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Selenoprotein K knockdown induces apoptosis in skeletal muscle satellite cells via calcium dyshomeostasis-mediated endoplasmic reticulum stress.

ABSTRACT: Skeletal muscle satellite cells (SMSCs), known as muscle stem cells, play an important role in muscle embryonic development, post-birth growth, and regeneration after injury. Selenoprotein K (SELENOK), an endoplasmic reticulum (ER) resident selenoprotein, is known to regulate calcium ion (Ca²⁺) flux and ER stress (ERS). SELENOK deficiency is involved in dietary selenium deficiency-induced muscle injury, but the regulatory mechanisms of SELENOK in SMSCs development remain poorly explored in chicken. Here, we established a SELENOK deficient model to explore the role of SELENOK in SMSCs. SELENOK knockdown inhibited SMSCs proliferation and differentiation by regulating the protein levels of paired box 7 (Pax7), myogenic factor 5 (Myf5), CyclinD1, myogenic differentiation (MyoD), and Myf6. Further analysis exhibited that SELENOK knockdown markedly activated the ERS signaling pathways, which ultimately induced apoptosis in SMSCs. SELENOK knockdown-induced ERS is related with ER Ca²⁺ ([Ca²⁺]_ER) overload via decreasing the protein levels of STIM2, Orai1, palmitoylation of inositol 1,4,5-trisphosphate receptor 1 (IP3R1), phospholamban (PLN), and plasma membrane Ca²⁺-ATPase (PMCA) while increasing the protein levels of sarco/endoplasmic Ca²⁺-ATPase 1 (SERCA1) and Na⁺/Ca²⁺ exchanger 1 (NCX1). Moreover, thimerosal, an activator of IP3R1, reversed the overload of [Ca²⁺]_ER, ERS, and subsequent apoptosis caused by SELENOK knockdown. These findings indicated that SELENOK knockdown triggered ERS driven by intracellular Ca²⁺ dyshomeostasis and further induced apoptosis, which ultimately inhibited SMSCs proliferation and differentiation.

SUBMITTER: Fan RF

PROVIDER: S-EPMC10507440 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Selenoprotein K knockdown induces apoptosis in skeletal muscle satellite cells via calcium dyshomeostasis-mediated endoplasmic reticulum stress.

Fan Rui-Feng RF Chen Xue-Wei XW Cui Han H Fu Hong-Yu HY Xu Wan-Xue WX Li Jiu-Zhi JZ Lin Hai H

Poultry science 20230822 11

Skeletal muscle satellite cells (SMSCs), known as muscle stem cells, play an important role in muscle embryonic development, post-birth growth, and regeneration after injury. Selenoprotein K (SELENOK), an endoplasmic reticulum (ER) resident selenoprotein, is known to regulate calcium ion (Ca<sup>2+</sup>) flux and ER stress (ERS). SELENOK deficiency is involved in dietary selenium deficiency-induced muscle injury, but the regulatory mechanisms of SELENOK in SMSCs development remain poorly explor ...[more]

