{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T23:56:17Z","timestamp":1769039777513,"version":"3.49.0"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T00:00:00Z","timestamp":1689811200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T00:00:00Z","timestamp":1689811200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pflugers Arch - Eur J Physiol"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Myonecrosis is a frequent clinical manifestation of envenomings by Viperidae snakes, mainly caused by the toxic actions of secreted phospholipase A<jats:sub>2<\/jats:sub> (sPLA<jats:sub>2<\/jats:sub>) enzymes and sPLA<jats:sub>2<\/jats:sub>-like homologs on skeletal muscle fibers. A hallmark of the necrotic process induced by these myotoxins is the rapid appearance of hypercontracted muscle fibers, attributed to the massive influx of Ca<jats:sup>2+<\/jats:sup> resulting from cell membrane damage. However, the possibility of myotoxins having, in addition, a direct effect on the contractile machinery of skeletal muscle fibers when internalized has not been investigated. This question is here addressed by using an <jats:italic>ex vivo<\/jats:italic> model of single-skinned muscle fibers, which lack membranes but retain an intact contractile apparatus. Rabbit psoas skinned fibers were exposed to two types of myotoxins of <jats:italic>Bothrops asper<\/jats:italic> venom: Mt-I, a catalytically active Asp49 sPLA<jats:sub>2<\/jats:sub> enzyme, and Mt-II, a Lys49 sPLA<jats:sub>2<\/jats:sub>-like protein devoid of phospholipolytic activity. Neither of these myotoxins affected the main parameters of force development in striated muscle sarcomeres of the skinned fibers. Moreover, no microscopical alterations were evidenced after their exposure to Mt-I or Mt-II. In contrast to the lack of effects on skinned muscle fibers, both myotoxins induced a strong hypercontraction in myotubes differentiated from murine C2C12 myoblasts, with drastic morphological alterations that reproduce those described in myonecrotic tissue <jats:italic>in vivo<\/jats:italic>. As neither Mt-I nor Mt-II showed direct effects upon the contractile apparatus of skinned fibers, it is concluded that the mechanism of hypercontraction triggered by both myotoxins in patients involves indirect effects, i.e., the large cytosolic Ca<jats:sup>2+<\/jats:sup> increase after sarcolemma permeabilization.<\/jats:p>","DOI":"10.1007\/s00424-023-02840-w","type":"journal-article","created":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T19:02:21Z","timestamp":1689879741000},"page":"1193-1202","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Skeletal muscle fiber hypercontraction induced by Bothrops asper myotoxic phospholipases A2 ex vivo does not involve a direct action on the contractile apparatus"],"prefix":"10.1007","volume":"475","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5189-7183","authenticated-orcid":false,"given":"Alfredo Jes\u00fas","family":"L\u00f3pez-D\u00e1vila","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2302-1045","authenticated-orcid":false,"given":"Natalie","family":"Weber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0888-1888","authenticated-orcid":false,"given":"Arnab","family":"Nayak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leon","family":"Fritz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kian Rami","family":"Moustafa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis