Reactive Oxygen/Nitrogen Species and the Myocardial Cell Homeostasis: An Ambiguous Relationship

Kuster, Gabriela M.; Häuselmann, Stéphanie P.; Rosc-Schlüter, Berit I.; Lorenz, Vera; Pfister, Otmar

doi:10.1089/ars.2010.3464

Cited by 15 publications

(20 citation statements)

References 109 publications

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“…Myotubes were also resistant to H 2 O 2 (data non shown), but the comparison with myoblasts was hampered by the induction of differentiation upon H 2 O 2 exposure. 17 Terminally differentiated muscle cells are therefore not only resistant to IR (Figure 1b), 14 but also to SSB-inducing agents.…”

Section: Resultsmentioning

confidence: 99%

DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity

et al. 2012

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DNA single-strand breaks (SSB) formation coordinates the myogenic program, and defects in SSB repair in post-mitotic cells have been associated with human diseases. However, the DNA damage response by SSB in terminally differentiated cells has not been explored yet. Here we show that mouse post-mitotic muscle cells accumulate SSB after alkylation damage, but they are extraordinarily resistant to the killing effects of a variety of SSB-inducers. We demonstrate that, upon SSB induction, phosphorylation of H2AX occurs in myotubes and is largely ataxia telangiectasia mutated (ATM)-dependent. However, the DNA damage signaling cascade downstream of ATM is defective as shown by lack of p53 increase and phosphorylation at serine 18 (human serine 15). The stabilization of p53 by nutlin-3 was ineffective in activating the cell death pathway, indicating that the resistance to SSB inducers is due to defective p53 downstream signaling. The induction of specific types of damage is required to activate the cell death program in myotubes. Besides the topoisomerase inhibitor doxorubicin known for its cardiotoxicity, we show that the mitochondria-specific inhibitor menadione is able to activate p53 and to kill effectively myotubes. Cell killing is p53-dependent as demonstrated by full protection of myotubes lacking p53, but there is a restriction of p53-activated genes. This new information may have important therapeutic implications in the prevention of muscle cell toxicity. Cells respond to genotoxic stress by activating a signaling cascade known as the DNA damage response (DDR). The DDR is a complex interlaced network comprised of DNA damage repair factors and cell cycle regulators. 1 Our knowledge of the mechanisms of DDR mainly relies on studies conducted in proliferating cells, in which the cell cycle machinery is integrated with the DNA damage signaling. Much less is known in post-mitotic cells that undergo irreversible cell cycle withdrawal. DNA repair is strongly affected by the exit from the cell cycle as revealed by downregulation of the major DNA repair pathways. 2 This occurs during differentiation-associated gene reprogramming at transcriptional level as in the case of genes coding for proteins shared by DNA repair and replication (e.g., replicative DNA polymerases, Flap structure-specific endonuclease 1, proliferating cell nuclear antigen and DNA ligase 1) 3 or repair proteins that are cell-cycle related (e.g., XRCC1 (X-ray repair complementing defective repair in Chinese hamster cells 1), uracil-DNA glycosylase). 4,5 Alternatively, post-translational modifications may modify the efficiency of specific DNA repair components as in the case of transcription factor II H that, because of reduced ubiquitination, may lead to decreased global genomic nucleotide excision repair typical of differentiated cells. 6 Exposure of single-stranded (ss) DNA and/or the generation of double-strand breaks (DSB) are powerful activators of DDR by recruiting and activating two protein kinases, ataxia telangiectasia and Rad3-related (ATR)...

