A5055409183- Cardiomyopathy and Myosin Studies
- Muscle Physiology and Disorders
- Cardiovascular Effects of Exercise
- Neurogenetic and Muscular Disorders Research
- Cellular Mechanics and Interactions
- Connective tissue disorders research
- Congenital heart defects research
- Tissue Engineering and Regenerative Medicine
- Ubiquitin and proteasome pathways
- Genetic Neurodegenerative Diseases
- E-Learning and Knowledge Management
- Blood properties and coagulation
- Genomics and Phylogenetic Studies
- Biochemical Analysis and Sensing Techniques
- Online Learning and Analytics
- Cancer-related gene regulation
- Cardiovascular Function and Risk Factors
- Sports Performance and Training
- Photosynthetic Processes and Mechanisms
- Dye analysis and toxicity
- Environmental Chemistry and Analysis
- Microtubule and mitosis dynamics
- Microbial Community Ecology and Physiology
- Muscle metabolism and nutrition
- Forensic Toxicology and Drug Analysis
University of Arizona
2014-2024
University of Michigan
2014
Ann Arbor VA Medical Center
2014
Children's Hospital at Westmead
2014
Westmead Institute
2014
University of Wyoming
2004
Nemaline myopathy (NM) is a genetic muscle disorder characterized by dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described 9 genes to date, but the basis remains unknown many cases. Here, using an approach that combined whole-exome sequencing (WES) Sanger sequencing, we identified homozygous or compound heterozygous variants LMOD3 21 patients from 14 families with severe, usually lethal, NM. encodes leiomodin-3 (LMOD3),...
Protein lysine methylation is one of the most widespread post-translational modifications in nuclei eukaryotic cells. Methylated lysines on histones and nonhistone proteins promote formation protein complexes that control gene expression DNA replication repair. In cytoplasm, however, role complex not well established. Here we report cytoplasmic chaperone Hsp90 methylated by methyltransferase Smyd2 various cell types. muscle, contributes to a containing Smyd2, Hsp90, sarcomeric titin....
Efficient muscle contraction requires regulation of actin filament lengths. In one highly cited model, the giant protein nebulin has been proposed to function as a molecular ruler specifying We directly challenged this hypothesis by constructing unique, small version (mini-nebulin). When endogenous was replaced with mini-nebulin in skeletal myocytes, thin filaments extended beyond end mini-nebulin, an observation which is inconsistent strict function. However, under conditions that promote...
Regulation of actin filament assembly is essential for efficient contractile activity in striated muscle. Leiomodin an actin-binding protein and homolog the pointed-end capping protein, tropomodulin. These proteins are structurally similar, sharing a common domain organization that includes two sites. also contains unique C-terminal extension has third WH2 domain. Recently, striated-muscle-specific isoform leiomodin (Lmod2) was reported to be nucleator cardiomyocytes. Here, we have...
Significance Mutations in titin are a major cause of heart failure, yet the functions large parts not understood. Here we studied titin’s I-band/A-band junction that has been proposed to be crucial for thick filament length control. We made mouse which IA was deleted. Super-resolution microscopy (structured illumination microscopy) revealed deleting increases strain on molecular spring elements without altering length. Single cell biomechanical measurements showed this passive stiffness...
Significance Modulation of actin filament architecture underlies a plethora cellular processes including cell shape, division, adhesion, and motility. In heart muscle cells actin-containing thin filaments form highly organized structures with precisely regulated lengths. This precision is required for efficient interaction myosin-containing provides the basis contraction. The mechanism whereby regulate assembly its consequences cardiac physiology are largely unknown. We discovered that...
Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and caused by mutations in genes encoding proteins that associated with skeletal muscle thin filament. Mechanisms underlying weakness poorly understood, but might involve length of filament, an important determinant force generation.We investigated sarcomere length-dependence force, a functional assay provides insights into contractile strength fibers as well filaments, from 51 patients myopathy...
The barbed ends of actin filaments in striated muscle are anchored within the Z-disc and capped by CapZ; this protein blocks polymerization depolymerization vitro. mature lengths thin likely specified giant "molecular ruler" nebulin, which spans length filament. Here, we report that CapZ specifically interacts with C terminus nebulin (modules 160-164) blot overlay, solid-phase binding, tryptophan fluorescence, SPOTs membrane assays. Binding modules 160-164 to does not affect ability cap...
