direct Role ◽  
Release Channel ◽  
Long Life ◽  
Organelle Communication ◽  
Er Calcium

AbstractFunctional crosstalk between organelles is critical for maintaining cellular homeostasis. Individually, dysfunction of both endoplasmic reticulum (ER) and mitochondria have been linked to cellular and organismal aging, but little is known about how mechanisms of inter-organelle communication might be targeted to extended longevity. The metazoan unfolded protein response (UPR) maintains ER health through a variety of mechanisms beyond its canonical role in proteostasis, including calcium storage and lipid metabolism. Here we provide evidence that in C. elegans, inhibition of the conserved UPR mediator, activating transcription factor (atf)-6 increases lifespan via modulation of calcium homeostasis and signaling to the mitochondria. Loss of atf-6 confers long life via downregulation of the ER calcium buffering protein, calreticulin. Function of the ER calcium release channel, the inositol triphosphate receptor (IP3R/itr-1), is required for atf-6 mutant longevity while a gain-of-function IP3R/itr-1 mutation is sufficient to extend lifespan. IP3R dysfunction leads to altered mitochondrial behavior and hyperfused morphology, which is sufficient to suppress long life in atf-6 mutants. Highlighting a novel and direct role for this inter-organelle coordination of calcium in longevity, the mitochondrial calcium import channel, mcu-1, is also required for atf-6 mutant longevity. Altogether this study reveals the importance of organellar coordination of calcium handling in determining the quality of aging, and highlights calcium homeostasis as a critical output for the UPR and atf-6 in particular.

Imaging elementary events of calcium release in skeletal muscle cells

Science ◽  
1995 ◽  
Vol 269 (5231) ◽  
pp. 1723-1726 ◽  
Author(s):  
A Tsugorka ◽  
E Rios ◽  
L. Blatter
Keyword(s):  
Skeletal Muscle ◽  
Calcium Release ◽  
Muscle Cells ◽  
Skeletal Muscle Cells
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