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Section: Resultsmentioning

confidence: 99%

DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity

et al. 2012

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“…It is obvious that extra-myocytegenerated ROS and RNS demonstrate paracrine signaling to myocytes, and several excellent reviews have been published that consider these pathways (12,15,40,41,55). Much less is known, however, about the mechanisms by which ROS/RNS is generated within the myocyte during contraction or stretch (34,54).…”

mentioning

confidence: 99%

Mechanical Stretch-Induced Activation of ROS/RNS Signaling in Striated Muscle

Ward

Prosser²,

Lederer³

2014

Antioxidants & Redox Signaling

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Significance: Mechanical activation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) occurs in striated muscle and affects Ca 2+ signaling and contractile function. ROS/RNS signaling is tightly controlled, spatially compartmentalized, and source specific. Recent Advances: Here, we review the evidence that within the contracting myocyte, the trans-membrane protein NADPH oxidase 2 (Nox2) is the primary source of ROS generated during contraction. We also review a newly characterized signaling cascade in cardiac and skeletal muscle in which the microtubule network acts as a mechanotransduction element that activates Nox2-dependent ROS generation during mechanical stretch, a pathway termed X-ROS signaling. Critical Issues: In the heart, X-ROS acts locally and affects the sarcoplasmic reticulum (SR) Ca 2+ release channels (ryanodine receptors) and tunes Ca 2+ signaling during physiological behavior, but excessive X-ROS can promote Ca 2+ -dependent arrhythmias in pathology. In skeletal muscle, X-ROS sensitizes Ca 2+ -permeable sarcolemmal ''transient receptor potential'' channels, a pathway that is critical for sustaining SR load during repetitive contractions, but when in excess, it is maladaptive in diseases such as Duchenne Musclar dystrophy. Future Directions: New advances in ROS/RNS detection as well as molecular manipulation of signaling pathways will provide critical new mechanistic insights into the details of X-ROS signaling. These efforts will undoubtedly reveal new avenues for therapeutic intervention in the numerous diseases of striated muscle in which altered mechanoactivation of ROS/RNS production has been identified. Antioxid. Redox Signal. 20,[929][930][931][932][933][934][935][936]

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“…Beyond this, nonenzymatic sources, such as the reduction of nitrite and the Fenton reaction, have been identified (36,50,57).…”

Section: Sources Of Ros/rns In the Heartmentioning

confidence: 99%

“…At the same time, accumulation of these reactive oxygen species (ROS) and reactive nitrogen species (RNS) can be pathological. Maintenance of the optimal reductive/oxidative potential within the cell is critical to numerous cellular functions, and the nitroso-redox imbalance contributes to aging and disease development, including in muscle (10,27,36,67).…”

mentioning

confidence: 99%

Oxidative Stress and Autophagy in Cardiovascular Homeostasis

Morales

Pedrozo

Lavandero

et al. 2014

Antioxidants & Redox Signaling

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Significance: Autophagy is an evolutionarily ancient process of intracellular protein and organelle recycling required to maintain cellular homeostasis in the face of a wide variety of stresses. Dysregulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) leads to oxidative damage. Both autophagy and ROS/RNS serve pathological or adaptive roles within cardiomyocytes, depending on the context. Recent Advances: ROS/RNS and autophagy communicate with each other via both transcriptional and post-translational events. This cross talk, in turn, regulates the structural integrity of cardiomyocytes, promotes proteostasis, and reduces inflammation, events critical to disease pathogenesis. Critical Issues: Dysregulation of either autophagy or redox state has been implicated in many cardiovascular diseases. Cardiomyocytes are rich in mitochondria, which make them particularly sensitive to oxidative damage. Maintenance of mitochondrial homeostasis and elimination of defective mitochondria are each critical to the maintenance of redox homeostasis. Future Directions: The complex interplay between autophagy and oxidative stress underlies a wide range of physiological and pathological events and its elucidation holds promise of potential clinical applicability. Antioxid. Redox Signal. 20, 507-518.

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Reactive Oxygen/Nitrogen Species and the Myocardial Cell Homeostasis: An Ambiguous Relationship

Cited by 15 publications

References 109 publications

DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity

DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity

Mechanical Stretch-Induced Activation of ROS/RNS Signaling in Striated Muscle

Oxidative Stress and Autophagy in Cardiovascular Homeostasis

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