المؤلفون: Sarah Jeanfavre, Kerry A. Pierce, Eitan Hoch, Alina Ainbinder, Suzanne B.R. Jacobs, Federico Centeno-Cruz, Courtney Dennis, Karen Gelinas-Roa, Amy Deik, Lorena Orozco, Patricia Glover, Kevin Bullock, Jesse Krejci, Francisco Barajas-Olmos, Anthony N. Hollenberg, Jose C. Florez, Carlos Zerrweck, Liping Zhao, Clary B. Clish, Eric S. Lander, Jinyoung Choi, Alycen Harney, Victor Rusu

مصطلحات موضوعية: Monocarboxylate transporter, medicine.medical_specialty, biology, Lipid metabolism, Metabolism, Carbohydrate metabolism, Energy homeostasis, medicine.anatomical_structure, Endocrinology, Internal medicine, Hepatocyte, Knockout mouse, medicine, biology.protein, Intracellular

الوصف: SUMMARYGenetic variation at the SLC16A11 locus contributes to the disproportionate impact of type 2 diabetes (T2D) on Latino populations. We recently demonstrated that T2D risk variants reduce SLC16A11 liver expression and function of MCT11, the monocarboxylate transporter encoded by the SLC16A11 gene. Here, we show that SLC16A11 expression within the liver is primarily localized to the low oxygen pericentral region, and that T2D risk variants disrupt oxygen-regulated SLC16A11 expression in human hepatocytes. Under physiologic oxygen conditions, MCT11 deficiency alters hepatocyte glucose metabolism, resulting in elevated intracellular lactate and a metabolic shift toward triacylglycerol accumulation. We also demonstrate an impact of Mct11 deficiency on glucose and lipid metabolism in Slc16a11 knockout mice, which display physiological changes that are observed in individuals with T2D. Our findings provide mechanistic insight into how SLC16A11 disruption impacts hepatic energy metabolism and T2D risk, and highlight MCT11-mediated regulation of lactate levels as a potential therapeutic target.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::fe176c8174e9997c0a00611592c8eb5fTest
https://doi.org/10.1101/2021.09.08.459307Test

المؤلفون: Garrett Garborcauskas, Alycen Harney, Hesam Dashti, Anne E. Carpenter, Miriam S. Udler, Elizabeth McGonagle, Aaron Leong, Hannah Ebert, Josée Dupuis, Maria Kost-Alimova, Cecilia M. Lindgren, Sierra Harken, Giacomo Deodato, Hans Hauner, Beth A. Cimini, Suzanne B.R. Jacobs, Josep M. Mercader, Saskia Reibe-Pal, Jose C. Florez, Adam Stefek, Samantha Laber, David R. Stirling, Gregory P. Way, Nasa Sinnott-Armstrong, Katherine Figueroa, Julius Honecker, Alham Saadat, Alina Ainbinder, Virtudes Calabuig, Melina Claussnitzer, Yixin Zhang, Sophie Strobel

مصطلحات موضوعية: Cell type, Context (language use), Genomics, Identification (biology), Computational biology, Metabolic disease, Biology, Gene, Phenotype, Function (biology)

الوصف: SummaryA primary obstacle in translating genetics and genomics data into therapeutic strategies is elucidating the cellular programs affected by genetic variants and genes associated with human diseases. Broadly applicable high-throughput, unbiased assays offer a path to rapidly characterize gene and variant function and thus illuminate disease mechanisms. Here, we report LipocyteProfiler, an unbiased high-throughput, high-content microscopy assay that is amenable to large-scale morphological and cellular profiling of lipid-accumulating cell types. We apply LipocyteProfiler to adipocytes and hepatocytes and demonstrate its ability to survey diverse cellular mechanisms by generating rich context-, and process-specific morphological and cellular profiles. We then use LipocyteProfiler to identify known and novel cellular programs altered by polygenic risk of metabolic disease, including insulin resistance, waist-to-hip ratio and the polygenic contribution to lipodystrophy. LipocyteProfiler paves the way for large-scale forward and reverse phenotypic profiling in lipid-storing cells, and provides a framework for the unbiased identification of causal relationships between genetic variants and cellular programs relevant to human disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::16e99c4f7b03bd908d4d964e2603077bTest
https://doi.org/10.1101/2021.07.17.452050Test