Small heat shock protein HSPB7 is highly expressed in the heart. Several mutations within are associated with dilated cardiomyopathy and heart failure human patients. However, precise role of still unclear. In this study, we generated global as well cardiac-specific KO mouse models found that loss globally or specifically cardiomyocytes resulted embryonic lethality before day 12.5. Using biochemical cell culture assays, identified an actin filament length regulator repressed polymerization...
A high-density oligonucleotide DNA microarray, a genechip, representing the 4.6-Mb genome of facultative phototrophic proteobacterium, Rhodobacter sphaeroides 2.4.1, was custom-designed and manufactured by Affymetrix, Santa Clara, Calif. The genechip contains probe sets for 4,292 open reading frames (ORFs), 47 rRNA tRNA genes, 394 intergenic regions. set sequences were derived from annotation generated Oak Ridge National Laboratory after extensive revision, which based primarily upon codon...
A prominent feature of striated muscle is the regular lateral alignment adjacent sarcomeres. An important intermyofibrillar linking protein intermediate filament desmin, and based on biochemical structural studies in primary cultures myocytes it has been proposed that desmin interacts with sarcomeric nebulin. Here we tested whether nebulin part a novel biomechanical linker complex, by using recently developed knockout (KO) mouse model measuring Z-disk displacement myofibrils both extensor...
Similarities between a mouse model and human patient informed diagnosis management of novel cause dilated cardiomyopathy.
The leiomodin (Lmod) family of actin-binding proteins play a critical role in muscle function, highlighted by the fact that mutations all three members (LMOD1-3) result human myopathies. Mutations cardiac predominant isoform, LMOD2 lead to severe neonatal dilated cardiomyopathy. Most disease-causing LMOD gene are nonsense, or frameshift, predicted expression truncated proteins. However, nearly cases disease, little no protein is expressed. We show here nonsense-mediated mRNA decay, cellular...
Abstract Dilated cardiomyopathy (DCM) is characterized by cardiac enlargement and impaired ventricular contractility leading to heart failure. A single report identified variants in leiomodin-2 ( LMOD2 ) as a cause of neonatally-lethal DCM. Here, we describe two siblings with DCM who died shortly after birth due Exome sequencing homozygous variant both siblings, (GRCh38)chr7:g.123656237G > A; NM_207163.2:c.273 + 1G A, ablating the donor 5′ splice-site intron-1. Pre-mRNA splicing studies...
Leiomodin is a potent actin nucleator related to tropomodulin, capping protein localized at the pointed end of thin filaments. Mutations in leiomodin-3 are associated with lethal nemaline myopathy humans, and leiomodin-2–knockout mice present dilated cardiomyopathy. The arrangement N-terminal actin- tropomyosin-binding sites leiomodin contradictory functionally not well understood. Using one-dimensional nuclear magnetic resonance pointed-end polymerization assay, we find that leiomodin-2,...
Muscle contraction is a regulated process driven by the sliding of actin-thin filaments over myosin-thick filaments. Lmod2 an actin filament length regulator and essential for life since human mutations complete loss in mice lead to dilated cardiomyopathy death. To study little-known role skeletal muscle, we created mouse model with expressed exclusively heart but absent muscle. Loss muscle results decreased force production fast- slow-twitch muscles. Soleus from rescued knockout have...
Missense mutations K15N and R21H in striated muscle tropomyosin are linked to dilated cardiomyopathy (DCM) hypertrophic (HCM), respectively. Tropomyosin, together with the troponin complex, regulates contraction and, along tropomodulin leiomodin, controls uniform thin-filament lengths crucial for normal sarcomere structure function. We used Förster resonance energy transfer study effects of on kinetics cardiac core domain associated Ca2+-dependent regulation thin filaments. found that...
A novel cardiac-specific transgenic mouse model was generated to identify the physiological consequences of elongated thin filaments during post-natal development in heart. Remarkably, increasing expression levels vivo just one sarcomeric protein, Lmod2, results ~10% longer (up 26% some individual sarcomeres) that produce up 50% less contractile force. Increasing Lmod2 (Lmod2-TG) also allows us probe contribution progression cardiac myopathy because Lmod2-TG mice present with a unique...