scholarly journals Force Generation via β-Cardiac Myosin, Titin, and α-Actinin Drives Cardiac Sarcomere Assembly from Cell-Matrix Adhesions

2018 ◽  
Vol 44 (1) ◽  
pp. 87-96.e5 ◽  
Author(s):  
Anant Chopra ◽  
Matthew L. Kutys ◽  
Kehan Zhang ◽  
William J. Polacheck ◽  
Calvin C. Sheng ◽  
...  
Keyword(s):  
Force Generation ◽  
Cardiac Myosin ◽  
Cardiac Sarcomere ◽  
Cell Matrix ◽  
Sarcomere Assembly

scholarly journals Altered C10 domain in cardiac myosin binding protein-C results in hypertrophic cardiomyopathy

2019 ◽  
Vol 115 (14) ◽  
pp. 1986-1997 ◽  
Author(s):  
Diederik W D Kuster ◽  
Thomas L Lynch ◽  
David Y Barefield ◽  
Mayandi Sivaguru ◽  
Gina Kuffel ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Protein C ◽  
Binding Protein ◽  
Force Generation ◽  
Contractile Dysfunction ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Abstract Aims A 25-base pair deletion in the cardiac myosin binding protein-C (cMyBP-C) gene (MYBPC3), proposed to skip exon 33, modifies the C10 domain (cMyBP-CΔC10mut) and is associated with hypertrophic cardiomyopathy (HCM) and heart failure, affecting approximately 100 million South Asians. However, the molecular mechanisms underlying the pathogenicity of cMyBP-CΔC10mutin vivo are unknown. We hypothesized that expression of cMyBP-CΔC10mut exerts a poison polypeptide effect leading to improper assembly of cardiac sarcomeres and the development of HCM. Methods and results To determine whether expression of cMyBP-CΔC10mut is sufficient to cause HCM and contractile dysfunction in vivo, we generated transgenic (TG) mice having cardiac-specific protein expression of cMyBP-CΔC10mut at approximately half the level of endogenous cMyBP-C. At 12 weeks of age, significant hypertrophy was observed in TG mice expressing cMyBP-CΔC10mut (heart weight/body weight ratio: 4.43 ± 0.11 mg/g non-transgenic (NTG) vs. 5.34 ± 0.25 mg/g cMyBP-CΔC10mut, P < 0.05). Furthermore, haematoxylin and eosin, Masson’s trichrome staining, as well as second-harmonic generation imaging revealed the presence of significant fibrosis and a greater relative nuclear area in cMyBP-CΔC10mut hearts compared with NTG controls. M-mode echocardiography analysis revealed hypercontractile hearts (EF: 53.4%±2.9% NTG vs. 66.4% ± 4.7% cMyBP-CΔC10mut; P < 0.05) and early diastolic dysfunction (E/E′: 28.7 ± 3.7 NTG vs. 46.3 ± 8.4 cMyBP-CΔC10mut; P < 0.05), indicating the presence of an HCM phenotype. To assess whether these changes manifested at the myofilament level, contractile function of single skinned cardiomyocytes was measured. Preserved maximum force generation and increased Ca2+-sensitivity of force generation were observed in cardiomyocytes from cMyBP-CΔC10mut mice compared with NTG controls (EC50: 3.6 ± 0.02 µM NTG vs. 2.90 ± 0.01 µM cMyBP-CΔC10mut; P < 0.0001). Conclusion Expression of cMyBP-C protein with a modified C10 domain is sufficient to cause contractile dysfunction and HCM in vivo.

scholarly journals Vinculin-dependent actin bundling regulates cell migration and traction forces

2015 ◽  
Vol 465 (3) ◽  
pp. 383-393 ◽  
Author(s):  
Karry M. Jannie ◽  
Shawn M. Ellerbroek ◽  
Dennis W. Zhou ◽  
Sophia Chen ◽  
David J. Crompton ◽  
...  
Keyword(s):  
Cell Migration ◽  
Traction Force ◽  
Force Generation ◽  
Actin Binding ◽  
Traction Forces ◽  
Cell Matrix ◽  
Cell Cell

