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2. New insights into the cellular and molecular mechanisms of skeletal muscle fatigue: the Marion J. Siegman Award Lectureships.

Author

Debold, Edward P. and Westerblad, Håkan

Subjects
*MUSCLE fatigue, *SINGLE molecules, *ANAEROBIC metabolism, *SARCOPLASMIC reticulum, *SKELETAL muscle, *MYOSIN, *CALCIUM metabolism
Abstract

Skeletal muscle fibers need to have mechanisms to decrease energy consumption during intense physical exercise to avoid devastatingly low ATP levels, with the formation of rigor cross bridges and defective ion pumping. These protective mechanisms inevitably lead to declining contractile function in response to intense exercise, characterizing fatigue. Through our work, we have gained insights into cellular and molecular mechanisms underlying the decline in contractile function during acute fatigue. Key mechanistic insights have been gained from studies performed on intact and skinned single muscle fibers and more recently from studies performed and single myosin molecules. Studies on intact single fibers revealed several mechanisms of impaired sarcoplasmic reticulum Ca2+ release and experiments on single myosin molecules provide direct evidence of how putative agents of fatigue impact myosin's ability to generate force and motion. We conclude that changes in metabolites due to an increased dependency on anaerobic metabolism (e.g., accumulation of inorganic phosphate ions and H+) act to directly and indirectly (via decreased Ca2+ activation) inhibit myosin's force and motion-generating capacity. These insights into the acute mechanisms of fatigue may help improve endurance training strategies and reveal potential targets for therapies to attenuate fatigue in chronic diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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29. Hypertrophic and dilated cardiomyopathy mutations differentially affect the molecular force generation of mouse [alpha]-cardiac myosin in the laser trap assay

Author

Debold, Edward P., Schmitt, J.P., Patlak, J.B., Beck, S.E., Moore, J.R., Seidman, J.G., Seidman, C., and Warshaw, D.M.

Subjects
Myosin -- Research, Heart cells -- Research, Cardiomyopathy, Hypertrophic -- Research, Heart failure -- Research, Cellular control mechanisms -- Research, Cardiovascular research, Biological sciences
Abstract

Point mutations in cardiac myosin, the heart's molecular motor, produce distinct clinical phenotypes: hypertrophic (HCM) and dilated (DCM) cardiomyopathy. Do mutations alter myosin's molecular mechanics in a manner that is predictive of the clinical outcome? We have directly characterized the maximal force-generating capacity ([F.sub.max]) of two HCM (R403Q, R453C) and two DCM (S532P, F764L) mutant myosins isolated from homozygous mouse models using a novel load-clamped laser trap assay. [F.sub.max] was 50% (R403Q) and 80% (R453C) greater for the HCM mutants compared with the wild type, whereas [F.sub.max] was severely depressed for one of the DCM mutants (65% S532P). Although [F.sub.max] was normal for the F764L DCM mutant, its actin-activated ATPase activity and actin filament velocity ([V.sub.actin]) in a motility assay were significantly reduced (Schmitt JP, Debold EP, Ahmad F, Armstrong A, Frederico A, Conner DA, Mende U, Lohse MJ, Warshaw D, Seidman CE, Seidman JG. Proc Natl Acad Sci USA 103: 14525-14530, 2006.). These [F.sub.max] data combined with previous [V.sub.actin] measurements suggest that HCM and DCM result from alterations to one or more of myosin's fundamental mechanical properties, with HCM-causing mutations leading to enhanced but DCM-causing mutations leading to depressed function. These mutation-specific changes in mechanical properties must initiate distinct signaling cascades that ultimately lead to the disparate phenotypic responses observed in HCM and DCM. familial hypertrophic cardiomyopathy; in vitro motility; force-velocity relationship; heart failure doi:10.1152/ajpheart.00128.2007