PMID: 37716231

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Project description:The ongoing Goose astrovirus (GoAstV) epidemic, which primarily infects goslings causing severe liver damage, has inflicted considerable damage on the poultry industry. Endoplasmic reticulum stress (ERS) is a significant modulator of several viral infections, while severe ERS may result in apoptosis. This study examined the roles and possible mechanisms of ERS and apoptosis in GoAstV-induced liver injury in goslings. Two hundred Xingguo gray geese were chosen and randomly separated into two groups (Con and Dis). The Dis group received a subcutaneous injection of GoAstV genotype 2 (GoAstV-2) JX01 (2 × 106 TCID50/0.2 mL), whereas the Con group received a subcutaneous injection of 0.2 mL physiological saline, both at 1 day of life. Subsequent analyses demonstrate that the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increased following GoAstV infection. Hematoxylin and eosin (HE) staining revealed swollen and ruptured hepatocytes, with significant inflammatory cell infiltration. Electron microscopy revealed expansion of the endoplasmic reticulum (ER) and aggregation of chromatin at the periphery. TUNEL testing further demonstrated an increase in the quantity of positive cells. RT-qPCR and Western blot analyses indicated that GoAstV infection enhanced the expression of ER Ca2+ release channels (IP3R and RYR) and calmodulin-dependent protein kinase II (CaMKII), while decreasing the expression of ER Ca2+ uptake channels (SERCA). Further, GoAstV infection activated ERS-related factors, including GRP78, IRE1α, PERK, ATF6, eIF2α, ATF4, CHOP, TRAF2, and JNK, induced the expression of pro-apoptotic factors (Caspase-3, Caspase-9, and Bax), and inhibited the mRNA and protein expression of the anti-apoptotic factor Bcl-2. Correlation analysis further revealed a potential relationship among ERS gene expression, apoptotic gene expression, and liver injury. In summary, GoAstV infection can lead to liver injury by interfering with ER Ca2+ homeostasis, exacerbating ERS and inducing hepatocyte apoptosis.

Project description:BackgroundThyroid cancer is the most common endocrine tumor. Our previous studies have demonstrated that curcumin can induce apoptosis in human papillary thyroid carcinoma BCPAP cells. However, the underlined mechanism has not been clearly elucidated. Endoplasmic reticulum (ER) is a major organelle for synthesis, maturation, and folding proteins as well as a large store for Ca. Overcoming chronically activated ER stress by triggering pro-apoptotic pathways of the unfolded protein response (UPR) is a novel strategy for cancer therapeutics. Our study aimed to uncover the ER stress pathway involved in the apoptosis caused by curcumin.MethodsBCPAP cells were treated with different doses of curcumin (12.5-50 μM). Annexin V/PI double staining was used to determine cell apoptosis. Rhod-2/AM calcium fluorescence probe assay was performed to measure the calcium level of endoplasmic reticulum. Western blot was used to examine the expression of ER stress marker C/EBP homologous protein 10 (CHOP) and glucose-regulated protein 78 (GRP78). X-box binding protein1 (XBP-1) spliced form was examined by reverse transcriptase-polymerase chain reaction (RT-PCR).ResultsCurcumin significantly inhibited anchorage-independent cell growth and induced apoptosis in BCPAP cells. Curcumin induced ER stress and UPR responses in a dose- and time-dependent manner, and the chemical chaperone 4-phenylbutyrate (4-PBA) partially reversed the antigrowth activity of curcumin. Moreover, curcumin significantly increased inositol-requiring enzyme 1α (IRE1α) phosphorylation and XBP-1 mRNA splicing to induce a subsets of ER chaperones. Increased cleavage of activating transcription factor 6 (ATF6), which enhances expression of its downstream target CHOP was also observed. Furthermore, curcumin induced intracellular Ca influx through inhibition of the sarco-endoplasmic reticulum ATPase 2A (SERCA2) pump. The increased cytosolic Ca then bound to calmodulin to activate calcium/calmodulin-dependent protein kinase II (CaMKII) signaling, leading to mitochondrial apoptosis pathway activation. Ca chelator BAPTA partially reversed curcumin-induced ER stress and growth suppression, confirming the possible involvement of calcium homeostasis disruption in this response.ConclusionsCurcumin inhibits thyroid cancer cell growth, at least partially, through ER stress-associated apoptosis. Our observations provoked that ER stress activation may be a promising therapeutic target for thyroid cancer treatment.(Figure is included in full-text article.).

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Selenoprotein K knockdown induces apoptosis in skeletal muscle satellite cells via calcium dyshomeostasis-mediated endoplasmic reticulum stress.

Publications

Selenoprotein K knockdown induces apoptosis in skeletal muscle satellite cells via calcium dyshomeostasis-mediated endoplasmic reticulum stress.

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