The effects of buthionine sulfoximine treatment on diaphragm contractility and SERCA pump function in adult and middle aged rats

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Abstract

This study examined the effects of 10 days of buthionine sulfoximine (BSO) treatment on in vitro contractility and sarcoplasmic reticulum calcium pump (SERCA) expression and function in adult (AD; 6–8 months old) and middle aged (MA; 14–17 months old) rat diaphragm in both the basal state and following fatiguing stimulation. BSO treatment reduced the cellular concentrations of free glutathione (GSH) by >95% and oxidized glutathione (GSSG) by >80% in both age cohorts. GSH content in AD Control diaphragm was 32% higher ( P < 0.01) than in MA Control, with no differences in GSSG. The ratio of GSH:GSSG, an indicator of cellular oxidative state, was 34.6 ± 7.4 in MA Control, 52.5 ± 10.1 in AD Control, 10.6 ± 1.7 in MA BSO, and 9.5 ± 1.1 in AD BSO (BSO vs. Control, P < 0.05). Several findings suggest that the effects of BSO treatment are age dependent. AD BSO diaphragm had 26% higher twitch and 28% higher tetanic force (both P < 0.05) than AD Controls, whereas no significant difference existed between the two MA groups. In contrast to our previous work on BSO-treated AD rats, BSO treatment did not influence maximal SERCA ATPase activity in MA rat diaphragm, nor did SERCA2a expression increase in BSO-treated MA diaphragm. Biotinylated iodoacetamide binding to SERCA1a, a specific marker of free cysteine residues, was reduced by 35% ( P < 0.05) in AD Control diaphragm following fatiguing stimulation, but was not reduced in any other group. Collectively, these results suggest an important role for redox regulation in both contractility and SERCA function which is influenced by aging.

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S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide.

Takeshi Adachi, V Sharov, Jason D. Pimentel … (2004)

Nitric oxide (NO) physiologically stimulates the sarco/endoplasmic reticulum calcium (Ca(2+)) ATPase (SERCA) to decrease intracellular Ca(2+) concentration and relax cardiac, skeletal and vascular smooth muscle. Here, we show that NO-derived peroxynitrite (ONOO(-)) directly increases SERCA activity by S-glutathiolation and that this modification of SERCA is blocked by irreversible oxidation of the relevant cysteine thiols during atherosclerosis. Purified SERCA was S-glutathiolated by ONOO(-) and the increase in Ca(2+)-uptake activity of SERCA reconstituted in phospholipid vesicles required the presence of glutathione. Mutation of the SERCA-reactive Cys674 to serine abolished these effects. Because superoxide scavengers decreased S-glutathiolation of SERCA and arterial relaxation by NO, ONOO(-) is implicated as the intracellular mediator. NO-dependent relaxation as well as S-glutathiolation and activation of SERCA were decreased by atherosclerosis and Cys674 was found to be oxidized to sulfonic acid. Thus, irreversible oxidation of key thiol(s) in disease impairs NO-induced relaxation by preventing reversible S-glutathiolation and activation of SERCA by NO/ONOO(-).

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Invited Review: redox modulation of skeletal muscle contraction: what we know and what we don't.

Michael Reid (2001)

Over the past decade, reactive oxygen species (ROS) and nitric oxide (NO) derivatives have been established as physiological modulators of skeletal muscle function. This mini-review addresses the roles of these molecules as endogenous regulators of muscle contraction. The article is organized in two parts. First, established concepts are briefly outlined. This section provides an overview of ROS production by muscle, antioxidant buffers that oppose ROS effects, enzymatic synthesis of NO in muscle, the effects of endogenous ROS on contractile function, and NO as a contractile modulator. Second, a selected group of unresolved topics are highlighted. These more controversial issues include putative source(s) of regulatory ROS, the relative importance of the two NO synthase isoforms constitutively coexpressed by muscle fibers, molecular mechanisms of ROS and NO action, and the physiological relevance of redox regulation. By discussing current questions, as well as the established paradigm, this article is intended to further debate and stimulate research in this area.

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F H Andrade, M B Reid, D G Allen … (1998)

1. We used intact single fibres from a mouse foot muscle to study the role of oxidation-reduction in the modulation of contractile function. 2. The oxidant hydrogen peroxide (H2O2, 100-300 microM) for brief periods did not change myoplasmic Ca2+ concentrations ([Ca2+]i) during submaximal tetani. However, force increased by 27 % during the same contractions. 3. The effects of H2O2 were time dependent. Prolonged exposures resulted in increased resting and tetanic [Ca2+]i, while force was significantly diminished. The force decline was mainly due to reduced myofibrillar Ca2+ sensitivity. There was also evidence of altered sarcoplasmic reticulum (SR) function: passive Ca2+ leak was increased and Ca2+ uptake was decreased. 4. The reductant dithiothreitol (DTT, 0.5-1 mM) did not change tetanic [Ca2+]i, but decreased force by over 40 %. This was completely reversed by subsequent incubations with H2O2. The force decline induced by prolonged exposure to H2O2 was reversed by subsequent exposure to DTT. 5. These results show that the elements of the contractile machinery are differentially responsive to changes in the oxidation-reduction balance of the muscle fibres. Myofibrillar Ca2+ sensitivity appears to be especially susceptible, while the SR functions (Ca2+ leak and uptake) are less so.

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Author and article information

Journal

Journal ID (nlm-ta): Physiol Rep

Journal ID (iso-abbrev): Physiol Rep

Journal ID (publisher-id): phy2

Title: Physiological Reports

Publisher: John Wiley & Sons, Ltd (Chichester, UK )

ISSN (Print): 2051-817X

ISSN (Electronic): 2051-817X

Publication date Collection: September 2015

Publication date (Electronic): 14 September 2015

Volume: 3

Issue: 9

Electronic Location Identifier: e12547

Affiliations

Department of Kinesiology, University of Waterloo Waterloo, Ontario, Canada

Author notes

Correspondence A. Russell Tupling, Department of Kinesiology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada N2L 3G1., Tel: 519-888-4567 (ext. 33652), Fax: 519-885-0470, E-mail: rtupling@ 123456uwaterloo.ca

Funding Information This study was supported by funds provided by the Natural Sciences and Engineering Research Council of Canada grant numbers 238342 (to JWER) and 311922 (to ART). I. C. Smith, C. Vigna, and S. G. Denniss were funded through postgraduate doctoral scholarships from Natural Sciences and Engineering Research Council of Canada. A. S. Levy was funded by a Canadian graduate scholarship from Natural Sciences and Engineering Research Council of Canada.

Article

DOI: 10.14814/phy2.12547

PMC ID: 4600388

PubMed ID: 26371231

SO-VID: 4b69b84c-7c80-47fa-9cb9-486990c7df82

License:

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 19 August 2015

Date accepted : 22 August 2015

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