Myosin essential light chain in health and disease

Hernandez, Olga M.; Jones, Michelle; Guzman, Georgianna; Szczesna‐Cordary, Danuta

doi:10.1152/ajpheart.00931.2006

Cited by 115 publications

(117 citation statements)

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“…Myl4, the third prioritized gene, is also atriaspecific in the adult. Interestingly, it is reexpressed in the ventricles of the diseased heart, suggesting a role in repair mechanisms (59). The up-regulation of Myl4 in EdnrB −/+ indicated cross-talk between the two genes (EdnrB and Myl4).…”

Section: Discussionmentioning

confidence: 99%

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Stobdan

Zhou

Ao-Ieong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature's experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole-genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB −/+ heterozygote mice are treated with lower levels of oxygen (O 2 ), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O 2 ) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O 2 delivery to vital organs was significantly higher and blood lactate was lower in EdnrB −/+ compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower in EdnrB −/+ mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB −/+ and wild type. Functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans.is often referred to as a biosignature, a chemical marker in the atmosphere closely associated with life, and in a complex organism, such as humans, various physiological systems have evolved to maintain an optimal O 2 homeostasis. Arguably, humans living at high altitude (HA) for thousands of years ought to have undergone a significant level of natural selection to adjust to the challenging hypoxic condition. Human adaptation to HA hypoxia, which can be protective to tissues, can potentially be harnessed for better therapeutic modalities for sea-level diseases that involve hypoxia and ischemia in their pathogenesis. Indeed, lessons from such an "experiment in nature" can be derived from HA adaptation and can advance lowaltitude medicine (1). With the advent of newer technology including next-generation sequencing (seq), this idea has recently led to intensive efforts, and a number of publications have appeared on studies of human populations living at HA (2-4). These studies also draw added significance not only to sea-level human diseases but also to more than 140 million people living at an altitude above 2,500 m, where the hypoxic condition presents a major challenge for survival (5). Although a number of laboratory methods that mimic hypoxia adaptation using model organisms (6) have been used as tools to identify causative genetic pathways (7,8), studies in human populations living at different H...

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Section: Discussionmentioning

confidence: 99%

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Stobdan

Zhou

Ao-Ieong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The deeply buried cTnI Ile148 residue is shown in space-filling spheres. d | The ternary complex of cNTnC, cTnI [147][148][149][150][151][152][153][154][155][156][157][158][159][160][161][162][163] and bepridil (shown in grey), showing bepridil bound to a deep hydrophobic pocket and displacing cTnI Ile148 (REF. 94).…”

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confidence: 99%

Targeting the sarcomere to correct muscle function

Hwang

Sykes

2015

Nat Rev Drug Discov

111

122

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“…A wealth of evidence suggests that it may play a role in force development and muscle contraction (17,24,36,40,54). The functional importance of myosin ELC in cardiac muscle has emerged through the identification of several mutations in the ELC gene (MYL3) shown to cause familial hypertrophic cardiomyopathy (FHC).…”

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confidence: 99%

Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy

Kazmierczak

Paulino

Huang

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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(alanine-to-glycine) mutation in the myosin ventricular essential light chain (ELC) were assessed in vitro and in vivo using previously generated transgenic (Tg) mice expressing A57G-ELC mutant vs. wild-type (WT) of human cardiac ELC and in recombinant A57G-or WT-protein-exchanged porcine cardiac muscle strips. Compared with the Tg-WT, there was a significant increase in the Ca 2ϩ sensitivity of force (⌬pCa50 Х 0.1) and an ϳ1.3-fold decrease in maximal force per cross section of muscle observed in the mutant preparations. In addition, a significant increase in passive tension in response to stretch was monitored in Tg-A57G vs. Tg-WT strips indicating a mutation-induced myocardial stiffness. Consistently, the hearts of Tg-A57G mice demonstrated a high level of fibrosis and hypertrophy manifested by increased heart weight-to-body weight ratios and a decreased number of nuclei indicating an increase in the two-dimensional size of Tg-A57G vs. Tg-WT myocytes. Echocardiography examination showed a phenotype of eccentric hypertrophy in Tg-A57G mice, enhanced left ventricular (LV) cavity dimension without changes in LV posterior/anterior wall thickness. Invasive hemodynamics data revealed significantly increased end-systolic elastance, defined by the slope of the pressure-volume relationship, indicating a mutation-induced increase in cardiac contractility. Our results suggest that the A57G allele causes disease by means of a discrete modulation of myofilament function, increased Ca 2ϩ sensitivity, and decreased maximal tension followed by compensatory hypertrophy and enhanced contractility. These and other contributing factors such as increased myocardial stiffness and fibrosis most likely activate cardiomyopathic signaling pathways leading to pathologic cardiac remodeling. myosin essential light chain; hypertrophic cardiomyopathy; Ca 2ϩ sensitivity of contraction; echocardiography; pressure-volume loops THE BEATING OF THE HEART DEPENDS on ATP-controlled synchronous interactions between two major contractile proteins; myosin and actin (15). The myosin cross bridges are the molecular motors of the heart, which bind and hydrolyze Mg-ATP and cyclically attach and dissociate from actin-tropomyosin (Tm)-troponin (Tn) thin filaments in a Ca 2ϩ -dependent manner. The cycle of Ca 2ϩ fluxes regulate the coupling between excitation and contraction and permit the highly synchronized action of cardiac sarcomeres causing the heart to contract (systole) or relax (diastole) (20). The two key components of the myosin cross bridge include the motor domain, consisting of the ATP and actin binding sites, and the neck domain also called the lever arm, which is structurally supported by two types of myosin light chains, the essential (ELC) and the regulatory (RLC) light chains (44). Attached to their respective IQ motifs on the myosin heavy chain (MHC), both light chains inherently participate in all biochemical steps of the acto-myosin cycle and execution of the power stroke (52). As components of the neck region of myosin, both ELC and RL...

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Myosin essential light chain in health and disease

Cited by 115 publications

References 114 publications

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Targeting the sarcomere to correct muscle function

Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy

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