Fast Skeletal Muscle Troponin Activation Increases Force of Mouse Fast Skeletal Muscle and Ameliorates Weakness Due to Nebulin-Deficiency
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{"title"=>"Fast Skeletal Muscle Troponin Activation Increases Force of Mouse Fast Skeletal Muscle and Ameliorates Weakness Due to Nebulin-Deficiency", "type"=>"journal", "authors"=>[{"first_name"=>"Eun Jeong", "last_name"=>"Lee", "scopus_author_id"=>"55317335100"}, {"first_name"=>"Josine M.", "last_name"=>"de Winter", "scopus_author_id"=>"55573726900"}, {"first_name"=>"Danielle", "last_name"=>"Buck", "scopus_author_id"=>"35572468100"}, {"first_name"=>"Jeffrey R.", "last_name"=>"Jasper", "scopus_author_id"=>"55604742200"}, {"first_name"=>"Fady I.", "last_name"=>"Malik", "scopus_author_id"=>"36448461700"}, {"first_name"=>"Siegfried", "last_name"=>"Labeit", "scopus_author_id"=>"7006443631"}, {"first_name"=>"Coen A.", "last_name"=>"Ottenheijm", "scopus_author_id"=>"8504199000"}, {"first_name"=>"Henk", "last_name"=>"Granzier", "scopus_author_id"=>"7004852034"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84874261774", "pui"=>"368400191", "doi"=>"10.1371/journal.pone.0055861", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "sgr"=>"84874261774", "pmid"=>"23437068"}, "id"=>"08a98046-ecf6-39a5-94d0-677303d5f21b", "abstract"=>"The effect of the fast skeletal muscle troponin activator, CK-2066260, on calcium-induced force development was studied in skinned fast skeletal muscle fibers from wildtype (WT) and nebulin deficient (NEB KO) mice. Nebulin is a sarcomeric protein that when absent (NEB KO mouse) or present at low levels (nemaline myopathy (NM) patients with NEB mutations) causes muscle weakness. We studied the effect of fast skeletal troponin activation on WT muscle and tested whether it might be a therapeutic mechanism to increase muscle strength in nebulin deficient muscle. We measured tension-pCa relations with and without added CK-2066260. Maximal active tension in NEB KO tibialis cranialis fibers in the absence of CK-2066260 was ∼60% less than in WT fibers, consistent with earlier work. CK-2066260 shifted the tension-calcium relationship leftwards, with the largest relative increase (up to 8-fold) at low to intermediate calcium levels. This was a general effect that was present in both WT and NEB KO fiber bundles. At pCa levels above ∼6.0 (i.e., calcium concentrations <1 µM), CK-2066260 increased tension of NEB KO fibers to beyond that of WT fibers. Crossbridge cycling kinetics were studied by measuring k(tr) (rate constant of force redevelopment following a rapid shortening/restretch). CK-2066260 greatly increased k(tr) at submaximal activation levels in both WT and NEB KO fiber bundles. We also studied the sarcomere length (SL) dependence of the CK-2066260 effect (SL 2.1 µm and 2.6 µm) and found that in the NEB KO fibers, CK-2066260 had a larger effect on calcium sensitivity at the long SL. We conclude that fast skeletal muscle troponin activation increases force at submaximal activation in both wildtype and NEB KO fiber bundles and, importantly, that this troponin activation is a potential therapeutic mechanism for increasing force in NM and other skeletal muscle diseases with loss of muscle strength.", "link"=>"http://www.mendeley.com/research/fast-skeletal-muscle-troponin-activation-increases-force-mouse-fast-skeletal-muscle-ameliorates-weak", "reader_count"=>20, "reader_count_by_academic_status"=>{"Researcher"=>7, "Student > Ph. D. Student"=>5, "Student > Master"=>1, "Other"=>1, "Student > Bachelor"=>2, "Lecturer > Senior Lecturer"=>1, "Student > Doctoral Student"=>3}, "reader_count_by_user_role"=>{"Researcher"=>7, "Student > Ph. D. Student"=>5, "Student > Master"=>1, "Other"=>1, "Student > Bachelor"=>2, "Lecturer > Senior Lecturer"=>1, "Student > Doctoral Student"=>3}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>6, "Medicine and Dentistry"=>9, "Chemistry"=>1, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Chemistry"=>{"Chemistry"=>1}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1004918"], "description"=>"<p>Results are mean ± SEM from 5 WT and 5 KO mice, except for the last 4 rows that are from 6 WT and 6 KO mice.