Vincens","family":"Gand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enke","family":"Wehry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8386-8088","authenticated-orcid":false,"given":"Theresia","family":"Kraft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4360-1511","authenticated-orcid":false,"given":"Thomas","family":"Thum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9169-2732","authenticated-orcid":false,"given":"Juli\u00e1n","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-3081","authenticated-orcid":false,"given":"Jos\u00e9 Mar\u00eda","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2419-6469","authenticated-orcid":false,"given":"Bruno","family":"Lomonte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,7,20]]},"reference":[{"key":"2840_CR1","doi-asserted-by":"publisher","first-page":"111702","DOI":"10.1016\/j.celrep.2022.111702","volume":"41","author":"M Amrute-Nayak","year":"2022","unstructured":"Amrute-Nayak M, Gand LV, Khan B, Holler T, Kefalakes E, Kosanke M, Kraft T, Nayak A (2022) SENP7 deSUMOylase-governed transcriptional program coordinates sarcomere assembly and is targeted in muscle atrophy. Cell Rep 41:111702. https:\/\/doi.org\/10.1016\/j.celrep.2022.111702","journal-title":"Cell Rep"},{"key":"2840_CR2","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/S0006-3495(83)84411-7","volume":"41","author":"B Brenner","year":"1983","unstructured":"Brenner B (1983) Technique for stabilizing the striation pattern in maximally calcium-activated skinned rabbit psoas fibers. Biophys J 41:99\u2013102. https:\/\/doi.org\/10.1016\/S0006-3495(83)84411-7","journal-title":"Biophys J"},{"key":"2840_CR3","doi-asserted-by":"publisher","first-page":"3265","DOI":"10.1073\/pnas.85.9.3265","volume":"85","author":"B Brenner","year":"1988","unstructured":"Brenner B (1988) Effect of Ca2+ on cross-bridge turnover kinetics in skinned single rabbit psoas fibers: implications for regulation of muscle contraction. Proc Natl Acad Sci U S A 85:3265\u20133269. https:\/\/doi.org\/10.1073\/pnas.85.9.3265","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2840_CR4","doi-asserted-by":"publisher","first-page":"2692","DOI":"10.1016\/S0006-3495(99)77103-1","volume":"77","author":"B Brenner","year":"1999","unstructured":"Brenner B, Chalovich JM (1999) Kinetics of thin filament activation probed by fluorescence of N-((2-(iodoacetoxy)ethyl)-N-methyl)amino-7-nitrobenz-2-oxa-1,3-diazole-labeled troponin I incorporated into skinned fibers of rabbit psoas muscle: implications for regulation of muscle contraction. Biophys J 77:2692\u20132708. https:\/\/doi.org\/10.1016\/S0006-3495(99)77103-1","journal-title":"Biophys J"},{"key":"2840_CR5","doi-asserted-by":"publisher","first-page":"2677","DOI":"10.1016\/S0006-3495(99)77102-X","volume":"77","author":"B Brenner","year":"1999","unstructured":"Brenner B, Kraft T, Yu LC, Chalovich JM (1999) Thin filament activation probed by fluorescence of N-((2-(iodoacetoxy)ethyl)-N-methyl)amino-7-nitrobenz-2-oxa-1,3-diazole-labeled troponin I incorporated into skinned fibers of rabbit psoas muscle. Biophys J 77:2677\u20132691. https:\/\/doi.org\/10.1016\/S0006-3495(99)77102-X","journal-title":"Biophys J"},{"key":"2840_CR6","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1042\/BJ20020092","volume":"366","author":"L Chioato","year":"2002","unstructured":"Chioato L, De Oliveira AH, Ruller R, Sa JM, Ward RJ (2002) Distinct sites for myotoxic and membrane-damaging activities in the C-terminal region of a Lys49-phospholipase A2. Biochem J 366:971\u2013976. https:\/\/doi.org\/10.1042\/BJ20020092","journal-title":"Biochem J"},{"key":"2840_CR7","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1016\/j.toxicon.2009.10.013","volume":"55","author":"M