Orai1 deficiency leads to heart failure and skeletal myopathy in zebrafish

Völkers, Mirko; Dolatabadi, Nima; Gude, Natalie; Most, Patrick; Sussman, Mark A.; Hassel, David

doi:10.1242/jcs.090464

Cited by 55 publications

(55 citation statements)

References 39 publications

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“…Our observation that STIM1 deficiency leads to dilated cardiomyopathy is supported by reports in the zebrafish, where inactivation of the Orai1 ortholog leads to heart failure and impaired mechanosignal transduction (39). In addition, Horton et al (15) have shown that mice deficient in Orai1 develop a dilated cardiomyopathy that was associated with reduced survival without any evidence of cardiac hypertrophy.…”

Section: Discussionsupporting

confidence: 84%

Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function

Collins

Zou

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Young ME, Marchase RB, Chatham JC. Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function. Am J Physiol Heart Circ Physiol 306: H1231-H1239, 2014. First published February 28, 2014 doi:10.1152/ajpheart.00075.2014.-The endoplasmic reticulum (ER) Ca 2ϩ sensor stromal interaction molecule 1 (STIM1) has been implicated as a key mediator of store-dependent and store-independent Ca 2ϩ entry pathways and maintenance of ER structure. STIM1 is present in embryonic, neonatal, and adult cardiomyocytes and has been strongly implicated in hypertrophic signaling; however, the physiological role of STIM1 in the adult heart remains unknown. We, therefore, developed a novel cardiomyocyte-restricted STIM1 knockout ( cr STIM1-KO) mouse. In cardiomyocytes isolated from cr STIM1-KO mice, STIM1 expression was reduced by ϳ92% with no change in the expression of related store-operated Ca 2ϩ entry proteins, STIM2, and Orai1. Immunoblot analyses revealed that cr STIM1-KO hearts exhibited increased ER stress from 12 wk, as indicated by increased levels of the transcription factor C/EBP homologous protein (CHOP), one of the terminal markers of ER stress. Transmission electron microscopy revealed ER dilatation, mitochondrial disorganization, and increased numbers of smaller mitochondria in cr S-TIM1-KO hearts, which was associated with increased mitochondrial fission. Using serial echocardiography and histological analyses, we observed a progressive decline in cardiac function in cr STIM1-KO mice, starting at 20 wk of age, which was associated with marked left ventricular dilatation by 36 wk. In addition, we observed the presence of an inflammatory infiltrate and evidence of cardiac fibrosis from 20 wk in cr STIM1-KO mice, which progressively worsened by 36 wk. These data demonstrate for the first time that STIM1 plays an essential role in normal cardiac function in the adult heart, which may be important for the regulation of ER and mitochondrial function. store-operated Ca 2ϩ entry; STIM1; cardiomyocytes; ER stress; mitochondria

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Section: Discussionsupporting

confidence: 84%

Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function

Collins

Zou

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…Interestingly, a similar combination of symptoms was observed in a genetically unresolved patient with a histopathological diagnosis of MmD, reported before the identification of the Orai1 gene [91]. Cells isolated from patients carrying mutations causing reduced Orai1expression display impaired Ca 2+ influx while in zebrafish lack of Orai1 leads to loss of skeletal (and cardiac) muscle integrity and myofibrillar disruption [92].…”

Section: Disorders Of Soce: Tubular Aggregate Myopathysupporting

confidence: 59%

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

Treves

Jungbluth

Voermans

et al. 2017

Seminars in Cell & Developmental Biology

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a b s t r a c tThe physiological process by which Ca 2+ is released from the sarcoplasmic reticulum is called excitationcontraction coupling; it is initiated by an action potential which travels deep into the muscle fiber where it is sensed by the dihydropyridine receptor, a voltage sensing L-type Ca 2+ channel localized on the transverse tubules. Voltage-induced conformational changes in the dihydropyridine receptor activate the ryanodine receptor Ca 2+ release channel of the sarcoplasmic reticulum. The released Ca 2+ binds to troponin C, enabling contractile thick-thin filament interactions. The Ca 2+ is subsequently transported back into the sarcoplasmic reticulum by specialized Ca 2+ pumps (SERCA), preparing the muscle for a new cycle of contraction. Although other proteins are involved in excitation-contraction coupling, the mechanism described above emphasizes the unique role played by the two Ca 2+ channels (the dihydropyridine receptor and the ryanodine receptor), the SERCA Ca 2+ pumps and the exquisite spatial organization of the membrane compartments endowed with the proteins responsible for this mechanism to function rapidly and efficiently. Research over the past two decades has uncovered the fine details of excitation-contraction coupling under normal conditions while advances in genomics have helped to identify mutations in novel genes in patients with neuromuscular disorders. While it is now clear that many patients with congenital muscle diseases carry mutations in genes encoding proteins directly involved in Ca 2+ homeostasis, it has become apparent that mutations are also present in genes encoding for proteins not thought to be directly involved in Ca 2+ regulation. Ongoing research in the field now focuses on understanding the functional effect of individual mutations, as well as understanding the role of proteins not specifically located in the sarcoplasmic reticulum which nevertheless are involved in Ca 2+ regulation or excitation-contraction coupling. The principal challenge for the future is the identification of drug targets that can be pharmacologically manipulated by small molecules, with the ultimate aim to improve muscle function and quality of life of patients with congenital muscle disorders. The aim of this review is to give an overview of the most recent findings concerning Ca 2+ dysregulation and its impact on muscle function in patients with congenital muscle disorders due to mutations in proteins involved in excitation-contraction coupling and more broadly on Ca 2+ homeostasis.