Published
2007

39. Colaboradores

Author

Abramson, Steven B., Aggarwal, Rohit, Ahn, Christine S., An, KaiNan, Andrade, Felipe, Ardoin, Stacy P., Awisat, Abid, Azevedo, Pedro Ming, Barbar-Smiley, Fatima, Barbhaiya, Medha, Barton, Anne, Baughman, Robert P., Beaton, Dorcas E., Beere, Helen M., Behrens, Edward M., Bermas, Bonnie L., Bertsias, George, Bewtra, Meenakshi, Bhardwaj, Nina, Bingham, Clifton O., III, Bockenstedt, Linda K., Boers, Maarten, Boilard, Eric, Boin, Francesco, Boumpas, Dimitrios T., Bozec, Aline, Broderick, Lori, Brown, Matthew, Buckley, Christopher D., Budd, Ralph C., Burg, Nathalie, Cannella, Amy C., Cappelli, Laura C., Carter, John D., Chan, Andrew C., Chang, Christopher, Cheng, Joseph S., Chiodo, Christopher P., Chung, Sharon A., Cleland, Leslie G., Cohen, Stanley, Colbert, Robert A., Cook, Paul P., Craft, Joseph E., Crofford, Leslie J., Cronstein, Bruce N., Crow, Mary K., Crowson, Cynthia S., Cuccurullo, Sara J., Cunnane, Gaye, Curtis, Jeffrey R., Dalbeth, Nicola, Dall’Era, Maria, Darrah, Erika, Dau, Jonathan, Davis, John M., III, De Bari, Cosimo, Debold, Edward P., Dell’Accio, Francesco, DeMarco, Paul J., Diamond, Betty, Di Cesare, Paul E., di Matteo, Andrea, Dixit, Rajiv, Donohue, Kenneth W., Dvergsten, Jeffrey, El-Gabalawy, Hani S., England, Bryant R., Erkan, Doruk, Eyre, Stephen, Fanouriakis, Antonis, Fearon, Ursula, Filer, Andrew, Fiorentino, David F., Firestein, Gary S., Fischer, Saloumeh K., Fishman, Felicity G., FitzGerald, Oliver, Flaherty, John P., Nieves, Cesar E. Fors, Gabriel, Sherine E., Gallentine, William, Gasque, Philippe, Gensler, Lianne S., Gershwin, M. Eric, Goldring, Mary B., Goldring, Steven R., Golightly, Yvonne M., Goodman, Stuart, Graf, Jonathan, Graham, Gerard, Green, Douglas R., Greenspan, Adam, Grimaldi, Christine, Grüneboom, Anika, Guilherme, Luiza, Guillot, Xavier, Haberman, Rebecca, Hajj-Ali, Rula A., Haudenschild, Dominik R., Hellmann, David B., Hoffman, Hal M., Holers, V. Michael, Holmdahl, Rikard, Hsu, Joyce J., Huddleston, James I., III, Hudson, Alan P., Hunder, Gene G., Itoh, Yoshifumi, Jacobs, Johannes W.G., Jaremko, Jacob L., Jeffries, Matlock A., Jen, Ho, Joki, Jaclyn, Jordan, Martha S., Jorizzo, Joseph L., Kalil, Jorge, Kaufman, Kenton R., Kavanaugh, Arthur, Keenan, Robert T., Kenna, Tony, Kerr, Darcy A., Kissin, Eugene Y., Knight, Rob, Kono, Dwight H., Koretzky, Gary A., Korsten, Peter, Kosty, Jennifer, Krakow, Deborah, Kumar, Deepak, Lachmann, Helen J., Lafeber, Floris P.J.G., Lambert, Robert G.W., Lane, Nancy E., Langford, Carol A., Laskin, Daniel M., Lauvau, Gregoire, Lee, Tzielan C., Leverenz, David L., Loeser, Richard F., Lozada, Carlos J., Luke, Ofure, Lundberg, Ingrid E., Luqmani, Raashid, Luyten, Frank P., Mader, Reuven, Magee, Conor, Maksymowych, Walter P., Manger, Bernhard, Markenson, Joseph A., Martin, Scott David, Matteson, Eric L., Maxwell, Lara, McCarthy, Katharine, McInnes, Iain B., Merkel, Peter A., Mikuls, Ted R., Miller, Mark S., Misra, Devyani, Mobasheri, Ali, Moder, Kevin G., Monach, Paul A., Montgomery, Anna, Moulton, Vaishali R., Mulders-Manders, Catharina M., Muniz, Luciana Ribeiro, Murphy, Louise B., Nagaraju, Kanneboyina, Nasser, Rani, Nelson, Amanda E., Neogi, Tuhina, Nigrovic, Peter A., O’Dell, James R., Ogdie, Alexis, Østergaard, Mikkel, Paley, Michael A., Panush, Richard S., Peng, Stanford L., Perlman, Harris, Pillai, Shiv, Pillinger, Michael H., Polston, Gregory R., Porcelli, Steven A., Price, Mark D., Pulles, Astrid E., Raza, Karim, Reddy, Virginia, Reed, Ann M., Reveille, John D., Rhee, Rennie L., Ritchlin, Christopher T., Robinson, Angela B., Rosen, Antony, Rosenbaum, James T., Rosenberg, Andrew E., Ruderman, Eric M., Saag, Kenneth G., Salmon, Jane E., Sammaritano, Lisa R., Samuels, Jonathan, Sandborg, Christy I., Sangeorzan, Adam P., Santora, Arthur C., II, Sattui, Sebastian E., Sawalha, Amr H., Saxena, Amit, Saxena, Mansi, Scanzello, Carla R., Schett, Georg, Semb, Anne Grete, Shah, Ami A., Shah, Binita, Sharpley, Faye A., Sikora, Keith A., Simon, Anna, Siraj, Dawd S., Sorkin, Linda S., Clair, E. William St., Stamp, Lisa K., Stone, John H., Strowd, Lindsay C., Suarez-Fueyo, Abel, Svensson, Camilla I., Sweiss, Nadera J., Swigart, Carrie R., Szekanecz, Zoltán, Tait, Stephen, Tanner, Stacy, Taylor, Peter C., Taylor, William J., Terkeltaub, Robert, Theofilopoulos, Argyrios N., Thornhill, Thomas S., Toprover, Michael, Torok, Kathryn S., Toth, Michael J., Townsend, Michael J., Tozman, Elaine C., Trouw, Leendert A., Tsokos, George C., Tugwell, Peter, Vabret, Nicolas, van der Goes, Marlies C., van der Linden, Sjef, van der Meer, Jos W.M., van Laar, Jacob M., Van Mater, Heather, van Vollenhoven, Ronald F., van Vulpen, Lize F.D., Varga, John, Vasquez, Raul A., Veale, Douglas J., Wakefield, Richard J., Wallace, Mark S., Wang, Ruoning, Wang, Tingting, Werth, Victoria P., Wigley, Fredrick M., Winter, Deborah R., Wofsy, David, Wong, Cyrus C., Yokoyama, Wayne M., Zamore, Richard, Zayat, Ahmed S., Zou, Yong-Rui, and Zurier, Robert B.