</p>*<p>comparison WT vs. KO;</p>#<p>comparison versus 0 µM CK-2066260;</p>√<p>comparison versus 5 µM CK-2066260; single symbol p<0.05, double symbol p<0.01. All measurements were at a sarcomere length (SL) of 2.1 µm, except the bottom 4 rows that were at 2.6 µm.</p>", "links"=>[], "tags"=>["pca", "calcium", "coefficient", "wt", "ko", "10"], "article_id"=>665536, "categories"=>["Physiology", "Cell Biology"], "users"=>["Eun-Jeong Lee", "Josine M. De Winter", "Danielle Buck", "Jeffrey R. Jasper", "Fady I. Malik", "Siegfried Labeit", "Coen A. Ottenheijm", "Henk Granzier"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055861.t001", "stats"=>{"downloads"=>5, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_T_max_tension_at_pCa_4_5_calcium_sensitivity_pCa_50_and_Hill_coefficient_n_H_of_WT_and_KO_in_0_5_and_10_181_M_CK_2066260_/665536", "title"=>"T<sub>max</sub> (tension at pCa 4.5); calcium sensitivity (pCa<sub>50</sub>) and Hill coefficient (n<sub>H</sub>) of WT and KO in 0, 5, and 10 µM CK-2066260.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-20 01:32:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/957781"], "description"=>"<p>A) Skinned skeletal muscle fibers (<i>TC</i> muscle) were stretched, held for 7 min, and were then released. During the hold phase, the muscle was exposed to various pCa activating solutions, and was then relaxed again. B) Effect of CK-2066260 on active tension at submaximal activation level (pCa = 6.25). Active tensions at a range of CK-2066260 concentrations (black symbols). The maximal active tension (pCa 4.5) at 0 µM CK-2066260 is shown to the right in red.</p>", "links"=>[], "tags"=>["ck-2066260", "submaximal"], "article_id"=>627856, "categories"=>["Physiology", "Cell Biology"], "users"=>["Eun-Jeong Lee", "Josine M. De Winter", "Danielle Buck", "Jeffrey R. Jasper", "Fady I. Malik", "Siegfried Labeit", "Coen A. Ottenheijm", "Henk Granzier"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055861.g002", "stats"=>{"downloads"=>2, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Experimental_Protocol_and_effect_of_CK_2066260_on_active_tension_at_submaximal_activation_/627856", "title"=>"Experimental Protocol and effect of CK-2066260 on active tension at submaximal activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 16:59:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/957800"], "description"=>"<div><p>The effect of the fast skeletal muscle troponin activator, CK-2066260, on calcium-induced force development was studied in skinned fast skeletal muscle fibers from wildtype (WT) and nebulin deficient (NEB KO) mice. Nebulin is a sarcomeric protein that when absent (NEB KO mouse) or present at low levels (nemaline myopathy (NM) patients with NEB mutations) causes muscle weakness. We studied the effect of fast skeletal troponin activation on WT muscle and tested whether it might be a therapeutic mechanism to increase muscle strength in nebulin deficient muscle. We measured tension–pCa relations with and without added CK-2066260. Maximal active tension in NEB KO tibialis cranialis fibers in the absence of CK-2066260 was ∼60% less than in WT fibers, consistent with earlier work. CK-2066260 shifted the tension-calcium relationship leftwards, with the largest relative increase (up