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“…Furthermore, in Orai1-deficient cardiomyocytes, the calcineurin-associated protein calsarcin was lost from the z-discs and mechanosignal transduction was impaired (131). Although these data support the notion that defects in SOCE are associated with significant cardiovascular complications, it should be noted that humans and mice with reduced STIM1 expression primarily exhibit extensive immunodeficiency and skeletal muscle pathology, with no signs of overt cardiovascular pathology (21).…”

Section: Orai1/trpcmentioning

confidence: 86%

“…Of note, inactivation of the Orai1 ortholog in zebrafish resulted in the development of heart failure and progressive loss of skeletal muscle myofiber integrity (131). Furthermore, in Orai1-deficient cardiomyocytes, the calcineurin-associated protein calsarcin was lost from the z-discs and mechanosignal transduction was impaired (131).…”

Section: Orai1/trpcmentioning

confidence: 99%

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Collins

Zhu-Mauldin

Marchase

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

110

102

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Collins HE, Zhu-Mauldin X, Marchase RB, Chatham JC. STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology. Am J Physiol Heart Circ Physiol 305: H446 -H458, 2013. First published June 21, 2013 doi:10.1152/ajpheart.00104.2013.-Store-operated Ca 2ϩ entry (SOCE) is critical for Ca 2ϩ signaling in nonexcitable cells; however, its role in the regulation of cardiomyocyte Ca 2ϩ homeostasis has only recently been investigated. The increased understanding of the role of stromal interaction molecule 1 (STIM1) in regulating SOCE combined with recent studies demonstrating the presence of STIM1 in cardiomyocytes provides support that this pathway co-exists in the heart with the more widely recognized Ca 2ϩ handling pathways associated with excitation-contraction coupling. There is now substantial evidence that STIM1-mediated SOCE plays a key role in mediating cardiomyocyte hypertrophy, both in vitro and in vivo, and there is growing support for the contribution of SOCE to Ca 2ϩ overload associated with ischemia/reperfusion injury. Here, we provide an overview of our current understanding of the molecular regulation of SOCE and discuss the evidence supporting the role of STIM1/Orai1-mediated SOCE in regulating cardiomyocyte function.store-operated Ca 2ϩ entry; stromal interaction molecule 1; orai1; cardiomyocytes STORE-OPERATED CA 2ϩ ENTRY (SOCE), also known as capacitative calcium entry (CCE), is the major mechanism of Ca 2ϩ entry in nearly all nonexcitable cells (97, 99). In addition, it is increasingly recognized to co-exist with voltage-gated Ca 2ϩ channels in excitable cells, including neurons, skeletal muscle cells, and cardiomyocytes (1,38,45,83,121). In response to inositol 1,4,5-triphosphate (IP 3 )-(43) or ryanodine receptor (RyR)-mediated (3) Ca 2ϩ release from ER/SR stores, SOCE facilitates the influx of Ca 2ϩ from the extracellular space, resulting in a sustained increase in cytosolic Ca 2ϩ levels. Thus, although one of the roles of SOCE is to rapidly refill the depleted ER/SR stores, the subsequent sustained increase in cytosolic Ca 2ϩ also regulates numerous gene transcription pathways (33,50,151). Indeed, aberrant SOCE has been observed in a growing number of diseases including severe combined immunodeficiency, acute pancreatitis, and Alzheimer's disease (86).The integration of SOCE into well-established models of Ca 2ϩ homeostasis was hampered for many years by the lack of specific molecular mediators; even as recently as 2004 there was considerable controversy as to the specific mechanisms regulating SOCE (90, 113). However, in 2005, stromal interaction molecule 1 (STIM1) was found to localize to the ER/SR membrane and shown to function as a primary mediator of SOCE (54, 102). The putative physiological and pathophysiological roles of SOCE and STIM1 that have been identified to date are summarized in Table 1. A number of studies have recently reported the presence of STIM1 in adult cardiomyocytes (37,59,153), and consistent with earlier evidence supporting a rol...

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Orai1 deficiency leads to heart failure and skeletal myopathy in zebrafish

Cited by 55 publications

References 39 publications

Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function

Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

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