Article
Multidisciplinary Sciences
Priyanka Parijat, Saraswathi Ponnam, Seetharamaiah Attili, Kenneth S. Campbell, Mohammed El-Mezgueldi, Mark Pfuhl, Thomas Kampourakis
Summary: The unmet demand for new heart failure therapeutics is well recognized and targeting the contractile myofilaments has shown potential for the development of new drugs. However, limited clinical use and incomplete understanding of myofilament function have hindered progress in this area. In this study, new high throughput screening platforms were designed and validated to explore the effects of small molecule effectors on the interactions between cardiac troponin C and troponin I subunits. The results suggest that sarcomeric protein-directed screening platforms are suitable for developing compounds that modulate cardiac myofilament function.
SCIENTIFIC REPORTS
(2023)
Review
Biochemistry & Molecular Biology
Ashley A. Martin, Brian R. Thompson, Dongwoo Hahn, Addeli Bez Batti Angulski, Nora Hosny, Houda Cohen, Joseph M. Metzger
Summary: This review emphasizes the signaling components and regulatory mechanisms that impact cardiac sarcomere function, with a focus on the roles of the thick and thin filaments. The emerging field of inter-myofilament signaling and its important mediators are also discussed. Additionally, recent methods for studying the sarcomere under intact, physiologically relevant conditions are reviewed.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Daren Elkrief, Yu-Shu Cheng, Oleg S. Matusovsky, Dilson E. Rassier
Summary: The interaction between actin and myosin is crucial for muscle contraction and force production. Oxidation of actin and myosin has been found to weaken the myofibrils in healthy and diseased muscles. This study shows that exposure to a chemical compound can affect the interactions between actin and myosin, leading to decreased velocity and force. Oxidation of both actin and myosin contributes to a decrease in contractile activity in muscles.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Article
Multidisciplinary Sciences
C. Arbore, M. Sergides, L. Gardini, G. Bianchi, A. Kashchuk, I Pertici, P. Bianco, F. S. Pavone, M. Capitanio
Summary: By using laser tweezers, the authors demonstrate that a single alpha-catenin molecule lacks force resistance on F-actin. However, clustering of multiple molecules and force application towards the pointed end of F-actin engage a molecular switch in alpha-catenin, causing it to unfold and strongly bind F-actin. These findings reveal the mechanosensitive properties of alpha-catenin at cell junctions.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
So-Jin Park-Holohan, Elisabetta Brunello, Thomas Kampourakis, Martin Rees, Malcolm Irving, Luca Fusi
Summary: The regulation of myosin activity in heart muscle involves the modulation of myosin motors available for interaction with thin filaments. Stretch or increased RLC phosphorylation do not have a direct effect on the activation of folded myosin motors at physiological conditions, but can lead to delayed activation and increased force production at higher calcium concentrations. This suggests a calcium-dependent interfilament signaling pathway involving thin filament sensitization and thick filament mechanosensing in the increased contractility induced by RLC phosphorylation and stretch in the heart.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Chemistry, Multidisciplinary
Xinpeng Hu, Xiaodan Zhao, Iong Ying Loh, Jie Yan, Zhisong Wang
Summary: This study demonstrates the sustained force generation capability of an artificial molecular motor at the single-molecule level, showcasing its autonomous chemically fueled operation and self-directed walking. The results suggest a reasonably efficient chemomechanical conversion of the motor compared to biomotors, with implications for similar force-demanding applications.
Review
Biochemistry & Molecular Biology
Kasturi Markandran, Jane Wenjin Poh, Michael A. Ferenczi, Christine Cheung
Summary: RLCs play a critical role in cardiac function, with phosphorylation levels affecting muscle contraction force significantly. While their role in cardiac development and disease is gradually being understood, the mechanisms triggering changes in RLC phosphorylation levels remain unclear.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cardiac & Cardiovascular Systems
Tatsuro Hitsumoto, Osamu Tsukamoto, Ken Matsuoka, Junjun Li, Li Liu, Yuki Kuramoto, Shuichiro Higo, Shou Ogawa, Noboru Fujino, Shohei Yoshida, Hidetaka Kioka, Hisakazu Kato, Hideyuki Hakui, Yuki Saito, Chisato Okamoto, Hijiri Inoue, Jo Hyejin, Kyoko Ueda, Takatsugu Segawa, Shunsuke Nishimura, Yoshihiro Asano, Hiroshi Asanuma, Akiyoshi Tani, Riyo Imamura, Shinsuke Komagawa, Toshio Kanai, Masayuki Takamura, Yasushi Sakata, Masafumi Kitakaze, Jun-ichi Haruta, Seiji Takashima
Summary: This study demonstrates that dysregulation of cMLCK contributes to the development of cardiac systolic dysfunction in humans, and restoring cMLCK activity could serve as a novel myotropic therapy for advanced systolic heart failure.