Cintra-Francischinelli","year":"2010","unstructured":"Cintra-Francischinelli M, Pizzo P, Angulo Y, Gutierrez JM, Montecucco C, Lomonte B (2010) The C-terminal region of a Lys49 myotoxin mediates Ca2+ influx in C2C12 myotubes. Toxicon 55:590\u2013596. https:\/\/doi.org\/10.1016\/j.toxicon.2009.10.013","journal-title":"Toxicon"},{"key":"2840_CR8","doi-asserted-by":"publisher","first-page":"1718","DOI":"10.1007\/s00018-009-9053-2","volume":"66","author":"M Cintra-Francischinelli","year":"2009","unstructured":"Cintra-Francischinelli M, Pizzo P, Rodrigues-Simioni L, Ponce-Soto LA, Rossetto O, Lomonte B, Gutierrez JM, Pozzan T, Montecucco C (2009) Calcium imaging of muscle cells treated with snake myotoxins reveals toxin synergism and presence of acceptors. Cell Mol Life Sci 66:1718\u20131728. https:\/\/doi.org\/10.1007\/s00018-009-9053-2","journal-title":"Cell Mol Life Sci"},{"key":"2840_CR9","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/0005-2736(91)90086-n","volume":"1070","author":"C Diaz","year":"1991","unstructured":"Diaz C, Gutierrez JM, Lomonte B, Gene JA (1991) The effect of myotoxins isolated from Bothrops snake venoms on multilamellar liposomes: relationship to phospholipase A2, anticoagulant and myotoxic activities. Biochim Biophys Acta 1070:455\u2013460. https:\/\/doi.org\/10.1016\/0005-2736(91)90086-n","journal-title":"Biochim Biophys Acta"},{"key":"2840_CR10","doi-asserted-by":"publisher","first-page":"2265","DOI":"10.1016\/j.bbapap.2014.09.015","volume":"1844","author":"CA Fernandes","year":"2014","unstructured":"Fernandes CA, Borges RJ, Lomonte B, Fontes MR (2014) A structure-based proposal for a comprehensive myotoxic mechanism of phospholipase A2-like proteins from viperid snake venoms. Biochim Biophys Acta 1844:2265\u20132276. https:\/\/doi.org\/10.1016\/j.bbapap.2014.09.015","journal-title":"Biochim Biophys Acta"},{"key":"2840_CR11","doi-asserted-by":"publisher","first-page":"3878","DOI":"10.1111\/febs.12386","volume":"280","author":"J Fernandez","year":"2013","unstructured":"Fernandez J, Caccin P, Koster G, Lomonte B, Gutierrez JM, Montecucco C, Postle AD (2013) Muscle phospholipid hydrolysis by Bothrops asper Asp49 and Lys49 phospholipase A2 myotoxins--distinct mechanisms of action. FEBS J 280:3878\u20133886. https:\/\/doi.org\/10.1111\/febs.12386","journal-title":"FEBS J"},{"key":"2840_CR12","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/0003-9861(91)90307-5","volume":"284","author":"B Francis","year":"1991","unstructured":"Francis B, Gutierrez JM, Lomonte B, Kaiser II (1991) Myotoxin II from Bothrops asper (Terciopelo) venom is a lysine-49 phospholipase A2. Arch Biochem Biophys 284:352\u2013359. https:\/\/doi.org\/10.1016\/0003-9861(91)90307-5","journal-title":"Arch Biochem Biophys"},{"key":"2840_CR13","doi-asserted-by":"publisher","first-page":"17063","DOI":"10.1038\/nrdp.2017.63","volume":"3","author":"JM Gutierrez","year":"2017","unstructured":"Gutierrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA (2017) Snakebite envenoming. Nat Rev Dis Primers 3:17063. https:\/\/doi.org\/10.1038\/nrdp.2017.63","journal-title":"Nat Rev Dis Primers"},{"key":"2840_CR14","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/0041-0101(89)90040-8","volume":"27","author":"JM Gutierrez","year":"1989","unstructured":"Gutierrez JM, Chaves F, Gene JA, Lomonte B, Camacho Z, Schosinsky K (1989) Myonecrosis induced in mice by a basic myotoxin isolated from the venom of the snake Bothrops nummifer (jumping viper) from Costa Rica. Toxicon 