المؤلفون: Yvette Cajigas, Peter Hamer, Alina Ainbinder, Angela Vasaturo, Douglas Wood, Kirsteen H. Maclean, Gourab Chatterjee

المصدر: Cancer Research. 82:3868-3868

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Immunotherapy has transformed the treatment of metastatic and recurrent solid tumors. Advances in technology in the past few years have created unprecedented opportunities to identify biomarkers of disease processes, especially by using multi-omics technologies and datasets to derive valid and useful signatures of disease. Advances in multiplexed immunofluorescence (mIF) staining and imaging technologies that allow for accurate phenotyping of individual cells while also preserving architectural features of the sample are critical to our understanding of the interplay of tumor and immune cells in the tumor immune microenvironment (TiME).Herein we describe the utility of our new flexible mIF assays (FlexVUE™ panels) to provide the necessary relevant distribution of infiltrating immune cells in tumors coupled to the use of our new UltiStacker™ software. This hardware and software package allows a detailed spatial characterization of specific cell phenotypes defined by co- or lack of expression that may help in predicting clinical responses and mechanisms of resistance to therapy. The FlexVUE™ mIF assay was used to conduct 8-plex immunophenotyping of FFPE tumor sections. Slides were stained with a cocktail of eight primary antibodies using Leica Biosystems BOND RX autostainer and imaged on the Zeiss Axio Scan.Z1. Following the first round of imaging, the slides were decoverslipped and the signal was removed. New targets were probed on the same tissue section in a reagent incubation step on the BOND RX, termed ‘exchange.’ Slides were re-imaged on the Zeiss Axio Scan Z1 using the same dye channels. The image pairs were automatically aligned using UltiStacker™ software and exported for downstream analysis with Indica Labs HALOv3.1 software. Our approach demonstrates a streamlined off the shelf workflow requiring no assay development time that supports whole slide imaging of a flexible high plex panel. In addition, our assays enable traditional same slide H&E fusion on a single tissue slide for comprehensive tissue immunophenotyping analysis of proliferating cells, tumor cells, tumor-infiltrating lymphocytes, macrophages or tertiary lymphoid structures. Citation Format: Yvette Cajigas, Peter Hamer, Alina Ainbinder, Angela Vasaturo, Douglas Wood, Kirsteen H. Maclean, Gourab Chatterjee. High throughput tissue phenotyping and imaging of the tumor immune microenvironment using novel FlexVUE™ multiplexed immunofluorescence assays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3868.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::0b342f147ec319b44d865508a5e8e611Test
https://doi.org/10.1158/1538-7445.am2022-3868Test

المؤلفون: Yvette Cajigas, Peter Hamer, Alina Ainbinder, Gourab Chatterjee, Angela Vasaturo, Mael Manesse, Kirsteen Maclean

المصدر: Cancer Research. 82:3863-3863

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Immunotherapy has transformed the treatment of metastatic and recurrent solid tumors. Advances in technology in the past few years have created unprecedented opportunities to identify biomarkers of disease processes, especially by using multi-omics technologies and datasets to derive valid and useful signatures of disease. Mouse tumor models are widely used tools to demonstrate activity of novel immunotherapies. Despite their widespread use, a comprehensive view of their tumor-immune compositions and their relevance to human tumors has only begun to emerge. The use of specific mouse tissue phenotyping and multiplex immunofluorescence (mIF) assays offer the unique advantage of preserving the architectural features of the tumor and revealing the spatial relationships between tumor cells and immune cells. The urgency to discover and implement new biomarkers lays bare the need to integrate a variety of advanced pre-clinical tools to probe the dynamic nature of events happening in the tumor immune microenvironment (TiME). Here, we present an established mIF assay, InSituPlex® technology, now enabled for rapid staining and visualization of dedicated 4-plex murine panels for deep, spatial phenotyping in the tumor microenvironment. Murine specific InSituPlex technology was used to perform singleplex and multiplex immune profiling on mouse FFPE tumor serial sections. Alternating serial sections were stained with a cocktail of four primary antibodies or a single primary antibody, in parallel, using Leica Biosystems BOND RX autostainer. Slides were imaged on the Zeiss Axio Scan Z1 providing high-quality images of the four targets (CD3, CD4, CD8, and FOXP3) in a single workday. The images were exported for downstream analysis with Indica Labs HALOv3.1 software. Concordance of the singleplex to the 4-plex mouse specific InSituPlex assay was assessed by quantifying the percent difference in cellular density of immune cell subtypes from 1-plex to 4-plex. Qualitative assessment and quantitative analysis revealed a high level of reproducibility of the assay, with each single markers’ coefficients of variation falling within an acceptable range. Each single marker tested showed an expected level of expression and expression pattern. The multiplex assay was highly concordant to the singleplex assay. Unique phenotypes from whole slide analysis followed the expected pattern, as indicated by the tumor type. Our protocol of mIF staining on mouse tissue provides an improved workflow to investigate the immune system, including the analysis of the tumor immune microenvironment and mechanisms of action of immune-related drugs in preclinical models. Citation Format: Yvette Cajigas, Peter Hamer, Alina Ainbinder, Gourab Chatterjee, Angela Vasaturo, Mael Manesse, Kirsteen Maclean. Development of specific multiplexed immunofluorescence immune assays to study mouse models of tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3863.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::335cf88bfedb86ed779f2a9910d677c0Test
https://doi.org/10.1158/1538-7445.am2022-3863Test

