A5065493839- Cardiomyopathy and Myosin Studies
- Cardiovascular Effects of Exercise
- Muscle Physiology and Disorders
- Cardiovascular Function and Risk Factors
- Force Microscopy Techniques and Applications
- Tissue Engineering and Regenerative Medicine
- Cellular Mechanics and Interactions
- Genetic Neurodegenerative Diseases
- Cardiac electrophysiology and arrhythmias
- Viral Infections and Immunology Research
- Congenital heart defects research
- Fossil Insects in Amber
- Microtubule and mitosis dynamics
- Ion channel regulation and function
- Mitochondrial Function and Pathology
- Malaria Research and Control
- Metabolomics and Mass Spectrometry Studies
- Mass Spectrometry Techniques and Applications
- Trypanosoma species research and implications
- Muscle activation and electromyography studies
- Neurogenetic and Muscular Disorders Research
- Circadian rhythm and melatonin
- Animal Vocal Communication and Behavior
- Advanced MRI Techniques and Applications
- Advanced Proteomics Techniques and Applications
University of Vermont
2015-2024
Garvan Institute of Medical Research
2024
UNSW Sydney
2024
The heart's pumping capacity results from highly regulated interactions of actomyosin molecular motors. Mutations in the gene for a potential regulator these motors, cardiac myosin-binding protein C (cMyBP-C), cause hypertrophic cardiomyopathy. However, cMyBP-C's ability to modulate contractility is not well understood. Using single-particle fluorescence imaging techniques, transgenic expression, proteomics, and modeling, we found that cMyBP-C slowed motion generation native thick filaments....
Myosin-binding protein C (MyBP-C) is an accessory of striated muscle thick filaments and a modulator cardiac contraction. Defects in the isoform, cMyBP-C, cause heart disease. cMyBP-C includes 11 Ig- fibronectin-like domains cMyBP-C-specific motif. In vitro studies show that addition to binding filament via its C-terminal region, can also interact with actin N-terminal domains, modulating thin motility. Structural observations F-actin decorated fragments suggest binds close low Ca(2+) site...
We hypothesize that age-related skeletal muscle dysfunction and physical disability may be partially explained by alterations in the function of myosin molecule. To test this hypothesis, at whole muscle, single fiber, molecular levels was measured young (21–35 yr) older (65–75 male female volunteers with similar activity levels. After adjusting for size, adults had knee extensor isometric torque values compared young, but lower isokinetic power, most notably women. At single-fiber levels,...
During each heartbeat, cardiac contractility results from calcium-activated sliding of actin thin filaments toward the centers myosin thick to shorten cellular length. Cardiac myosin-binding protein C (cMyBP-C) is a component filament that appears tune these mechanochemical interactions by its N-terminal domains transiently interacting with and/or S2 domain, sensitizing calcium and governing maximal velocity. Both functional mechanisms are potentially further tunable phosphorylation an...
Mutations in cardiac myosin binding protein C (MyBP-C, encoded by MYBPC3) are the most common cause of hypertrophic cardiomyopathy (HCM). Most MYBPC3 mutations result premature termination codons (PTCs) that RNA degradation and a reduction MyBP-C HCM patient hearts. However, has not been consistently observed MYBPC3-mutant induced pluripotent stem cell cardiomyocytes (iPSCMs). To determine early mutation effects, we used genome-engineered iPSCMs. iPSCMs with frameshift were compared promoter...
Background: Defects in energetics are thought to be central the pathophysiology of hypertrophic cardiomyopathy (HCM); yet, determinants ATP availability not known. The purpose this study is ascertain nature and extent metabolic reprogramming human HCM, its potential impact on contractile function. Methods: We conducted proteomic targeted, quantitative metabolomic analyses heart tissue from patients with HCM nonfailing control hearts. Results: In analysis, greatest differences observed...
Aging is associated with decreased skeletal muscle mass and function. These changes are thought to derive, in part, from a reduction protein synthesis. Although some studies have shown reduced postabsorptive synthesis age humans, recent failed find an effect. In addition this disparity, few attempted characterize the hormonal factors that may contribute Thus we examined effect of on metabolism, specific emphasis myosin heavy chain (MHC) protein, relationship rates plasma hormone levels. We...
The beating heart exhibits remarkable contractile fidelity over a lifetime, which reflects the tight coupling of electrical, chemical, and mechanical elements within sarcomere, elementary unit. On beat-to-beat basis, calcium is released from ends sarcomere must diffuse toward center to fully activate myosin- actin-based proteins. resultant spatial temporal gradient in free across should lead nonuniform inefficient activation contraction. We show that myosin-binding protein C (MyBP-C),...