27:735\u2013745. https:\/\/doi.org\/10.1016\/0041-0101(89)90040-8","journal-title":"Toxicon"},{"key":"2840_CR15","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.toxicon.2012.09.006","volume":"62","author":"JM Gutierrez","year":"2013","unstructured":"Gutierrez JM, Lomonte B (2013) Phospholipases A2: unveiling the secrets of a functionally versatile group of snake venom toxins. Toxicon 62:27\u201339. https:\/\/doi.org\/10.1016\/j.toxicon.2012.09.006","journal-title":"Toxicon"},{"key":"2840_CR16","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/j.toxicon.2003.11.005","volume":"42","author":"JM Gutierrez","year":"2003","unstructured":"Gutierrez JM, Ownby CL (2003) Skeletal muscle degeneration induced by venom phospholipases A2: insights into the mechanisms of local and systemic myotoxicity. Toxicon 42:915\u2013931. https:\/\/doi.org\/10.1016\/j.toxicon.2003.11.005","journal-title":"Toxicon"},{"key":"2840_CR17","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/0014-4800(84)90054-6","volume":"40","author":"JM Gutierrez","year":"1984","unstructured":"Gutierrez JM, Ownby CL, Odell GV (1984) Pathogenesis of myonecrosis induced by crude venom and a myotoxin of Bothrops asper. Exp Mol Pathol 40:367\u2013379. https:\/\/doi.org\/10.1016\/0014-4800(84)90054-6","journal-title":"Exp Mol Pathol"},{"key":"2840_CR18","doi-asserted-by":"publisher","first-page":"e13719","DOI":"10.1111\/apha.13719","volume":"233","author":"M Kalakoutis","year":"2021","unstructured":"Kalakoutis M, Di Giulio I, Douiri A, Ochala J, Harridge SDR, Woledge RC (2021) Methodological considerations in measuring specific force in human single skinned muscle fibres. Acta Physiol (Oxf) 233:e13719. https:\/\/doi.org\/10.1111\/apha.13719","journal-title":"Acta Physiol (Oxf)"},{"key":"2840_CR19","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1016\/j.bbrc.2017.06.130","volume":"490","author":"H Komatsu","year":"2017","unstructured":"Komatsu H, Koseki Y, Kanno T, Aoki S, Kodama T (2017) 2,3-Butandione 2-monoxime inhibits skeletal myosin II by accelerating ATP cleavage. Biochem Biophys Res Commun 490:849\u2013854. https:\/\/doi.org\/10.1016\/j.bbrc.2017.06.130","journal-title":"Biochem Biophys Res Commun"},{"key":"2840_CR20","doi-asserted-by":"publisher","first-page":"2404","DOI":"10.1016\/S0006-3495(95)80423-6","volume":"68","author":"T Kraft","year":"1995","unstructured":"Kraft T, Chalovich JM, Yu LC, Brenner B (1995) Parallel inhibition of active force and relaxed fiber stiffness by caldesmon fragments at physiological ionic strength and temperature conditions: additional evidence that weak cross-bridge binding to actin is an essential intermediate for force generation. Biophys J 68:2404\u20132418. https:\/\/doi.org\/10.1016\/S0006-3495(95)80423-6","journal-title":"Biophys J"},{"key":"2840_CR21","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1016\/S0006-3495(95)80018-4","volume":"69","author":"T Kraft","year":"1995","unstructured":"Kraft T, Messerli M, Rothen-Rutishauser B, Perriard JC, Wallimann T, Brenner B (1995) Equilibration and exchange of fluorescently labeled molecules in skinned skeletal muscle fibers visualized by confocal microscopy. Biophys J 69:1246\u20131258. https:\/\/doi.org\/10.1016\/S0006-3495(95)80018-4","journal-title":"Biophys J"},{"key":"2840_CR22","doi-asserted-by":"publisher","first-page":"107024","DOI":"10.1016\/j.toxicon.2023.107024","volume":"224","author":"B Lomonte","year":"2023","unstructured":"Lomonte B (2023) Lys49 myotoxins, secreted phospholipase A2-like proteins of viperid venoms: A comprehensive review. Toxicon 224:107024. https:\/\/doi.org\/10.1016\/j.toxicon.2023.107024","journal-title":"Toxicon"},{"key":"2840_CR23","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/s0041-0101(98)00171-8","volume":"37","author":"B