Published
2022
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42. Contributors

Author

Abramson, Steven B., Aggarwal, Rohit, Ahn, Christine S., An, KaiNan, Andrade, Felipe, Ardoin, Stacy P., Awisat, Abid, Azevedo, Pedro Ming, Barbar-Smiley, Fatima, Barbhaiya, Medha, Barton, Anne, Baughman, Robert P., Beaton, BScOT, Dorcas E., Beere, Helen M., Behrens, Edward M., Bermas, Bonnie L., Bertsias, George, Bewtra, Meenakshi, Bhardwaj, Nina, Bingham, Clifton O., III, Bockenstedt, Linda K., Boers, Maarten, Boilard, Eric, Boin, Francesco, Boumpas, Dimitrios T., Bozec, Aline, Broderick, Lori, Brown, Matthew, Buckley, Christopher D., Budd, Ralph C., Burg, Nathalie, Cannella, Amy C., Cappelli, Laura C., Carter, John D., Chan, Andrew C., Chang, Christopher, Cheng, Joseph S., Chiodo, Christopher P., Chung, Sharon A., Cleland, Leslie G., Cohen, Stanley, Colbert, Robert A., Cook, Paul P., Craft, Joseph E., Crofford, Leslie J., Cronstein, Bruce N., Crow, Mary K., Crowson, Cynthia S., Cuccurullo, Sara J., Cunnane, Gaye, Curtis, Jeffrey R., Dalbeth, Nicola, Dall’Era, Maria, Darrah, Erika, Dau, Jonathan, Davis, John M., III, De Bari, Cosimo, Debold, Edward P., Dell’Accio, Francesco, DeMarco, Paul J., Diamond, Betty, Di Cesare, Paul E., di Matteo, Andrea, Dixit, Rajiv, Donohue, Kenneth W., Dvergsten, Jeffrey, El-Gabalawy, Hani S., England, Bryant R., Erkan, Doruk, Eyre, Stephen, Fanouriakis, Antonis, Fearon, Ursula, Filer, Andrew, Fiorentino, David F., Firestein, Gary S., Fischer, Saloumeh K., Fishman, Felicity G., FitzGerald, Oliver, Flaherty, John P., Fors Nieves, Cesar E., Gabriel, Sherine E., Gallentine, William, Gasque, Philippe, Gensler, Lianne S., Gershwin, M. Eric, Goldring, Mary B., Goldring, Steven R., Golightly, Yvonne M., Goodman, Stuart, Graf, Jonathan, Graham, Gerard, Green, Douglas R., Greenspan, Adam, Grimaldi, Christine, Grüneboom, Anika, Guilherme, Luiza, Guillot, Xavier, Haberman, Rebecca, Hajj-Ali, Rula A., Haudenschild, Dominik R., Hellmann, David B., Hoffman, Hal M., Holers, V. Michael, Holmdahl, Rikard, Hsu, Joyce J., Huddleston, James I., III, Hudson, Alan P., Hunder, Gene G., Itoh, Yoshifumi, Jacobs, Johannes W.G., Jaremko, Jacob L., Jeffries, Matlock A., Jen, Ho, Joki, Jaclyn, Jordan, Martha S., Jorizzo, Joseph L., Kalil, Jorge, Kaufman, Kenton R., Kavanaugh, Arthur, Keenan, Robert T., Kenna, Tony, Kerr, Darcy A., Kissin, Eugene Y., Knight, Rob, Kono, Dwight H., Koretzky, Gary A., Korsten, Peter, Kosty, Jennifer, Krakow, Deborah, Kumar, Deepak, Lachmann, Helen J., Lafeber, Floris