Abstract Plasmodium parasites are obligate intracellular protozoa and causative agents of malaria, responsible for half a million deaths each year. The lifecycle progression the parasite is reliant on cell motility, process driven by myosin A, an unconventional single-headed class XIV molecular motor. Here we demonstrate that A from falciparum (PfMyoA) critical red blood invasion. Further, using combination X-ray crystallography, kinetics, in vitro motility assays, elucidate non-canonical...
Proteomics investigations typically yield information regarding static gene expression profiles. The central issues that limit the study of proteome dynamics include how to (i) administer a labeled amino acid in vivo, (ii) measure isotopic labeling protein(s) (which may be low), and (iii) reliably interpret precursor/product relationships. In this study, we demonstrate potential quantifying by coupling administration stable isotopes with mass spectrometric assays. Although direct acid(s) is...
Significance Diverse demands on cardiac muscle require the fine-tuning of contraction. Cardiac myosin binding protein-C (cMyBP-C) is involved in this regulation; however, its precise molecular mechanism action remains uncertain. By imaging interactions single and cMyBP-C molecules interacting with suspended thin filaments vitro we observe N-terminal fragments assist activation modulate contraction velocity by affecting to filament. Fluorescent Cy3-labeled revealed that it diffusively scans...
Significance Myosin-binding protein C (MyBP-C) is a critical component of the skeletal muscle sarcomere, muscle’s smallest contractile unit. MyBP-C’s importance evident by genetic mutations leading to human myopathies, such as distal arthrogryposis (i.e., club foot). However, molecular basis functional impact on contractility far from certain. Complicating matters further expression fast- and slow-type MyBP-C isoforms that depend whether or slow-twitch. Using multiscale proteomic,...
Muscle contraction, which is initiated by Ca2+, results in precise sliding of myosin-based thick and actin-based thin filament contractile proteins. The interactions between myosin actin are finely tuned three isoforms binding protein-C (MyBP-C): slow-skeletal, fast-skeletal, cardiac (ssMyBP-C, fsMyBP-C cMyBP-C, respectively), each with distinct N-terminal regulatory regions. skeletal MyBP-C conditionally coexpressed muscle, but little known about their function. Therefore, to characterize...
Myosin and actin filaments are highly organized within muscle sarcomeres. Myosin-binding protein C (MyBP-C) is a flexible, rod-like located the C-zone of sarcomere. The C-terminal domain MyBP-C tethered to myosin filament backbone, N-terminal domains postulated interact with and/or head modulate sliding. To define where localized in sarcomere active relaxed mouse myocardium, relative positions N terminus were imaged fixed samples using super-resolution fluorescence microscopy. resolution...
Abstract Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) allow investigations in a human cardiac model system, but disorganized mechanics and immaturity of hPSC-CMs on standard two-dimensional surfaces have been hurdles. Here, we developed platform micron-scale muscle bundles to control biomechanics arrays thousands purified, independently contracting strips elastomer substrates with far greater throughput than single cell methods. By defining geometry workload this...
Abstract Vocal signals, including human speech and birdsong, are produced by complicated, precisely coordinated body movements, whose execution is fitness-determining in resource competition mate choice. While the acquisition maintenance of motor skills generally requires practice to develop maintain both circuitry muscle performance, it unknown whether vocal muscles, like limb exhibit exercise-induced plasticity. Here, we show that juvenile adult zebra finches ( Taeniopygia castanotis )...
Motility of the apicomplexan malaria parasite Plasmodium falciparum is enabled by a multiprotein glideosome complex, whose core class XIV myosin motor, PfMyoA, and divergent actin (PfAct1). Parasite motility necessary for host-cell invasion virulence, but studying its molecular basis has been hampered unavailability sufficient amounts PfMyoA. Here, we expressed milligram quantities functional full-length PfMyoA with baculovirus/Sf9 cell expression system, which required UCS...
Mutations in atrial-enriched genes can cause a primary atrial myopathy that contribute to overall cardiovascular dysfunction. MYBPHL encodes myosin-binding protein H-like (MyBP-HL), an sarcomere shares domain homology with the carboxy-terminus of cardiac protein-C (cMyBP-C). The function MyBP-HL and relationship between cMyBP-C is unknown. To decipher roles MyBP-HL, we used structured illumination microscopy, immuno-electron mass spectrometry establish localization stoichiometry MyBP-HL. We...