to 8-fold) at low to intermediate calcium levels. This was a general effect that was present in both WT and NEB KO fiber bundles. At pCa levels above ∼6.0 (i.e., calcium concentrations <1 µM), CK-2066260 increased tension of NEB KO fibers to beyond that of WT fibers. Crossbridge cycling kinetics were studied by measuring <i>k<sub>tr</sub></i> (rate constant of force redevelopment following a rapid shortening/restretch). CK-2066260 greatly increased <i>k<sub>tr</sub></i> at submaximal activation levels in both WT and NEB KO fiber bundles. We also studied the sarcomere length (SL) dependence of the CK-2066260 effect (SL 2.1 µm and 2.6 µm) and found that in the NEB KO fibers, CK-2066260 had a larger effect on calcium sensitivity at the long SL. We conclude that fast skeletal muscle troponin activation increases force at submaximal activation in both wildtype and NEB KO fiber bundles and, importantly, that this troponin activation is a potential therapeutic mechanism for increasing force in NM and other skeletal muscle diseases with loss of muscle strength.</p> </div>", "links"=>[], "tags"=>["skeletal", "troponin", "activation", "ameliorates", "nebulin-deficiency"], "article_id"=>627874, "categories"=>["Physiology", "Cell Biology"], "users"=>["Eun-Jeong Lee", "Josine M. De Winter", "Danielle Buck", "Jeffrey R. Jasper", "Fady I. Malik", "Siegfried Labeit", "Coen A. Ottenheijm", "Henk Granzier"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055861", "stats"=>{"downloads"=>1, "page_views"=>53, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Fast_Skeletal_Muscle_Troponin_Activation_Increases_Force_of_Mouse_Fast_Skeletal_Muscle_and_Ameliorates_Weakness_Due_to_Nebulin_Deficiency__/627874", "title"=>"Fast Skeletal Muscle Troponin Activation Increases Force of Mouse Fast Skeletal Muscle and Ameliorates Weakness Due to Nebulin-Deficiency", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 17:07:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/957786"], "description"=>"<p>A) Average active tension-pCa curves in WT (open symbols, dashed) and KO (closed symbols, solid) mice with 0 (blue), 5 µM (green) and 10 µM (red) CK-2066260 at SL = 2.1 µm. Curves in CK were shifted to the left in both WT and KO, i.e. calcium sensitivity is increased. Note that at pCa>6.0, CK-2066260 increased active tension of NEB-KO muscle beyond that of WT. B) Relative active tension increase (plotted on a log scale) in 5 and 10 µM of CK over 0 µM of CK at various pCa levels. Regardless of genotype, active tensions were significantly increased from ∼800% at the pCa 6.4 to ∼10% at pCa 4.5. Results from five WT and five KO mice.</p>", "links"=>[], "tags"=>["relations", "wt", "neb", "ko", "skinned", "tc"], "article_id"=>627860, "categories"=>["Physiology", "Cell Biology"], "users"=>["Eun-Jeong Lee", "Josine M. De Winter", "Danielle Buck", "Jeffrey R. Jasper", "Fady I. Malik", "Siegfried Labeit", "Coen A. Ottenheijm", "Henk Granzier"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055861.g003", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tension_8211_pCa_relations_in_WT_and_NEB_KO_skinned_TC_muscle_fibers_/627860", "title"=>"Tension–pCa relations in WT and NEB KO skinned TC muscle fibers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 17:00:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/957788"], "description"=>"<p>A) Examples of <i>k<sub>tr</sub></i> experiments on WT and NEB KO fiber bundles activated at pCa 5.95 before (control) and after the addition of 10 µM CK-2066260. Shown is the tension recovery phase following the re-stretch (see Methods for details). In the presence of 10 µM CK-2066260 (darker traces) tension recovery is faster than in absence of CK-2066260. B) and C) k<i><sub>tr</sub></i> results of WT (B) and NEB KO fibers (C). Addition of 10 µM CK-2066260 increases <i>k<sub>tr</sub></i> in both WT and NEB-KO fibers. A two-way ANOVA reveals in WT bundles significant effects of pCa and CK-2066260 on <i>k<sub>tr</sub></i> with a significant interaction between pCa and CK (p<0.001). The same is the case for the KO data, except that the p-value of the interaction term is p = 0.02. D) Change in <i>k<sub>tr</sub></i> in CK 2066260 (as percentage of control values). Results from six WT and six KO mice.