المؤلفون: Lan Wei-LaPierre, Alina Ainbinder, Robert T. Dirksen, Kevin M. Tylock

المصدر: Archives of Biochemistry and Biophysics. 665:122-131

مصطلحات موضوعية: 0301 basic medicine, Biophysics, Oxidative phosphorylation, Biochemistry, Article, Substrate Specificity, 03 medical and health sciences, medicine, Animals, Myocyte, Glycolysis, Muscle, Skeletal, Molecular Biology, Mice, Knockout, Membrane potential, 030102 biochemistry & molecular biology, Chemistry, Myocardium, Cardiac muscle, Skeletal muscle, Depolarization, Mitochondria, Muscle, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Mitochondrial matrix, Cyclophilin D

الوصف: Mitochondrial flashes (mitoflashes) are stochastic events in the mitochondrial matrix detected by mitochondrial-targeted cpYFP (mt-cpYFP). Mitoflashes are quantal bursts of reactive oxygen species (ROS) production accompanied by modest matrix alkalinization and depolarization of the mitochondrial membrane potential. Mitoflashes are fundamental events present in a wide range of cell types. To date, the precise mechanisms for mitoflash generation and termination remain elusive. Transient opening of the mitochondrial membrane permeability transition pore (mPTP) during a mitoflash is proposed to account for the mitochondrial membrane potential depolarization. Here, we set out to compare the tissue-specific effects of cyclophilin D (CypD)-deficiency and mitochondrial substrates on mitoflash activity in skeletal and cardiac muscle. In contrast to previous reports, we found that CypD knockout did not alter the mitoflash frequency or other mitoflash properties in acutely isolated cardiac myocytes, skeletal muscle fibers, or isolated mitochondria from skeletal muscle and the heart. However, in skeletal muscle fibers, CypD deficiency resulted in a parallel increase in both activity-dependent mitochondrial Ca2+ uptake and activity-dependent mitoflash activity. Increases in both mitochondrial Ca2+ uptake and mitoflash activity following electrical stimulation were abolished by inhibition of mitochondrial Ca2+ uptake. We also found that mitoflash frequency and amplitude differ greatly between intact skeletal muscle fibers and cardiac myocytes, but that this difference is absent in isolated mitochondria. We propose that this difference may be due, in part, to differences in substrate availability in intact skeletal muscle fibers (primarily glycolytic) and cardiac myocytes (largely oxidative). Overall, we find that CypD does not contribute significantly in mitoflash biogenesis under basal conditions in skeletal and cardiac muscle, but does regulate mitoflash events during muscle activity. In addition, tissue-dependent differences in mitoflash frequency are strongly regulated by mitochondrial substrate availability.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6330608a34dbe8477cf851a20002e925Test
https://doi.org/10.1016/j.abb.2019.03.003Test

المؤلفون: Simona Boncompagni, Robert T. Dirksen, Feliciano Protasi, Antonio Michelucci, Alessandra D’Incecco, Laura Pietrangelo, Helmut Kern, Alina Ainbinder