Lomonte","year":"1999","unstructured":"Lomonte B, Angulo Y, Rufini S, Cho W, Giglio JR, Ohno M, Daniele JJ, Geoghegan P, Gutierrez JM (1999) Comparative study of the cytolytic activity of myotoxic phospholipases A2 on mouse endothelial (tEnd) and skeletal muscle (C2C12) cells in vitro. Toxicon 37:145\u2013158. https:\/\/doi.org\/10.1016\/s0041-0101(98)00171-8","journal-title":"Toxicon"},{"key":"2840_CR24","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1016\/0041-0101(89)90039-1","volume":"27","author":"B Lomonte","year":"1989","unstructured":"Lomonte B, Gutierrez JM (1989) A new muscle damaging toxin, myotoxin II, from the venom of the snake Bothrops asper (terciopelo). Toxicon 27:725\u2013733. https:\/\/doi.org\/10.1016\/0041-0101(89)90039-1","journal-title":"Toxicon"},{"key":"2840_CR25","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1201\/9780429054204-30","volume-title":"Handbook of Venoms and Toxins of Reptiles","author":"B Lomonte","year":"2021","unstructured":"Lomonte B, Kri\u017eaj I (2021) Snake venom phospholipase A2 toxins. In: Handbook of Venoms and Toxins of Reptiles. In: Mackessy SP (ed) Handbook of Venoms and Toxins of Reptiles, 2nd edn. CRC Press, Boca Raton, pp 389\u2013411","edition":"2"},{"key":"2840_CR26","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/0041-0101(94)90020-5","volume":"32","author":"B Lomonte","year":"1994","unstructured":"Lomonte B, Lundgren J, Johansson B, Bagge U (1994) The dynamics of local tissue damage induced by Bothrops asper snake venom and myotoxin II on the mouse cremaster muscle: an intravital and electron microscopic study. Toxicon 32:41\u201355. https:\/\/doi.org\/10.1016\/0041-0101(94)90020-5","journal-title":"Toxicon"},{"key":"2840_CR27","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1016\/j.toxicon.2012.02.007","volume":"60","author":"B Lomonte","year":"2012","unstructured":"Lomonte B, Rangel J (2012) Snake venom Lys49 myotoxins: From phospholipase A2 to non-enzymatic membrane disruptors. Toxicon 60:520\u2013530. https:\/\/doi.org\/10.1016\/j.toxicon.2012.02.007","journal-title":"Toxicon"},{"key":"2840_CR28","doi-asserted-by":"publisher","first-page":"144","DOI":"10.3389\/fphys.2020.00144","volume":"11","author":"AJ Lopez-Davila","year":"2020","unstructured":"Lopez-Davila AJ, Chalovich JM, Zittrich S, Piep B, Matinmehr F, Malnasi-Csizmadia A, Rauscher AA, Kraft T, Brenner B, Stehle R (2020) Cycling cross-bridges contribute to thin filament activation in human slow-twitch fibers. Front Physiol 11:144. https:\/\/doi.org\/10.3389\/fphys.2020.00144","journal-title":"Front Physiol"},{"key":"2840_CR29","doi-asserted-by":"publisher","first-page":"19452","DOI":"10.1038\/s41598-021-98594-5","volume":"11","author":"AJ Lopez-Davila","year":"2021","unstructured":"Lopez-Davila AJ, Weber N, Kraft T, Matinmehr F, Arias-Hidalgo M, Fernandez J, Lomonte B, Gutierrez JM (2021) Cytotoxicity of snake venom Lys49 PLA2-like myotoxin on rat cardiomyocytes ex vivo does not involve a direct action on the contractile apparatus. Sci Rep 11:19452. https:\/\/doi.org\/10.1038\/s41598-021-98594-5","journal-title":"Sci Rep"},{"key":"2840_CR30","doi-asserted-by":"publisher","first-page":"4189","DOI":"10.1021\/acs.biochem.0c00499","volume":"59","author":"AJ Lopez Davila","year":"2020","unstructured":"Lopez Davila AJ, Zhu L, Fritz L, Kraft T, Chalovich JM (2020) The positively charged C-terminal region of human skeletal troponin T retards activation and decreases calcium sensitivity. Biochemistry 