-
Journal of the American Society of... Oct 2021Rhabdomyolysis, the destruction of skeletal muscle, is a significant cause of AKI and death in the context of natural disaster and armed conflict. Rhabdomyolysis may...
BACKGROUND
Rhabdomyolysis, the destruction of skeletal muscle, is a significant cause of AKI and death in the context of natural disaster and armed conflict. Rhabdomyolysis may also initiate CKD. Development of specific pharmacologic therapy is desirable because supportive care is nearly impossible in austere environments. Myoglobin, the principal cause of rhabdomyolysis-related AKI, undergoes megalin-mediated endocytosis in proximal tubule cells, a process that specifically injures these cells.
METHODS
To investigate whether megalin is protective in a mouse model of rhabdomyolysis-induced AKI, we used male C57BL/6 mice and mice (14-32 weeks old) with proximal tubule-specific deletion of megalin. We used a well-characterized rhabdomyolysis model, injection of 50% glycerol in normal saline preceded by water deprivation.
RESULTS
Inducible proximal tubule-specific deletion of megalin was highly protective in this mouse model of rhabdomyolysis-induced AKI. The megalin knockout mice demonstrated preserved GFR, reduced proximal tubule injury (as indicated by kidney injury molecule-1), and reduced renal apoptosis 24 hours after injury. These effects were accompanied by increased urinary myoglobin clearance. Unlike littermate controls, the megalin-deficient mice also did not develop progressive GFR decline and persistent new proteinuria. Administration of the pharmacologic megalin inhibitor cilastatin to wild-type mice recapitulated the renoprotective effects of megalin deletion. This cilastatin-mediated renoprotective effect was dependent on megalin. Cilastatin administration caused selective proteinuria and inhibition of tubular myoglobin uptake similar to that caused by megalin deletion.
CONCLUSIONS
We conclude that megalin plays a critical role in rhabdomyolysis-induced AKI, and megalin interference and inhibition ameliorate rhabdomyolysis-induced AKI. Further investigation of megalin inhibition may inform translational investigation of a novel potential therapy.
Topics: Acute Kidney Injury; Animals; Apoptosis; Blood Urea Nitrogen; Cilastatin; Disease Models, Animal; Endocytosis; Glomerular Filtration Rate; Kidney Tubules, Proximal; Low Density Lipoprotein Receptor-Related Protein-2; Male; Mice; Mice, Knockout; Myoglobin; Myoglobinuria; Protease Inhibitors; Rhabdomyolysis
PubMed: 34341182
DOI: 10.1681/ASN.2020030263 -
Journal of Applied Physiology... May 2019Near infrared spectroscopy (NIRS) is a powerful noninvasive tool with which to study the matching of oxygen delivery to oxygen utilization and the number of new... (Review)
Review
Near infrared spectroscopy (NIRS) is a powerful noninvasive tool with which to study the matching of oxygen delivery to oxygen utilization and the number of new publications utilizing this technique has increased exponentially in the last 20 yr. By measuring the state of oxygenation of the primary heme compounds in skeletal muscle (hemoglobin and myoglobin), greater understanding of the underlying control mechanisms that couple perfusive and diffusive oxygen delivery to oxidative metabolism can be gained from the laboratory to the athletic field to the intensive care unit or emergency room. However, the field of NIRS has been complicated by the diversity of instrumentation, the inherent limitations of some of these technologies, the associated diversity of terminology, and a general lack of standardization of protocols. This Cores of Reproducibility in Physiology (CORP) will describe in basic but important detail the most common methodologies of NIRS, their strengths and limitations, and discuss some of the potential confounding factors that can affect the quality and reproducibility of NIRS data. Recommendations are provided to reduce the variability and errors in data collection, analysis, and interpretation. The goal of this CORP is to provide readers with a greater understanding of the methodology, limitations, and best practices so as to improve the reproducibility of NIRS research in skeletal muscle.