المصدر: Oncotarget

مصطلحات موضوعية: Male, Sarcopenia, medicine.medical_specialty, Ca, Triad, SOD1, 2+, Sarcoplasmic reticulum, SOD2, chemistry.chemical_element, Calcium, Mitochondrion, Biology, Inbred C57BL, medicine.disease_cause, Mice, Research Paper: Gerotarget (Focus on Aging), Ca2+ signalling, Internal medicine, medicine, Animals, Humans, signalling, Muscle, Skeletal, Gerotarget, Age Factors, Skeletal muscle, Skeletal, medicine.disease, Excitation-contraction coupling, Mitochondria, Mice, Inbred C57BL, Endocrinology, medicine.anatomical_structure, Oncology, chemistry, Muscle, Tetanic stimulation, Oxidative stress, Signal Transduction

الوصف: Calcium release units (CRUs) and mitochondria control myoplasmic [Ca2+] levels and ATP production in muscle, respectively. We recently reported that these two organelles are structurally connected by tethers, which promote proximity and proper Ca2+ signaling.Here we show that disposition, ultrastructure, and density of CRUs and mitochondria and their reciprocal association are compromised in muscle from aged mice. Specifically, the density of CRUs and mitochondria is decreased in muscle fibers from aged (>24 months) vs. adult (3-12 months), with an increased percentage of mitochondria being damaged and misplaced from their normal triadic position. A significant reduction in tether (13.8 ± 0.4 vs. 5.5 ± 0.3 tethers/100 µm2) and CRU-mitochondrial pair density (37.4 ± 0.8 vs. 27.0 ± 0.7 pairs/100 µm2) was also observed in aged mice. In addition, myoplasmic Ca2+ transient (1.68 ± 0.08 vs 1.37 ± 0.03) and mitochondrial Ca2+ uptake (9.6 ± 0.050 vs 6.58 ± 0.54) during repetitive high frequency tetanic stimulation were significantly decreased. Finally oxidative stress, assessed from levels of 3-nitrotyrosine (3-NT), Cu/Zn superoxide-dismutase (SOD1) and Mn superoxide dismutase (SOD2) expression, were significantly increased in aged mice. The reduced association between CRUs and mitochondria with aging may contribute to impaired cross-talk between the two organelles, possibly resulting in reduced efficiency in activity-dependent ATP production and, thus, to age-dependent decline of skeletal muscle performance.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8d75671672dac9e6880bd7d58a64f2dfTest
https://doi.org/10.18632/oncotarget.6139Test

المؤلفون: Simona Boncompagni, Alina Ainbinder, Robert T. Dirksen, Feliciano Protasi

المصدر: Cell Calcium. 57:14-24

مصطلحات موضوعية: Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone, Physiology, Muscle Fibers, Skeletal, MFN2, Mitochondrion, Biology, Sarcomere, Article, GTP Phosphohydrolases, Mice, medicine, Animals, Mitochondrial calcium uptake, RNA, Small Interfering, Egtazic Acid, Molecular Biology, Membrane Potential, Mitochondrial, Microscopy, Confocal, Skeletal muscle, Cell Biology, Mitochondria, Mice, Inbred C57BL, Sarcoplasmic Reticulum, medicine.anatomical_structure, mitochondrial fusion, Biochemistry, Biophysics, Calcium, RNA Interference, medicine.symptom, Tetanic stimulation, Muscle contraction

