A5035430785- Cardiomyopathy and Myosin Studies
- Muscle Physiology and Disorders
- Neurogenetic and Muscular Disorders Research
- Cellular Mechanics and Interactions
- Cardiovascular Effects of Exercise
- Congenital heart defects research
- Tissue Engineering and Regenerative Medicine
- Genetic Neurodegenerative Diseases
- Cardiovascular Function and Risk Factors
- Atmospheric Ozone and Climate
- Protease and Inhibitor Mechanisms
- Metabolism, Diabetes, and Cancer
- Caveolin-1 and cellular processes
- Atherosclerosis and Cardiovascular Diseases
- Menopause: Health Impacts and Treatments
- ATP Synthase and ATPases Research
- Blood Coagulation and Thrombosis Mechanisms
- Cassava research and cyanide
- Cardiac Fibrosis and Remodeling
- Estrogen and related hormone effects
- RNA Research and Splicing
- Cell Adhesion Molecules Research
University of Arizona
2015-2025
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...
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...
Similarities between a mouse model and human patient informed diagnosis management of novel cause dilated cardiomyopathy.
Risk of cardiovascular disease (CVD) in women increases with the menopausal transition. Using a chemical model (4-vinylcyclohexene diepoxide; VCD) accelerated ovarian failure, we previously demonstrated that females are more susceptible to CVD compared peri- or pre-menopausal like humans. Yet, cellular and molecular mechanisms underlying this shift susceptibility across pre- menopause continuum remain understudied. In work utilizing VCD mouse model, phenotyped signatures from hearts at each...
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...
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,...
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...
Increases in lung vascular permeability is a cardinal feature of inflammatory disease and represents an imbalance contractile forces barrier-restorative forces, with both highly dependent upon the actin cytoskeleton. The current study investigates role Ena-VASP-like (EVL), member Ena-VASP family known to regulate cytoskeleton, regulating responses endothelial cell barrier integrity. Utilizing changes transendothelial electricial resistance (TEER) measure responses, we demonstrate that EVL...
Actin is a highly expressed protein in eukaryotic cells and essential for numerous cellular processes. In particular, efficient striated muscle contraction dependent upon the precise regulation of actin-based thin filament structure function. Alterations lengths actin-thin filaments can lead to development myopathies. Leiomodins tropomodulins are members an actin-binding family that fine-tune lengths, their dysfunction implicated diseases. An Lmod3 mutation [G326R] was previously identified...
Neonatal dilated cardiomyopathy (DCM) is a poorly understood muscular disease of the heart. Several homozygous biallelic variants in LMOD2, gene encoding actin-binding protein Leiomodin 2, have been identified to result severe DCM. Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting neonatal death. Thus, it evident that Lmod2 essential normal human muscle function. This study aimed understand underlying pathophysiology...
Prior to menopause, women are protected against cardiovascular disease (CVD) compared age-matched men; this protection is gradually lost after menopause. Mechanisms responsible for loss of CVD unknown. We previously demonstrated that menopause and suppress the AMP-activated protein kinase (AMPK) signaling pathway in mice. also validated cellular mechanism by which estrogen (E2) potentiates AMPK activity through a direct interaction receptors (ER) with members complex. Because down we...