Article
Biology
Axel J. Fenwick, David C. Lin, Bertrand C. W. Tanner
Summary: Muscle contraction results from force-generating interactions between myosin and actin, with factors influencing cross-bridge kinetics at the molecular level propagating through tissues to modulate whole-muscle function. Researchers found that cross-bridge kinetics vary with whole-muscle length during intact, isometric contraction, suggesting a feedback pathway between muscle function and cross-bridge activity. The study highlights the complexity of muscle contraction and the potential impact of length-dependent cross-bridge kinetics on force generation and energetics.
PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Alf Mansson, Dilson E. Rassier
Summary: Bottom-up mechanokinetic models predict ensemble function of actin and myosin based on parameter values derived from studies using isolated proteins. This study tests the prediction capability of a model for different drugs and concentrations, and finds that it qualitatively predicts the effects of most drugs but quantitatively fails to account for the effects of one specific drug. By adjusting key model parameters, the modified model not only improves the prediction of the effects of the specific drug, but also maintains good prediction accuracy for normal physiological ensemble function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Physiology
Kristian Overgaard, William Gittings, Rene Vandenboom
Summary: Moderately elevated extracellular potassium concentration can enhance muscle twitch force but depress high-frequency force, and this enhancement is independent of phosphorylation of myosin regulatory light chains.
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2022)
Article
Multidisciplinary Sciences
Yohei Mizoguchi, Kaoru Nakashima, Ayato Sato, Asako Shindo
Summary: This study reveals the important contribution of ADRB2 to the extensibility of epithelial tissues and body elongation during development, as well as its impact on the physiology of mature epithelial organs.
Article
Biochemistry & Molecular Biology
Daria S. Yampolskaya, Galina V. Kopylova, Daniil Shchepkin, Salavat R. Nabiev, Larisa V. Nikitina, Jonathan Walklate, Rustam H. Ziganshin, Sergey Y. Bershitsky, Michael A. Geeves, Alexander M. Matyushenko, Dmitrii I. Levitsky
Summary: The study aimed to investigate the effects of phosphorylation of myosin essential light chain (LC1) on the functional properties of the myosin molecule. Mass-spectrometry was used to identify phosphorylated peptides of LC1 in different skeletal muscles. Mutations mimicking natural phosphorylation were produced and their effects on the entire myosin molecule and isolated myosin head (S1) were studied. The results showed that pseudo-phosphorylation of LC1 differentially affected the properties of the whole myosin molecule and its isolated head.
BIOPHYSICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Tingfei Hu, Hema Kalyanaraman, Renate B. Pilz, Darren E. Casteel
Summary: Cardiac contraction is regulated by the phosphorylation state of myosin regulatory light chain 2 (MLC-2v). MLC-2v phosphorylation is controlled by the activities of MLC kinases and phosphatases. MYPT2 is the main MLC phosphatase in cardiac myocytes. Overexpression of MYPT2 decreases MLC phosphorylation and impairs cardiac function, while the effect of MYPT2 knockout on cardiac function is unknown.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Ayelen M. Santamans, Valle Montalvo-Romeral, Alfonso Mora, Juan Antonio Lopez, Francisco Gonzalez-Romero, Daniel Jimenez-Blasco, Elena Rodriguez, Aranzazu Pintor-Chocano, Cristina Casanueva-Benitez, Rebeca Acin-Perez, Luis Leiva-Vega, Jordi Duran, Joan J. Guinovart, Jesus Jimenez-Borreguero, Jose Antonio Enriquez, Maria Villlalba-Orero, Juan P. Bolanos, Patricia Aspichueta, Jesus Vazquez, Barbara Gonzalez-Teran, Guadalupe Sabio
Summary: During the early postnatal heart development, activation of the p38 gamma and p38 delta protein kinases leads to a metabolic shift in the heart, potentially inhibiting glycogen synthase and reducing glycogen production. Premature activation of these kinases may result in inadequate cardiac fuel supply and systemic metabolic disruption.