59:4189\u20134201. https:\/\/doi.org\/10.1021\/acs.biochem.0c00499","journal-title":"Biochemistry"},{"key":"2840_CR31","doi-asserted-by":"publisher","first-page":"10619","DOI":"10.1038\/s41598-018-28846-4","volume":"8","author":"ML Massimino","year":"2018","unstructured":"Massimino ML, Simonato M, Spolaore B, Franchin C, Arrigoni G, Marin O, Monturiol-Gross L, Fernandez J, Lomonte B, Tonello F (2018) Cell surface nucleolin interacts with and internalizes Bothrops asper Lys49 phospholipase A2 and mediates its toxic activity. Sci Rep 8:10619. https:\/\/doi.org\/10.1038\/s41598-018-28846-4","journal-title":"Sci Rep"},{"key":"2840_CR32","doi-asserted-by":"publisher","first-page":"2897","DOI":"10.1007\/s00018-008-8113-3","volume":"65","author":"C Montecucco","year":"2008","unstructured":"Montecucco C, Gutierrez JM, Lomonte B (2008) Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action. Cell Mol Life Sci 65:2897\u20132912. https:\/\/doi.org\/10.1007\/s00018-008-8113-3","journal-title":"Cell Mol Life Sci"},{"key":"2840_CR33","doi-asserted-by":"publisher","first-page":"e569","DOI":"10.7717\/peerj.569","volume":"2","author":"D Mora-Obando","year":"2014","unstructured":"Mora-Obando D, Diaz C, Angulo Y, Gutierrez JM, Lomonte B (2014) Role of enzymatic activity in muscle damage and cytotoxicity induced by Bothrops asper Asp49 phospholipase A2 myotoxins: are there additional effector mechanisms involved? PeerJ 2:e569. https:\/\/doi.org\/10.7717\/peerj.569","journal-title":"PeerJ"},{"key":"2840_CR34","doi-asserted-by":"publisher","first-page":"e109846","DOI":"10.1371\/journal.pone.0109846","volume":"9","author":"D Mora-Obando","year":"2014","unstructured":"Mora-Obando D, Fernandez J, Montecucco C, Gutierrez JM, Lomonte B (2014) Synergism between basic Asp49 and Lys49 phospholipase A2 myotoxins of viperid snake venom in vitro and in vivo. PLoS One 9:e109846. https:\/\/doi.org\/10.1371\/journal.pone.0109846","journal-title":"PLoS One"},{"key":"2840_CR35","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1016\/j.tibs.2018.06.006","volume":"43","author":"AA Rauscher","year":"2018","unstructured":"Rauscher AA, Gyimesi M, Kovacs M, Malnasi-Csizmadia A (2018) Targeting myosin by blebbistatin derivatives: optimization and pharmacological potential. Trends Biochem Sci 43:700\u2013713. https:\/\/doi.org\/10.1016\/j.tibs.2018.06.006","journal-title":"Trends Biochem Sci"},{"key":"2840_CR36","doi-asserted-by":"publisher","first-page":"11627","DOI":"10.1016\/S0021-9258(17)39077-4","volume":"260","author":"R Renetseder","year":"1985","unstructured":"Renetseder R, Brunie S, Dijkstra BW, Drenth J, Sigler PB (1985) A comparison of the crystal structures of phospholipase A2 from bovine pancreas and Crotalus atrox venom. J Biol Chem 260:11627\u201311634","journal-title":"J Biol Chem"},{"key":"2840_CR37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s1388-1981(00)00105-0","volume":"1488","author":"DA Six","year":"2000","unstructured":"Six DA, Dennis EA (2000) The expanding superfamily of phospholipase A(2) enzymes: classification and characterization. Biochim Biophys Acta 1488:1\u201319. https:\/\/doi.org\/10.1016\/s1388-1981(00)00105-0","journal-title":"Biochim Biophys Acta"},{"key":"2840_CR38","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.toxicon.2021.04.006","volume":"197","author":"S Vargas-Valerio","year":"2021","unstructured":"Vargas-Valerio S, Robleto J, Chaves-Araya S, Monturiol-Gross L, Lomonte B, Tonello F, Fernandez J (2021) Localization of Myotoxin I and Myotoxin II from the venom of Bothrops asper in a murine model. Toxicon 