Pathological mechanisms of vacuolar aggregate myopathy arising from a
            <i>Casq1</i>
            mutation

Hanna, Amy D.; Lee, Chang Seok; Babcock, Lyle; Wang, Hui J.; Recio, Joseph; Hamilton, Susan L.

doi:10.1096/fj.202001653rr

Cited by 4 publications

(1 citation statement)

References 76 publications

(199 reference statements)

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“…Furthermore, three DE-ERSRGs in our results showed a trend of downregulation in response to psychological stress and upregulation after treatment. Among them, Tfrc and Casq1 usually play a protective role and lead to the generation of ER stress when external factors cause their lowering ( Jung et al, 2015 ; Hanna et al, 2021 ), which is also consistent with our results. Payne et al suggested that Nos2 could protect against the development of ER stress ( Payne et al, 2001 ), whereas in other studies, increased Nos2 expression has been suggested to exacerbate ER stress ( Deslauriers et al, 2011 ; Zanotto et al, 2017 ).…”

Section: Discussionsupporting

confidence: 92%

Transcriptome-wide analysis reveals the molecular mechanisms of cannabinoid type II receptor agonists in cardiac injury induced by chronic psychological stress

Qin

Wang²,

Zhang³

et al. 2023

Front. Genet.

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Background: Growing evidence has supported that chronic psychological stress would cause heart damage, However the mechanisms involved are not clear and effective interventions are insufficient. Cannabinoid type 2 receptor (CB2R) can be a potential treatment for cardiac injury. This study is aimed to investigate the protective mechanism of CB2R agonist against chronic psychological stress-induced cardiac injury.Methods: A mouse chronic psychological stress model was constructed based on a chronic unpredictable stress pattern. Mice were performed a three-week psychological stress procedure, and cardiac tissues of them were collected for whole-transcriptome sequencing. Overlap analysis was performed on differentially expressed mRNAs (DE-mRNAs) and ER stress-related genes (ERSRGs), and bioinformatic methods were used to predict the ceRNA networks and conduct pathway analysis. The expressions of the DE-ERSRGs were validated by RT-qPCR.Results: In the comparison of DE mRNA in Case group, Control group and Treatment group, three groups of ceRNA networks and ceRNA (circ) networks were constructed. The DE-mRNAs were mainly enriched in chromatid-relevant terms and Hematopoietic cell lineage pathway. Additionally, 13 DE-ERSRGs were obtained by the overlap analysis, which were utilized to establish a ceRNA network with 15 nodes and 14 edges and a ceRNA (circ) network with 23 nodes and 28 edges. Furthermore, four DE-ERSRGs (Cdkn1a, Atf3, Fkbp5, Gabarapl1) in the networks were key, which were mainly enriched in response to extracellular stimulus, response to nutrient levels, cellular response to external stimulus, and FoxO signaling pathway. Finally, the RT-qPCR results showed almost consistent expression patterns of 13 DE-ERSRGs between the transcriptome and tissue samples.Conclusion: The findings of this study provide novel insights into the molecular mechanisms of chronic psychological stress-induced cardiac diseases and reveal novel targets for the cardioprotective effects of CB2R agonists.

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Section: Discussionsupporting

confidence: 92%

Transcriptome-wide analysis reveals the molecular mechanisms of cannabinoid type II receptor agonists in cardiac injury induced by chronic psychological stress

Qin

Wang²,

Zhang³

et al. 2023

Front. Genet.

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TAM-associated CASQ1 mutants diminish intracellular Ca2+ content and interfere with regulation of SOCE

Gamberucci,

Nanni,

Pierantozzi

et al. 2024

J Muscle Res Cell Motil

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Tubular aggregate myopathy (TAM) is a rare myopathy characterized by muscle weakness and myalgia. Muscle fibers from TAM patients show characteristic accumulation of membrane tubules that contain proteins from the sarcoplasmic reticulum (SR). Gain-of-function mutations in STIM1 and ORAI1, the key proteins participating in the Store-Operated Ca2+ Entry (SOCE) mechanism, were identified in patients with TAM. Recently, the CASQ1 gene was also found to be mutated in patients with TAM. CASQ1 is the main Ca2+ buffer of the SR and a negative regulator of SOCE. Previous characterization of CASQ1 mutants in non-muscle cells revealed that they display altered Ca2+dependent polymerization, reduced Ca2+storage capacity and alteration in SOCE inhibition. We thus aimed to assess how mutations in CASQ1 affect calcium regulation in skeletal muscles, where CASQ1 is naturally expressed. We thus expressed CASQ1 mutants in muscle fibers from Casq1 knockout mice, which provide a valuable model for studying the Ca2+ storage capacity of TAM-associated mutants. Moreover, since Casq1 knockout mice display a constitutively active SOCE, the effect of CASQ1 mutants on SOCE inhibition can be also properly examined in fibers from these mice. Analysis of intracellular Ca2+ confirmed that CASQ1 mutants have impaired ability to store Ca2+and lose their ability to inhibit skeletal muscle SOCE; this is in agreement with the evidence that alterations in Ca2+entry due to mutations in either STIM1, ORAI1 or CASQ1 represents a hallmark of TAM.

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Speg interactions that regulate the stability of excitation-contraction coupling protein complexes in triads and dyads

Lee,

Jung,

Yee

et al. 2023

Commun Biol

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Here we show that striated muscle preferentially expressed protein kinase α (Spegα) maintains cardiac function in hearts with Spegβ deficiency. Speg is required for stability of excitation-contraction coupling (ECC) complexes and interacts with esterase D (Esd), Cardiomyopathy-Associated Protein 5 (Cmya5), and Fibronectin Type III and SPRY Domain Containing 2 (Fsd2) in cardiac and skeletal muscle. Mice with a sequence encoding a V5/HA tag inserted into the first exon of the Speg gene (HA-Speg mice) display a >90% decrease in Spegβ but Spegα is expressed at ~50% of normal levels. Mice deficient in both Spegα and Speg β (Speg KO mice) develop a severe dilated cardiomyopathy and muscle weakness and atrophy, but HA-Speg mice display mild muscle weakness with no cardiac involvement. Spegα in HA-Speg mice suppresses Ca2+ leak, proteolytic cleavage of Jph2, and disruption of transverse tubules. Despite it’s low levels, HA-Spegβ immunoprecipitation identified Esd, Cmya5 and Fsd2 as Spegβ binding partners that localize to triads and dyads to stabilize ECC complexes. This study suggests that Spegα and Spegβ display functional redundancy, identifies Esd, Cmya5 and Fsd2 as components of both cardiac dyads and skeletal muscle triads and lays the groundwork for the identification of new therapeutic targets for centronuclear myopathy.

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Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation

Cited by 4 publications

References 76 publications

Transcriptome-wide analysis reveals the molecular mechanisms of cannabinoid type II receptor agonists in cardiac injury induced by chronic psychological stress

Transcriptome-wide analysis reveals the molecular mechanisms of cannabinoid type II receptor agonists in cardiac injury induced by chronic psychological stress

TAM-associated CASQ1 mutants diminish intracellular Ca2+ content and interfere with regulation of SOCE

Speg interactions that regulate the stability of excitation-contraction coupling protein complexes in triads and dyads

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