الوصف: As muscle contraction requires ATP and Ca(2+), skeletal muscle function is highly dependent on communication between two major intracellular organelles: mitochondria and sarcoplasmic reticulum (SR). In adult skeletal muscle, mitochondria located within the I-band of the sarcomere are connected to the SR by small ∼10 nm electron dense tethers that bridge the outer mitochondrial membrane to the region of SR that is ∼130 nm from the site of Ca(2+) release. However, the molecular composition of tethers and their precise impact on mitochondrial Ca(2+) uptake in skeletal muscle is unclear. Mitofusin-2 (Mfn2) is a transmembrane GTPase present in both mitochondria and ER/SR membranes that forms trans-dimers and participates in mitochondrial fusion. Here we evaluated the role Mfn2 plays in mitochondrial morphology, localization, and functional SR-mitochondrial Ca(2+) crosstalk in adult skeletal muscle. Compared to a non-targeting (CTRL) siRNA, in vivo electroporation of 400 nM Mfn2 siRNA (Mfn2 KD) into mouse footpads resulted in a marked acute reduction (67±3%) in Mfn2 protein levels in flexor digitorum brevis (FDB) muscles that occurred without a change in other key Ca(2+) regulatory proteins. Electron microscopy analyses revealed that Mfn2 knockdown resulted in a change in mitochondria morphology and mis-localization of some mitochondria from the I-band to the A-band region of the sarcomere. To assess the role of Mfn2 in SR-mitochondrial crosstalk, we measured mitochondrial Ca(2+) uptake and myoplasmic Ca(2+) transients with rhod-2 and mag-fluo-4, respectively, during repetitive high frequency tetanic stimulation (5×100 Hz tetani, 500 ms/tetani, 0.2 duty cycle) in CTRL and Mfn2 KD fibers. Mitochondrial Ca(2+) uptake during repetitive tetanic stimulation was significantly reduced (40%) in Mfn2 KD FDB fibers, which was accompanied by a parallel elevation in the global electrically evoked myoplasmic Ca(2+) transient. Mfn2 KD also resulted in a reduction of the mitochondrial membrane potential, which contributed to the observed decrease in activity-dependent mitochondrial Ca(2+) uptake. Consistent with this idea, a similar decrease in mitochondrial Ca(2+) uptake was also observed in wild type fibers following a comparable reduction in mitochondrial membrane potential induced by acute exposure to a low concentration (50 nM) of carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP). In addition, both global and mitochondrial Ca(2+) transients during repetitive tetanic stimulation were similarly reduced by both slow (EGTA) and fast (BAPTA) Ca(2+) chelating agents. Together, these results indicate that Mfn2 promotes proper mitochondrial morphology, localization, and membrane potential required for optimal activity-dependent mitochondrial Ca(2+) uptake and buffering of the global myoplasmic Ca(2+) transient in adult skeletal muscle.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::834cc7d0af5fda866db94d81ff52fb6cTest
https://doi.org/10.1016/j.ceca.2014.11.002Test

المؤلفون: Anna Raffaello, Jyotsna Mishra, Wang Wang, Godfrey L. Smith, Xiaoyun Liu, Stephen Hurst, Shangcheng Xu, Polina Gross, Shey-Shing Sheu, Rosario Rizzuto, Jin O-Uchi, Huiliang Zhang, Alina Ainbinder, Bing Yi, Bong Sook Jhun, Robert T. Dirksen, Sarah Kettlewell

المصدر: Antioxidants & Redox Signaling. 21:863-879

مصطلحات موضوعية: Physiology, Clinical Biochemistry, Biology, Mitochondrion, Models, Biological, Biochemistry, Mitochondrial apoptosis-induced channel, Cell Line, chemistry.chemical_compound, Cytosol, Forum Original Research Communication, Receptors, Adrenergic, alpha-1, Animals, Humans, Myocytes, Cardiac, Phosphorylation, Uniporter, Molecular Biology, General Environmental Science, Tyrosine phosphorylation, Cell Biology, Mitochondria, Rats, Cell biology, Protein Transport, Focal Adhesion Kinase 2, Mitochondrial permeability transition pore, chemistry, General Earth and Planetary Sciences, Calcium, Calcium Channels, ATP–ADP translocase, Protein Multimerization, Signal transduction, Apoptosis Regulatory Proteins, Reactive Oxygen Species, Protein Binding, Signal Transduction