197:48\u201354. https:\/\/doi.org\/10.1016\/j.toxicon.2021.04.006","journal-title":"Toxicon"},{"key":"2840_CR39","doi-asserted-by":"publisher","first-page":"26141","DOI":"10.1038\/srep26141","volume":"6","author":"BH Varkuti","year":"2016","unstructured":"Varkuti BH, Kepiro M, Horvath IA, Vegner L, Rati S, Zsigmond A, Hegyi G, Lenkei Z, Varga M, Malnasi-Csizmadia A (2016) A highly soluble, non-phototoxic, non-fluorescent blebbistatin derivative. Sci Rep 6:26141. https:\/\/doi.org\/10.1038\/srep26141","journal-title":"Sci Rep"},{"key":"2840_CR40","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1016\/j.tiv.2007.04.010","volume":"21","author":"JC Villalobos","year":"2007","unstructured":"Villalobos JC, Mora R, Lomonte B, Gutierrez JM, Angulo Y (2007) Cytotoxicity induced in myotubes by a Lys49 phospholipase A2 homologue from the venom of the snake Bothrops asper: evidence of rapid plasma membrane damage and a dual role for extracellular calcium. Toxicol In Vitro 21:1382\u20131389. https:\/\/doi.org\/10.1016\/j.tiv.2007.04.010","journal-title":"Toxicol In Vitro"},{"key":"2840_CR41","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/S0140-6736(09)61754-2","volume":"375","author":"DA Warrell","year":"2010","unstructured":"Warrell DA (2010) Snake bite. Lancet 375:77\u201388. https:\/\/doi.org\/10.1016\/S0140-6736(09)61754-2","journal-title":"Lancet"},{"key":"2840_CR42","doi-asserted-by":"publisher","first-page":"3673","DOI":"10.1016\/j.bpj.2009.01.049","volume":"96","author":"S Xu","year":"2009","unstructured":"Xu S, White HD, Offer GW, Yu LC (2009) Stabilization of helical order in the thick filaments by blebbistatin: further evidence of coexisting multiple conformations of myosin. Biophys J 96:3673\u20133681. https:\/\/doi.org\/10.1016\/j.bpj.2009.01.049","journal-title":"Biophys J"},{"key":"2840_CR43","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1016\/S0006-3495(89)82838-3","volume":"55","author":"LC Yu","year":"1989","unstructured":"Yu LC, Brenner B (1989) Structures of actomyosin crossbridges in relaxed and rigor muscle fibers. Biophys J 55:441\u2013453. https:\/\/doi.org\/10.1016\/S0006-3495(89)82838-3","journal-title":"Biophys J"},{"key":"2840_CR44","doi-asserted-by":"publisher","first-page":"3322","DOI":"10.1529\/biophysj.108.137067","volume":"95","author":"FQ Zhao","year":"2008","unstructured":"Zhao FQ, Padron R, Craig R (2008) Blebbistatin stabilizes the helical order of myosin filaments by promoting the switch 2 closed state. Biophys J 95:3322\u20133329. https:\/\/doi.org\/10.1529\/biophysj.108.137067","journal-title":"Biophys J"}],"container-title":["Pfl\u00fcgers Archiv - European Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00424-023-02840-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00424-023-02840-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00424-023-02840-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T06:02:46Z","timestamp":1694584966000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00424-023-02840-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,20]]},"references-count":44,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["2840"],"URL":"https:\/\/doi.org\/10.1007\/s00424-023-02840-w","relation":{},"ISSN":["0031-6768","1432-2013"],"issn-type":[{"value":"0031-6768","type":"print"},{"value":"1432-2013","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,20]]},"assertion":[{"value":"29 April 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 June 2023","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 July 2023","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 July 2023","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}