P.J.G., Lambert, Robert G.W., Lane, Nancy E., Langford, Carol A., Laskin, Daniel M., Lauvau, Gregoire, Lee, Tzielan C., Leverenz, David L., Loeser, Richard F., Lozada, Carlos J., Luke, Ofure, Lundberg, Ingrid E., Luqmani, Raashid, Luyten, Frank P., Mader, Reuven, Magee, Conor, Maksymowych, Walter P., Manger, Bernhard, Markenson, Joseph A., Martin, Scott David, Matteson, Eric L., Maxwell, Lara, McCarthy, Katharine, McInnes, Iain B., Merkel, Peter A., Mikuls, Ted R., Miller, Mark S., Misra, Devyani, Mobasheri, Ali, Moder, Kevin G., Monach, Paul A., Montgomery, Anna, Moulton, Vaishali R., Mulders-Manders, Catharina M., Muniz, Luciana Ribeiro, Murphy, Louise B., Nagaraju, Kanneboyina, Nasser, Rani, Nelson, Amanda E., Neogi, Tuhina, Nigrovic, Peter A., O’Dell, James R., Ogdie, Alexis, Østergaard, Mikkel, Paley, Michael A., Panush, Richard S., Peng, Stanford L., Perlman, Harris, Pillai, Shiv, Pillinger, Michael H., Polston, Gregory R., Porcelli, Steven A., Price, Mark D., Pulles, Astrid E., Raza, Karim, Reddy, Virginia, Reed, Ann M., Reveille, John D., Rhee, Rennie L., Ritchlin, Christopher T., Robinson, Angela B., Rosen, Antony, Rosenbaum, James T., Rosenberg, Andrew E., Ruderman, Eric M., Saag, Kenneth G., Salmon, Jane E., Sammaritano, Lisa R., Samuels, Jonathan, Sandborg, Christy I., Sangeorzan, Adam P., Santora, Arthur C., II, Sattui, Sebastian E., Sawalha, Amr H., Saxena, Amit, Saxena, Mansi, Scanzello, Carla R., Schett, Georg, Semb, Anne Grete, Shah, Ami A., Shah, Binita, Sharpley, Faye A., Sikora, Keith A., Simon, Anna, Siraj, Dawd S., Sorkin, Linda S., St. Clair, E. William, Stamp, Lisa K., Stone, John H., Strowd, Lindsay C., Suarez-Fueyo, Abel, Svensson, Camilla I., Sweiss, Nadera J., Swigart, Carrie R., Szekanecz, Zoltán, Tait, Stephen, Tanner, Stacy, Taylor, Peter C., Taylor, William J., Terkeltaub, Robert, Theofilopoulos, Argyrios N., Thornhill, Thomas S., Toprover, Michael, Torok, Kathryn S., Toth, Michael J., Townsend, Michael J., Tozman, Elaine C., Trouw, Leendert A., Tsokos, George C., Tugwell, Peter, Vabret, Nicolas, van der Goes, Marlies C., van der Linden, Sjef, van der Meer, Jos W.M., van Laar, Jacob M., Van Mater, Heather, van Vollenhoven, Ronald F., van Vulpen, Lize F.D., Varga, John, Vasquez, Raul A., Veale, Douglas J., Wakefield, Richard J., Wallace, Mark S., Wang, Ruoning, Wang, Tingting, Werth, Victoria P., Wigley, Fredrick M., Winter, Deborah R., Wofsy, David, Wong, Cyrus C., Yokoyama, Wayne M., Zamore, Richard, Zayat, Ahmed S., Zou, Yong-Rui, and Zurier, Robert B.