</p>", "links"=>[], "tags"=>["ck", "2066260", "redevelopment"], "article_id"=>627862, "categories"=>["Physiology", "Cell Biology"], "users"=>["Eun-Jeong Lee", "Josine M. De Winter", "Danielle Buck", "Jeffrey R. Jasper", "Fady I. Malik", "Siegfried Labeit", "Coen A. Ottenheijm", "Henk Granzier"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055861.g004", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_CK_2066260_on_the_rate_constant_of_force_redevelopment_k_tr_/627862", "title"=>"Effect of CK 2066260 on the rate constant of force redevelopment (<i>k<sub>tr</sub></i>).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 17:01:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/957789"], "description"=>"<p>Result in WT in A and in NEB KO fibers in B. Increasing SL slightly shifts the curves left-ward (i.e., calcium sensitivity is increased) and CK results in an additional large shift. Results from six WT and six KO mice.</p>", "links"=>[], "tags"=>["10", "ck-2066260", "tension-pca", "curves", "sl"], "article_id"=>627863, "categories"=>["Physiology", "Cell Biology"], "users"=>["Eun-Jeong Lee", "Josine M. De Winter", "Danielle Buck", "Jeffrey R. Jasper", "Fady I. Malik", "Siegfried Labeit", "Coen A. Ottenheijm", "Henk Granzier"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055861.g005", "stats"=>{"downloads"=>3, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_10_181_M_CK_2066260_on_tension_pCa_curves_at_short_2_1_181_m_and_long_SL_2_6_181_m_/627863", "title"=>"Effect of 10 µM CK-2066260 on tension-pCa curves at short (2.1 µm) and long SL (2.6 µm).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 17:01:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/957790"], "description"=>"<p>A) Effect of increasing SL from 2.1 to 2.6 µm on calcium sensitivity (SL-induced ΔpCa<sub>50</sub>) without and with 10 µM CK 2066260. In KO fibers CK-2066260 increased the SL-induced ΔpCa<sub>50</sub> (#, p<0.05). B) CK-2066260 (10 µM) induced ΔpCa<sub>50</sub> at SL 2.1 µm and 2.6 µm. Only in KO fibers CK 2066260-induced ΔpCa<sub>50</sub> was significantly greater at SL 2.6 µm compared to 2.1 µm (†, p<0.05). Furthermore, at SL 2.6 µm CK 2066260-induced ΔpCa<sub>50</sub> in KO fibers was significantly greater than in WT (*, p<0.05). Results from six WT and six KO mice.</p>", "links"=>[], "tags"=>["10", "ck-2066260", "ck", "2066260-induced", "sl"], "article_id"=>627864, "categories"=>["Physiology", "Cell Biology"], "users"=>["Eun-Jeong Lee", "Josine M. De Winter", "Danielle Buck", "Jeffrey R. Jasper", "Fady I. Malik", "Siegfried Labeit", "Coen A. Ottenheijm", "Henk Granzier"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055861.g006", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SL_induced_pCa_50_at_0_and_10_181_M_CK_2066260_and_CK_2066260_induced_916_pCa_50_at_SL_2_1_181_m_and_SL_2_6_181_m_/627864", "title"=>"SL-induced ΔpCa<sub>50</sub> at 0 and 10 µM CK-2066260 and CK 2066260-induced ΔpCa<sub>50</sub> at SL 2.1 µm and SL 2.6 µm.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 17:02:03"}

PMC Usage Stats | Further Information

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Relative Metric

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