الوصف: Aims: Mitochondrial Ca2+ homeostasis is crucial for balancing cell survival and death. The recent discovery of the molecular identity of the mitochondrial Ca2+ uniporter pore (MCU) opens new possibilities for applying genetic approaches to study mitochondrial Ca2+ regulation in various cell types, including cardiac myocytes. Basal tyrosine phosphorylation of MCU was reported from mass spectroscopy of human and mouse tissues, but the signaling pathways that regulate mitochondrial Ca2+ entry through posttranslational modifications of MCU are completely unknown. Therefore, we investigated α1-adrenergic-mediated signal transduction of MCU posttranslational modification and function in cardiac cells. Results: α1-adrenoceptor (α1-AR) signaling translocated activated proline-rich tyrosine kinase 2 (Pyk2) from the cytosol to mitochondrial matrix and accelerates mitochondrial Ca2+ uptake via Pyk2-dependent MCU phosphorylation and tetrametric MCU channel pore formation. Moreover, we found that α1-AR stimulation increases reactive oxygen species production at mitochondria, mitochondrial permeability transition pore activity, and initiates apoptotic signaling via Pyk2-dependent MCU activation and mitochondrial Ca2+ overload. Innovation: Our data indicate that inhibition of α1-AR-Pyk2-MCU signaling represents a potential novel therapeutic target to limit or prevent mitochondrial Ca2+ overload, oxidative stress, mitochondrial injury, and myocardial death during pathophysiological conditions, where chronic adrenergic stimulation is present. Conclusion: The α1-AR-Pyk2-dependent tyrosine phosphorylation of the MCU regulates mitochondrial Ca2+ entry and apoptosis in cardiac cells. Antioxid. Redox Signal. 21, 863–879.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::da71751c0979cec19bd222f8e1b5fb28Test
https://doi.org/10.1089/ars.2013.5394Test

المؤلفون: Qing Cheng, Johanna T. Lanner, Robert T. Dirksen, George G. Rodney, Susan L. Hamilton, Zanwen Chen, Tanner O. Monroe, Chang Seok Lee, Arturo Santillan, Joshua M. Oakes, Laurie J. Goodyear, Viktor Yarotskyy, Dimitra K. Georgiou, Alina Ainbinder, Adan Dagnino-Acosta, Iskander I. Ismailov, Keke Dong, Aditya D. Joshi

المصدر: Nature medicine

مصطلحات موضوعية: Male, medicine.medical_specialty, Hot Temperature, chemistry.chemical_element, Mice, Transgenic, Calcium, AMP-Activated Protein Kinases, Heat Stress Disorders, Sudden death, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Death, Sudden, Mice, 0302 clinical medicine, Adenosine Triphosphate, AMP-activated protein kinase, Internal medicine, medicine, Animals, Muscle, Skeletal, 030304 developmental biology, RYR1, 0303 health sciences, biology, Ryanodine receptor, Calcium channel, Malignant hyperthermia, AMPK, Ryanodine Receptor Calcium Release Channel, General Medicine, Ribonucleotides, medicine.disease, Aminoimidazole Carboxamide, Reactive Nitrogen Species, Mice, Mutant Strains, 3. Good health, Enzyme Activation, Sarcoplasmic Reticulum, Endocrinology, chemistry, biology.protein, Reactive Oxygen Species, 030217 neurology & neurosurgery

الوصف: Mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation that is associated with malignant hyperthermia in humans, die when exposed to short periods of temperature elevation (≥37 °C). We show here that treatment with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) prevents this heat-induced sudden death in this mouse model. The protection by AICAR is independent of AMP-activated protein kinase (AMPK) activation and results from a newly identified action of the compound on mutant Ryr1 to reduce Ca(2+) leak from the sarcoplasmic reticulum to the sarcoplasm. AICAR thus prevents Ca(2+)-dependent increases in the amount of both reactive oxygen species (ROS) and reactive nitrogen species (RNS) that act to further increase resting Ca(2+) concentrations. If unchecked, the temperature-driven increases in resting Ca(2+) concentrations and the amounts of ROS and RNS create an amplifying cycle that ultimately triggers sustained muscle contractions, rhabdomyolysis and death. Although antioxidants are effective in reducing this cycle in vitro, only AICAR prevents heat-induced death in vivo. Our findings suggest that AICAR is probably effective in prophylactic treatment of humans with enhanced susceptibility to exercise- and/or heat-induced sudden death associated with RYR1 mutations.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::24bbf216e1e317b385d7655f89825848Test
http://europepmc.org/articles/PMC3274651Test

المؤلفون: Jin O-Uchi, Bong Sook Jhun, Shangcheng Xu, Stephen Hurst, Anna Raffaello, Xiaoyun Liu, Bing Yi, Huiliang Zhang, Polina Gross, Jyotsna Mishra, Alina Ainbinder, Sarah Kettlewell, Godfrey L. Smith, Robert T. Dirksen, Wang Wang, Rosario Rizzuto, Shey-Shing Sheu

المصدر: Antioxidants and Redox Signaling.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=erc_________::0a9bac93be01914132fc86b790d19638Test