Effects of reactive oxygen and nitrogen species on actomyosin and their implications for muscle contractility

Experimental evidence accumulated during recent years is pointing out that numerous pathological conditions in skeletal and cardiac muscle are associated with an oxidative stress-induced muscle injury. Additionally, it has been postulated that several oxidants can directly alter contractile function by oxidative modification of the myofibril proteins – actin and myosin. Peroxynitrite (ONOO-), a potent biological oxidizing agent formed in the nearly instantaneous reaction of nitric oxide with superoxide anion, is increasingly recognized as playing a major role in the skeletal and cardiac muscle dysfunction. This is supported by detection of 3-nitrotyrosine, a protein modification produced by the reaction of peroxynitrite with tyrosine, on skeletal and cardiac muscle proteins during aging or in diseases associated with myocardial inflammation or ischemia/reperfusion insults. Although some studies point to a correlation of protein nitration with functional and structural modifications, the mechanism by which peroxynitrite may impair muscle contractility remains far from being elucidated. In the present review we address the role of reactive oxygen and nitrogen species on the structural and functional impairment of actomyosin ATPase activity and their implications for muscle contraction with particular emphasis on the oxidative modifications promoted by peroxynitrite on actin and myosin

Monomeric versus decameric vanadate in the elucidation of muscle contraction regulation: a kinetic, spectroscopic and structural overview

Vanadium (V) was rediscovered for biology as a “muscle inhibitor factor” when it was found in commercial ATP prepared from equine muscle almost thirty years ago. Since then it has been used as a molecular probe of the mechanisms of several enzyme reactions involving hydrolysis of phosphate ester bonds. Besides acting as a phosphate analogue, vanadate has also the potential to exhibit biological activities through oligomeric vanadate species. Among the vanadate oligomers, decavanadate is one of the most potent inhibitors and has revealed an excellent kinetic and spectroscopic probe. This is particularly relevant for myosin, the major muscle ATPase which along with actin is able to convert the chemical energy of ATP hydrolysis into mechanical work. Apparently, vanadate is able to populate different conformational states of the myosin ATPase cycle depending on its oligomerization state. While monomeric vanadate (VO4 3-) mimics the transition state for the g-phosphate hydrolysis blocking myosin in a pre-power stroke state, decameric vanadate (V10O28 6-) induces the formation of the intermediate myosin·MgATP·V10 complex blocking the actomyosin cycle in a pre-hydrolysis state. These recent findings, that are now reviewed, point out to the importance of taking into account vanadate species variety in studies describing the interaction of vanadate with biological systems and incite the use of decavanadate as a biochemical tool to the elucidation of muscle contraction regulation

Decavanadate toxicity effects following in vivo administration

Very few in vivo animal studies involving vanadium consider the contribution of decavanadate (V10) to vanadium biological effects. Recently, it is been suggested that decameric vanadate may not completely fall apart into other vanadate oligomers before induces changes in cell homeostasis, namely in several stress markers. An acute exposure of different fish species (Halobactrachus didactilus, Lusitanian toadfish, and Sparus aurata, gilthead seabream) to decavanadate, but not to other vanadate oligomers, induced different effects than vanadate in catalase activity, glutathione content, lipid peroxidation, mitochondrial superoxide anion production and vanadium accumulation, whereas both solutions seem to equally depress reactive oxygen species (ROS) production as well as total intracellular reducing power. Vanadium is accumulated in Sparus aurata mitochondria in particular when decavanadate is administrated. Moreover, exposure to different vanadate oligomers induced morphological changes in fish cardiac, hepatic and renal tissues causing tissues lesions in the liver and kidney, but not cardiac tissue. Nevertheless, the results highlight that different vanadate oligomers seem to follow, not only in vitro but also in vivo, different pathways, with different targets and effects. These recent findings, that are now summarized, point out the decameric vanadate species contributions to in vivo effects induced by vanadium in biological systems

Decavanadate induces mitochondrial membrane depolarization and inhibits oxygen consumption

Decavanadate induced rat liver mitochondrial depolarization at very low concentrations, half-depolarization with 39 nM decavanadate, while it was needed a 130-fold higher concentration of monomeric vanadate (5 lM) to induce the same effect. Decavanadate also inhibits mitochondrial repolarization induced by reduced glutathione in vitro, with an inhibition constant of 1 lM, whereas no effect was observed up to 100 lM of monomeric vanadate. The oxygen consumption by mitochondria is also inhibited by lower decavanadate than monomeric vanadate concentrations, i.e. 50% inhibition is attained with 99 nM decavanadate and 10 lM monomeric vanadate. Thus, decavanadate is stronger as mitochondrial depolarization agent than as inhibitor of mitochondrial oxygen consumption. Up to 5 lM, decavanadate does not alter mitochondrial NADH levels nor inhibit neither FOF1-ATPase nor cytochrome c oxidase activity, but it induces changes in the redox steady-state of mitochondrial b-type cytochromes (complex III). NMR spectra showed that decameric vanadate is the predominant vanadate species in decavanadate solutions. It is concluded that decavanadate is much more potent mitochondrial depolarization agent and a more potent inhibitor of mitochondrial oxygen consumption than monomeric vanadate, pointing out the importance to take into account the contribution of higher oligomeric species of vanadium for the biological effects of vanadate solutions

Binding modes of decavanadate to myosin and inhibition of the actomyosin ATPase activity