Topics: Exercise; Hemoglobins; Humans; Muscle, Skeletal; Myoglobin; Oxygen; Oxygen Consumption; Reproducibility of Results; Spectroscopy, Near-Infrared
PubMed: 30844336
DOI: 10.1152/japplphysiol.00166.2018 -
Journal of Advanced Research Dec 2023Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It is characterized by systemic inflammatory... (Review)
Review
BACKGROUND
Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It is characterized by systemic inflammatory reaction, myoglobinuria, hyperkalemia and acute kidney injury (AKI). Especially AKI, it is the leading cause of death from CS. There are various cell death forms in AKI, among which ferroptosis is a typical form of cell death. However, the role of ferroptosis has not been fully revealed in CS-AKI.
AIM OF REVIEW
This review aimed to summarize the evidence of ferroptosis in CS-AKI and its related molecular mechanism, discuss the therapeutic significance of ferroptosis in CS-AKI, and open up new ideas for the treatment of CS-AKI.
KEY SCIENTIFIC CONCEPTS OF REVIEW
One of the main pathological manifestations of CS-AKI is renal tubular epithelial cell dysfunction and cell death, which has been attributed to massive deposition of myoglobin. Large amounts of myoglobin released from damaged muscle deposited in the renal tubules, impeding the normal renal tubules function and directly damaging the tubules with oxidative stress and elevated iron levels. Lipid peroxidation damage and iron overload are the distinguishing features of ferroptosis. Moreover, high levels of pro-inflammatory cytokines and damage-associated molecule pattern molecules (HMGB1, double-strand DNA, and macrophage extracellular trap) in renal tissue have been shown to promote ferroptosis. However, how ferroptosis occurs in CS-AKI and whether it can be a therapeutic target remains unclear. In our current work, we systematically reviewed the occurrence and underlying mechanism of ferroptosis in CS-AKI.
Topics: Humans; Acute Kidney Injury; Cell Death; Crush Syndrome; Ferroptosis; Myoglobin
PubMed: 36702249
DOI: 10.1016/j.jare.2023.01.016 -
Kidney360 Nov 2022Heme proteins, the stuff of life, represent an ingenious biologic strategy that capitalizes on the biochemical versatility of heme, and yet is one that avoids the... (Review)
Review
Heme proteins, the stuff of life, represent an ingenious biologic strategy that capitalizes on the biochemical versatility of heme, and yet is one that avoids the inherent risks to cellular vitality posed by unfettered and promiscuously reactive heme. Heme proteins, however, may be a double-edged sword because they can damage the kidney in certain settings. Although such injury is often viewed mainly within the context of rhabdomyolysis and the nephrotoxicity of myoglobin, an increasing literature now attests to the fact that involvement of heme proteins in renal injury ranges well beyond the confines of this single disease (and its analog, hemolysis); indeed, through the release of the defining heme motif, destabilization of intracellular heme proteins may be a common pathway for acute kidney injury, in general, and irrespective of the underlying insult. This brief review outlines current understanding regarding processes underlying such heme protein-induced acute kidney injury (AKI) and chronic kidney disease (CKD). Topics covered include, among others, the basis for renal injury after the exposure of the kidney to and its incorporation of myoglobin and hemoglobin; auto-oxidation of myoglobin and hemoglobin; destabilization of heme proteins and the release of heme; heme/iron/oxidant pathways of renal injury; generation of reactive oxygen species and reactive nitrogen species by NOX, iNOS, and myeloperoxidase; and the role of circulating cell-free hemoglobin in AKI and CKD. Also covered are the characteristics of the kidney that render this organ uniquely vulnerable to injury after myolysis and hemolysis, and pathobiologic effects emanating from free, labile heme. Mechanisms that defend against the toxicity of heme proteins are discussed, and the review concludes by outlining the therapeutic strategies that have arisen from current understanding of mechanisms of renal injury caused by heme proteins and how such mechanisms may be interrupted.
