المؤلفون: Tanya R. Cully, George G. Rodney

المصدر: Redox Biology, Vol 36, Iss, Pp 101557-(2020)
Redox Biology

مصطلحات موضوعية: 0301 basic medicine, mdx mouse, Clinical Biochemistry, Skeletal muscle, Protein degradation, medicine.disease_cause, Biochemistry, Dystrophy, Mice, 03 medical and health sciences, Nox4, 0302 clinical medicine, Nox2, DMD, medicine, Animals, Mdx, Muscle, Skeletal, lcsh:QH301-705.5, RYR1, lcsh:R5-920, Chemistry, Organic Chemistry, Autophagy, NAD(P)H oxidase, NADPH Oxidases, Ryanodine Receptor Calcium Release Channel, Cell biology, Muscular Dystrophy, Duchenne, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), NADPH Oxidase 4, RyR1, NADPH Oxidase 2, Mice, Inbred mdx, Calcium, NAD+ kinase, Reactive Oxygen Species, lcsh:Medicine (General), 030217 neurology & neurosurgery, Oxidative stress, Research Paper

الوصف: The ability for skeletal muscle to perform optimally can be affected by the regulation of Ca2+ within the triadic junctional space at rest. Reactive oxygen species impact muscle performance due to changes in oxidative stress, damage and redox regulation of signaling cascades. The interplay between ROS and Ca2+ signaling at the triad of skeletal muscle is therefore important to understand as it can impact the performance of healthy and diseased muscle. Here, we aimed to examine how changes in Ca2+ and redox signaling within the junctional space micro-domain of the mouse skeletal muscle fibre alters the homeostasis of these complexes. The dystrophic mdx mouse model displays increased RyR1 Ca2+ leak and increased NAD(P)H Oxidase 2 ROS. These alterations make the mdx mouse an ideal model for understanding how ROS and Ca2+ handling impact each other. We hypothesised that elevated t-tubular Nox2 ROS increases RyR1 Ca2+ leak contributing to an increase in cytoplasmic Ca2+, which could then initiate protein degradation and impaired cellular functions such as autophagy and ER stress. We found that inhibiting Nox2 ROS did not decrease RyR1 Ca2+ leak observed in dystrophin-deficient skeletal muscle. Intriguingly, another NAD(P)H isoform, Nox4, is upregulated in mice unable to produce Nox2 ROS and when inhibited reduced RyR1 Ca2+ leak. Our findings support a model in which Nox4 ROS induces RyR1 Ca2+ leak and the increased junctional space [Ca2+] exacerbates Nox2 ROS; with the cumulative effect of disruption of downstream cellular processes that would ultimately contribute to reduced muscle or cellular performance.
Graphical abstract Image 1
Highlights • Nox2 ROS does not influence RyR1 Ca2+ leak in skeletal muscle. • Lack of Nox2 ROS increases Nox4 expression. • Nox4 ROS induces RyR1 Ca2+ leak via S-nitrosylation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f39fbe83970b93fc7a3b3f0b550b1f8dTest
http://www.sciencedirect.com/science/article/pii/S221323172030416XTest

المؤلفون: Gary R. Stinnett, George G. Rodney, Robia G. Pautler, Wesley T. Roten, Mayra Hernández-Rivera, Lon J. Wilson, James A. Loehr

المصدر: The Journal of Physiology. 594:6395-6405

مصطلحات موضوعية: chemistry.chemical_classification, Reactive oxygen species, Sarcolemma, biology, Physiology, Duchenne muscular dystrophy, Skeletal muscle, chemistry.chemical_element, Inflammation, Calcium, medicine.disease, 030218 nuclear medicine & medical imaging, Cell biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, chemistry, Biochemistry, In vivo, medicine, biology.protein, medicine.symptom, Dystrophin, 030217 neurology & neurosurgery

الوصف: Key points Inhibiting Nox2 reactive oxygen species (ROS) production reduced in vivo calcium influx in dystrophic muscle. The lack of Nox2 ROS production protected against decreased in vivo muscle function in dystrophic mice. Manganese-enhanced magnetic resonance imaging (MEMRI) was able to detect alterations in basal calcium levels in skeletal muscle and differentiate disease status. Administration of Mn2+ did not affect muscle function or the health of the animal, and Mn2+ was cleared from skeletal muscle rapidly. We conclude that MEMRI may be a viable, non-invasive technique to monitor molecular alterations in disease progression and evaluate the effectiveness of potential therapies for Duchenne muscular dystrophy. Abstract Duchenne muscular dystrophy (DMD) is an X-linked progressive degenerative disease resulting from a mutation in the gene that encodes dystrophin, leading to decreased muscle mechanical stability and force production. Increased Nox2 reactive oxygen species (ROS) production and sarcolemmal Ca2+ influx are early indicators of disease pathology, and eliminating Nox2 ROS production reduces aberrant Ca2+ influx in young mdx mice, a model of DMD. Various imaging modalities have been used to study dystrophic muscle in vivo; however, they are based upon alterations in muscle morphology or inflammation. Manganese has been used for indirect monitoring of calcium influx across the sarcolemma and may allow detection of molecular alterations in disease progression in vivo using manganese-enhanced magnetic resonance imaging (MEMRI). Therefore, we hypothesized that eliminating Nox2 ROS production would decrease calcium influx in adult mdx mice and that MEMRI would be able to monitor and differentiate disease status in dystrophic muscle. Both in vitro and in vivo data demonstrate that eliminating Nox2 ROS protected against aberrant Ca2+ influx and improved muscle function in dystrophic muscle. MEMRI was able to differentiate between different pathological states in vivo, with no long-term effects on animal health or muscle function. We conclude that MEMRI is a viable, non-invasive technique to differentiate disease status and might provide a means to monitor and evaluate the effectiveness of potential therapies in dystrophic muscle.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::e59d58745c2c5374514e6780c10f7099Test
https://doi.org/10.1113/jp272907Test