Vinculin transduces force and orchestrates mechanical signalling at cell–cell and cell–matrix adhesions. Cells expressing a mutant vinculin deficient in actin binding and bundling display migration and traction force defects. Vinculin binding to actin is critical for cell migration and force generation.

scholarly journals Author response: Single molecule mechanics resolves the earliest events in force generation by cardiac myosin

2019 ◽  
Author(s):  
Michael S Woody ◽  
Donald A Winkelmann ◽  
Marco Capitanio ◽  
E Michael Ostap ◽  
Yale E Goldman
Keyword(s):  
Single Molecule ◽  
Force Generation ◽  
Author Response ◽  
Cardiac Myosin

scholarly journals A reverse stroke characterizes the force generation of cardiac myofilaments, leading to an understanding of heart function

2021 ◽  
Vol 118 (23) ◽  
pp. e2011659118
Author(s):  
Yongtae Hwang ◽  
Takumi Washio ◽  
Toshiaki Hisada ◽  
Hideo Higuchi ◽  
Motoshi Kaya
Keyword(s):  
Heart Function ◽  
Force Production ◽  
Cardiac Contraction ◽  
Force Generation ◽  
Power Stroke ◽  
Phosphate Solution ◽  
Cardiac Myosin ◽  
Collective Behaviors ◽  
Reverse Stroke ◽  
Skeletal Myosin

Changes in the molecular properties of cardiac myosin strongly affect the interactions of myosin with actin that result in cardiac contraction and relaxation. However, it remains unclear how myosin molecules work together in cardiac myofilaments and which properties of the individual myosin molecules impact force production to drive cardiac contractility. Here, we measured the force production of cardiac myofilaments using optical tweezers. The measurements revealed that stepwise force generation was associated with a higher frequency of backward steps at lower loads and higher stall forces than those of fast skeletal myofilaments. To understand these unique collective behaviors of cardiac myosin, the dynamic responses of single cardiac and fast skeletal myosin molecules, interacting with actin filaments, were evaluated under load. The cardiac myosin molecules switched among three distinct conformational positions, ranging from pre– to post–power stroke positions, in 1 mM ADP and 0 to 10 mM phosphate solution. In contrast to cardiac myosin, fast skeletal myosin stayed primarily in the post–power stroke position, suggesting that cardiac myosin executes the reverse stroke more frequently than fast skeletal myosin. To elucidate how the reverse stroke affects the force production of myofilaments and possibly heart function, a simulation model was developed that combines the results from the single-molecule and myofilament experiments. The results of this model suggest that the reversal of the cardiac myosin power stroke may be key to characterizing the force output of cardiac myosin ensembles and possibly to facilitating heart contractions.

scholarly journals A cardiac myosin light chain kinase regulates sarcomere assembly in the vertebrate heart

2007 ◽  
Vol 117 (10) ◽  
pp. 2812-2824 ◽  
Author(s):  
Osamu Seguchi ◽  
Seiji Takashima ◽  
Satoru Yamazaki ◽  
Masanori Asakura ◽  
Yoshihiro Asano ◽  
...  
Keyword(s):  
Light Chain ◽  
Myosin Light Chain Kinase ◽  
Myosin Light Chain ◽  
Cardiac Myosin ◽  
Sarcomere Assembly

scholarly journals Electrostatic Interactions Within Loop 1 and the Force Generation Region of Human Cardiac Myosin Affect the Rate of Actomyosin Dissociation and ADP Release

2019 ◽  
Vol 116 (3) ◽  
pp. 259a-260a
Author(s):  
Akhil Gargey ◽  
Jinghua Ge ◽  
Alex Grdzelishvili ◽  
Yaroslav Tkachev ◽  
Yuri E. Nesmelov
Keyword(s):  
Electrostatic Interactions ◽  
Force Generation ◽  
Cardiac Myosin ◽  
Adp Release ◽  
Generation Region
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