Decavanadate, a vanadate oligomer, is known to interact with myosin and to inhibit the ATPase activity, but the putative binding sites and the mechanism of inhibition are still to be clarified. We have previously proposed that the decavanadate (V10O28 6−) inhibition of the actin-stimulated myosin ATPase activity is non-competitive towards both actin and ATP. A likely explanation for these results is that V10 binds to the so-called back-door at the end of the Pi-tube opposite to the nucleotide-binding site. In order to further investigate this possibility, we have carried out molecular docking simulations of the V10 oligomer on three different structures of the myosin motor domain of Dictyostelium discoideum, representing distinct states of the ATPase cycle. The results indicate a clear preference of V10 to bind at the back-door, but only on the “open” structures where there is access to the phosphate binding-loop. It is suggested that V10 acts as a “back-door stop” blocking the closure of the 50- kDa cleft necessary to carry out ATP-γ-phosphate hydrolysis. This provides a simple explanation to the non-competitive behavior of V10 and spurs the use of the oligomer as a tool to elucidate myosin back-door conformational changes in the process of muscle contraction

Peroxynitrite induces F-actin depolymerization and blockade of myosin ATPase stimulation

Treatment of F-actin with the peroxynitrite-releasing agent 3-morpholinosydnonimine (SIN-1) produced a dose-dependent F-actin depolymerization. This is due to released peroxynitrite because it is not produced by ‘decomposed SIN-1’, and it is prevented by superoxide dismutase concentrations efficiently preventing peroxynitrite formation. F-actin depolymerization has been found to be very sensitive to peroxynitrite, as exposure to fluxes as low as 50–100 nM peroxynitrite leads to nearly 50% depolymerization in about 1 h. G-actin polymerization is also impaired by peroxynitrite although with nearly 2-fold lower sensitivity. Exposure of F-actin to submicromolar fluxes of peroxynitrite produced cysteine oxidation and also a blockade of the ability of actin to stimulate myosin ATPase activity. Our results suggest that an imbalance of the F-actin/G-actin equilibrium can account for the observed structural and functional impairment of myofibrils under the peroxynitrite-mediated oxidative stress reported for some pathophysiological conditions

Multistrange hyperon production on nuclear targets

We consider the experimental data on yields of protons, strange Λ′s, and multistrange baryons (Ξ, Ω), and antibaryons production on nuclear targets, and the experimental ratios of multistrange to strange antibaryon production, at the energy region from SPS up to LHC, and compare them to the results of the quark-gluon string model calculations. In the case of heavy nucleus collisions, the experimental dependence of the ¯Ξ+/¯Λ, and, in particular, of the ¯Ω+/¯Λ ratios, on the centrality of the collision, shows a manifest violation of quark combinatorial rulesThis paper was supported by Ministerio de Economía, Industria y Competitividad, Spain (María de Maeztu Unit of Excellence MDM-2016-0692), and by Xunta de Galicia, Galiza-Spain (Consolidación e Estructuración 2021 GEC GI-2033-TEOFPACC)S

Production of φ Mesons on Nuclear Targets in the Quark–Gluon String Model

This version of the article has been accepted for publication, after peer review and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1134/S1063778817060035Experimental data on the production of φ mesons in proton–nucleus and nucleus–nucleus collisions are considered. These data show unusually small shadowing corrections to the inclusive density for φ-meson production in the midrapidity region. It is found that the results of calculations based on the quark–gluon string model are in qualitative agreement with experimental data on the density of produced φ mesons as a function of both the initial energy ranging from the Collaboration NA49 energy to the LHC high energies and the target atomic number A.We are grateful to M.G. Ryskin for stimulating discussions and enlightening comments. This work was supported by the Russian Science Foundation (grant no. 14-22-00281), the State Committee for Science of Republic of Armenia (Grant-15Т-1C223), Spanish Ministry of Education and Science (project FPA2014-58293-C2-1- P), as well as by the Consolider-Ingenio 2010 CPAN (CSD2007-00042) program and the Government of Galicia (2011/PC043).S

Description of ϕ -meson production in hadronic and nuclear collisions at very high energies

We expose the current experimental and theoretical situation of the interesting case of the production of ϕ mesons in up to very high energy collisions of hadrons on both nucleon and nuclear targets, and we present a quantitatively good theoretical description of the corresponding experimental data, based on the formalism of the well established Quark–Gluon String Model, that has proved to be valid for a wide energy range. All the available experimental data for ϕ -meson production in hadron–nucleon collisions on the spectra of secondary ϕ , and on the ratios of ϕ/π− and ϕ/K− production cross-sections, as well the corresponding ones for ϕ -meson production on nuclear targets, are considered. In particular, it is seen that the production of ϕ -mesons on nuclear targets presents unusually small shadow corrections for the inclusive density in the central rapidity region.S

Theoretical description of hadroproduction and production on nuclear targets of ϕ-mesons at very high energies

We expose the current experimental and theoretical situation of the interesting case of the production of ϕ mesons in up to very high energy collisions of hadrons on both nucleon and nuclear targets.CM wants to congratulate the organizers of BEACH 2018 for the nice scientific atmosphere created at the conference. This work has been supported by Russian RSCF grant No. 14-22- 00281, by Ministerio de Ciencia e Innovaci´on of Spain under project FPA2017-83814-P, and Maria de Maeztu Unit of Excellence MDM-2016-0692, and by Xunta de Galicia, Spain, under 2015-AEFIS (2015-PG034), AGRUP2015/11.S