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Reductive stress in striated muscle cells

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Abstract

Reductive stress is defined as a condition of sustained increase in cellular glutathione/glutathione disulfide and NADH/NAD+ ratios. Reductive stress is emerging as an important pathophysiological event in several diseased states, being as detrimental as is oxidative stress. Occurrence of reductive stress has been documented in several cardiomyopathies and is an important pathophysiological factor particularly in coronary artery disease and myocardial infarction. Excess activation of the transcription factor, Nrf2—the master regulator of the antioxidant response—, consequent in most cases to defective autophagy, can lead to reductive stress. In addition, hyperglycemia-induced activation of the polyol pathway can lead to increased NADH/NAD+ ratio, which might translate into increased levels of hydrogen sulfide—via enhanced activity of cystathionine β-synthase—that would fuel reductive stress through inhibition of mitochondrial complex I. Reductive stress may be either a potential weapon against cancer priming tumor cells to apoptosis or a cancer’s ally promoting tumor cell proliferation and making tumor cells resistant to reactive oxygen species-inducing drugs. In non-cancer pathological states reductive stress is definitely harmful paradoxically leading to reactive oxygen species overproduction via excess NADPH oxidase 4 activity. In face of the documented occurrence of reductive stress in several heart diseases, there is much less information about the occurrence and effects of reductive stress in skeletal muscle tissue. In the present review we describe relevant results emerged from studies of reductive stress in the heart and review skeletal muscle conditions in which reductive stress has been experimentally documented and those in which reductive stress might have an as yet unrecognized pathophysiological role. Establishing whether reductive stress has a (patho)physiological role in skeletal muscle will hopefully contribute to answer the question whether antioxidant supplementation to the general population, athletes, and a large cohort of patients (e.g. heart, sarcopenic, dystrophic, myopathic, cancer, and bronco-pulmonary patients) is harmless or detrimental.

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Abbreviations

AP-1:

Activating protein 1

ARE:

Antioxidant response element

BAG3:

Bcl-2-associated athanogene-3

CBS:

Cystathionine β-synthase

ER:

Endoplasmic reticulum

ERO1:

ER oxidoreductin 1

GPX1:

Glutathione peroxidase-1

GRP78/BiP:

Glucose regulated protein 78/immunoglobulin-heavy-chain-binding protein

GSH:

Reduced glutathione

GSSG:

Glutathione disulfide

HSPs:

Heat-shock proteins

I/R:

Ischemia/reperfusion

IRE-1α:

Inositol-requiring 1α

Keap1:

Kelch-like ECH-associated protein-1

Klf9:

Kruppel-like factor 9

Maf:

Musculoaponeurotic fibrosarcoma oncogene homolog

NADH:

Reduced nicotinamide adenine dinucleotide

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NOX:

NADPH oxidase

Nrf2:

NF-E2-related factor 2

OS:

Oxidative stress

PDI:

Protein disulphide isomerase

PERK:

Double-stranded RNA-dependent protein kinase (PKR)-like ER kinase

ROS:

Reactive oxygen species

RS:

Reductive stress

SOD2:

Superoxide dismutase 2

SQR:

Sulfide quinone reductase

SQSTM1:

Sequestosome 1

TAG:

Triacylglycerol

TRPA1:

Transient receptor potential ankyrin 1

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Acknowledgements

Ministero dell’Istruzione, dell’Università e della Ricerca, Italy (FIRB RBFR12BUMH) (I.B.); Ministero dell’Istruzione, dell’Università e della Ricerca, Italy (PRIN 2012N8YJC3), Fondazione Cassa di Risparmio di Perugia (Project 2015.0325.021) and Parent Project Onlus, Italia (G.S.); and Ministero dell’Istruzione, dell’Università e della Ricerca, Italy (PRIN 2010R8JK2X_004), Association Française contre les Myopathies (Project 16812), Associazione Italiana per la Ricerca sul Cancro (Project 17581) and Fondazione Cassa di Risparmio di Perugia (CRP 2016-0136.021) (R.D.). The authors declare no conflict of interest. We wish to thank the reviewers for helping us improve the manuscript.

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Authors and Affiliations

  1. Department of Experimental Medicine, Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy

    Ilaria Bellezza, Francesca Riuzzi, Sara Chiappalupi, Cataldo Arcuri, Ileana Giambanco, Guglielmo Sorci & Rosario Donato

  2. Interuniversity Institute of Myology (IIM), University of Perugia, 06132, Perugia, Italy

    Francesca Riuzzi, Sara Chiappalupi, Guglielmo Sorci & Rosario Donato

  3. Centro Universitario Di Ricerca Sulla Genomica Funzionale, University of Perugia, 06132, Perugia, Italy

    Guglielmo Sorci

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Bellezza, I., Riuzzi, F., Chiappalupi, S. et al. Reductive stress in striated muscle cells. Cell. Mol. Life Sci. 77, 3547–3565 (2020). https://doi.org/10.1007/s00018-020-03476-0

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