Published
2021
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48. Acidosis decreases the Ca2+ sensitivity of thin filaments by preventing the first actomyosin interaction.

Author

Unger, Matthew and Debold, Edward P.

Subjects
*MYOSIN, *ACIDOSIS, *SINGLE molecules, *MUSCLE fatigue, *FIBERS, *FATIGUE (Physiology), *SKELETAL muscle
Abstract

Intracellular acidosis is a putative agent of skeletal muscle fatigue, in part, because it depresses the calcium (Ca2+) sensitivity of the myofilaments. However, the molecular mechanism behind this depression in Ca2+ sensitivity is unknown, providing a significant challenge to a complete understanding of the fatigue process. To elucidate this mechanism, we directly determined the effect of acidosis on the ability of a single myosin molecule to bind to a regulated actin filament in a laser trap assay. Decreasing pH from 7.4 to 6.5 significantly (P < 0.05) reduced the frequency of single actomyosin-binding events at submaximal (pCa 8-pCa 6) but not at maximal Ca2+ concentration (pCa 5-pCa 4). To delineate whether this was due to a direct effect on myosin versus an indirect effect on the regulatory proteins troponin (Tn) and tropomyosin (Tm), binding frequency was also quantified in the absence of Tn and Tm. This revealed that acidosis did not significantly alter the frequency of actomyosin binding events in the absence of regulatory proteins (1.4 ± 0.15 vs. 1.4 ± 0.15 events/s for pH 7.4 and 6.5, respectively). Acidosis also did not significantly affect the size of myosin's powerstroke or the duration of binding events in the presence of regulatory proteins, at every [Ca2+]. These data suggest acidosis impedes activation of the thin filament by competitively inhibiting Ca2+ binding to TnC. This slows the rate at which myosin initially attaches to actin; therefore, less cross bridges will be bound and generating force at any given submaximal [Ca2+]. These data provide a molecular explanation for the acidosis-induced decrease in force observed at the submaximal Ca2+ concentrations that might contribute to the loss of force during muscle fatigue. [ABSTRACT FROM AUTHOR]

Published
2019
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49. Modeling thick filament activation suggests a molecular basis for force depression

Author

Liu, Shuyue, Marang, Chris, Woodward, Mike, Joumaa, Venus, Leonard, Tim, Scott, Brent, Debold, Edward, Herzog, Walter, and Walcott, Sam

Abstract

Multiscale models aiming to connect muscle’s molecular and cellular function have been difficult to develop, in part due to a lack of self-consistent multiscale data. To address this gap, we measured the force response from single-skinned rabbit psoas muscle fibers to ramp shortenings and step stretches performed on the plateau region of the force-length relationship. We isolated myosin from the same muscles and, under similar conditions, performed single-molecule and ensemble measurements of myosin’s ATP-dependent interaction with actin using laser trapping and in vitro motility assays. We fit the fiber data by developing a partial differential equation model that includes thick filament activation, whereby an increase in force on the thick filament pulls myosin out of an inhibited state. The model also includes a series elastic element and a parallel elastic element. This parallel elastic element models a titin-actin interaction proposed to account for the increase in isometric force after stretch (residual force enhancement). By optimizing the model fit to a subset of our fiber measurements, we specified seven unknown parameters. The model then successfully predicted the remainder of our fiber measurements and also our molecular measurements from the laser trap and in vitro motility. The success of the model suggests that our multiscale data are self-consistent and can serve as a testbed for other multiscale models. Moreover, the model captures the decrease in isometric force observed in our muscle fibers after active shortening (force depression), suggesting a molecular mechanism for force depression, whereby a parallel elastic element combines with thick filament activation to decrease the number of cycling cross-bridges.

Published
2024
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