المؤلفون: James A. Loehr, Reem eAbo-Zahrah, Rituraj ePal, George G. Rodney

المصدر: Frontiers in Physiology, Vol 5 (2015)
Frontiers in Physiology

مصطلحات موضوعية: Mitochondrial ROS, Physiology, NADPH Oxidase, Mitochondrion, lcsh:Physiology, Superoxide dismutase, 03 medical and health sciences, 0302 clinical medicine, Nox2, Physiology (medical), medicine, Original Research Article, skeletal muscle, redox signaling, sphingomyelinase, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Gene knockdown, Reactive oxygen species, NADPH oxidase, biology, lcsh:QP1-981, sphingomylenase, Skeletal muscle, ROS, Cell biology, medicine.anatomical_structure, Biochemistry, chemistry, biology.protein, Sphingomyelin, Reactive Oxygen Species, force, 030217 neurology & neurosurgery

الوصف: Elevated concentrations of sphingomyelinase (SMase) have been detected in a variety of diseases. SMase has been shown to increase muscle derived oxidants and decrease skeletal muscle force; however, the sub-cellular site of oxidant production has not been elucidated. Using redox sensitive biosensors targeted to the mitochondria and NADPH oxidase (Nox2), we demonstrate that SMase increased Nox2-dependent ROS and had no effect on mitochondrial ROS in isolated FDB fibers. Pharmacological inhibition and genetic knockdown of Nox2 activity prevented SMase induced ROS production and provided protection against decreased force production in the diaphragm. In contrast, genetic overexpression of superoxide dismutase within the mitochondria did not prevent increased ROS production and offered no protection against decreased diaphragm function in response to SMase. Our study shows that SMase induced ROS production occurs in specific sub-cellular regions of skeletal muscle; however, the increased ROS does not completely account for the decrease in muscle function.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4df64d38390e5e1cd8c7540596a2f1aaTest
http://journal.frontiersin.org/Journal/10.3389/fphys.2014.00530/fullTest

المؤلفون: George G. Rodney, Shumin Li, Charles G. Minard, Poulami Basu Thakur, Rituraj Pal

المصدر: PLoS ONE, Vol 8, Iss 5, p e63989 (2013)
PLoS ONE

مصطلحات موضوعية: Lipopolysaccharides, Anatomy and Physiology, Time Factors, Mouse, Muscle Fibers, Skeletal, lcsh:Medicine, Stimulation, Biosensing Techniques, Green fluorescent protein, RoGFP, Mice, 0302 clinical medicine, Genes, Reporter, Immune Physiology, Molecular Cell Biology, Muscular dystrophy, lcsh:Science, Musculoskeletal System, Image Cytometry, chemistry.chemical_classification, 0303 health sciences, Membrane Glycoproteins, Multidisciplinary, Muscle Biochemistry, Animal Models, respiratory system, Molecular Imaging, 3. Good health, medicine.anatomical_structure, Biochemistry, NADPH Oxidase 2, cardiovascular system, Muscle, Cellular Types, medicine.symptom, Oxidation-Reduction, Research Article, Muscle contraction, circulatory and respiratory physiology, inorganic chemicals, Cell Physiology, Cell Survival, Immune Cells, Green Fluorescent Proteins, In Vitro Techniques, Biology, Fluorescence, 03 medical and health sciences, Model Organisms, Computer Systems, medicine, Animals, Humans, NOx, 030304 developmental biology, Muscle Cells, Reactive oxygen species, lcsh:R, NADPH Oxidases, Skeletal muscle, Macrophage Activation, medicine.disease, Electric Stimulation, chemistry, lcsh:Q, Physiological Processes, Extracellular Space, Reactive Oxygen Species, Cytometry, 030217 neurology & neurosurgery

الوصف: Production of reactive oxygen species (ROS) has been implicated in the pathology of many conditions, including cardiovascular, inflammatory and degenerative diseases, aging, muscular dystrophy, and muscle fatigue. NADPH oxidases (Nox) have recently gained attention as an important source of ROS involved in redox signaling. However, our knowledge of the source of ROS has been limited by the relatively impoverished array of tools available to study them and the limitations of all imaging probes to provide meaningful spatial resolution. By linking redox-sensitive GFP (roGFP) to the Nox organizer protein, p47(phox), we have developed a redox sensitive protein to specifically assess Nox activity (p47-roGFP). Stimulation of murine macrophages with endotoxin resulted in rapid, reversible oxidation of p47-roGFP. In murine skeletal muscle, both passive stretch and repetitive electrical stimulation resulted in oxidation of p47-roGFP. The oxidation of p47-roGFP in both macrophages and skeletal muscle was blocked by a Nox specific peptide inhibitor. Furthermore, expression of p47-roGFP in p47(phox) deficient cells restored Nox activity. As Nox has been linked to pathological redox signaling, our newly developed Nox biosensor will allow for the direct assessment of Nox activity and the development of therapeutic Nox inhibitors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a78ddfe9d3de228148107381af0bb275Test
http://europepmc.org/articles/PMC3660327?pdf=renderTest