Topics: Humans; Myoglobin; Hemolysis; Rhabdomyolysis; Kidney; Acute Kidney Injury; Heme; Hemoglobins; Renal Insufficiency, Chronic
PubMed: 36514409
DOI: 10.34067/KID.0005442022 -
Nature Oct 2022Directed evolution is a powerful tool for improving existing properties and imparting completely new functionalities to proteins. Nonetheless, its potential in even...
Directed evolution is a powerful tool for improving existing properties and imparting completely new functionalities to proteins. Nonetheless, its potential in even small proteins is inherently limited by the astronomical number of possible amino acid sequences. Sampling the complete sequence space of a 100-residue protein would require testing of 20 combinations, which is beyond any existing experimental approach. In practice, selective modification of relatively few residues is sufficient for efficient improvement, functional enhancement and repurposing of existing proteins. Moreover, computational methods have been developed to predict the locations and, in certain cases, identities of potentially productive mutations. Importantly, all current approaches for prediction of hot spots and productive mutations rely heavily on structural information and/or bioinformatics, which is not always available for proteins of interest. Moreover, they offer a limited ability to identify beneficial mutations far from the active site, even though such changes may markedly improve the catalytic properties of an enzyme. Machine learning methods have recently showed promise in predicting productive mutations, but they frequently require large, high-quality training datasets, which are difficult to obtain in directed evolution experiments. Here we show that mutagenic hot spots in enzymes can be identified using NMR spectroscopy. In a proof-of-concept study, we converted myoglobin, a non-enzymatic oxygen storage protein, into a highly efficient Kemp eliminase using only three mutations. The observed levels of catalytic efficiency exceed those of proteins designed using current approaches and are similar with those of natural enzymes for the reactions that they are evolved to catalyse. Given the simplicity of this experimental approach, which requires no a priori structural or bioinformatic knowledge, we expect it to be widely applicable and to enable the full potential of directed enzyme evolution.
Topics: Biocatalysis; Catalytic Domain; Directed Molecular Evolution; Magnetic Resonance Spectroscopy; Mutation; Myoglobin; Oxygen
PubMed: 36198791
DOI: 10.1038/s41586-022-05278-9 -
Physiological Reviews Apr 2022Globin proteins exist in every cell type of the vasculature, from erythrocytes to endothelial cells, vascular smooth muscle cells, and peripheral nerve cells. Many... (Review)
Review
Globin proteins exist in every cell type of the vasculature, from erythrocytes to endothelial cells, vascular smooth muscle cells, and peripheral nerve cells. Many globin subtypes are also expressed in muscle tissues (including cardiac and skeletal muscle), in other organ-specific cell types, and in cells of the central nervous system (CNS). The ability of each of these globins to interact with molecular oxygen (O) and nitric oxide (NO) is preserved across these contexts. Endothelial α-globin is an example of extraerythrocytic globin expression. Other globins, including myoglobin, cytoglobin, and neuroglobin, are observed in other vascular tissues. Myoglobin is observed primarily in skeletal muscle and smooth muscle cells surrounding the aorta or other large arteries. Cytoglobin is found in vascular smooth muscle but can also be expressed in nonvascular cell types, especially in oxidative stress conditions after ischemic insult. Neuroglobin was first observed in neuronal cells, and its expression appears to be restricted mainly to the CNS and the peripheral nervous system. Brain and CNS neurons expressing neuroglobin are positioned close to many arteries within the brain parenchyma and can control smooth muscle contraction and thus tissue perfusion and vascular reactivity. Overall, reactions between NO and globin heme iron contribute to vascular homeostasis by regulating vasodilatory NO signals and scavenging reactive species in cells of the mammalian vascular system. Here, we discuss how globin proteins affect vascular physiology, with a focus on NO biology, and offer perspectives for future study of these functions.
Topics: Animals; Cardiovascular Physiological Phenomena; Cytoglobin; Endothelial Cells; Globins; Humans; Myoglobin; Neuroglobin
PubMed: 34486392
DOI: 10.1152/physrev.00037.2020 -
IUBMB Life Jun 2017Iron is an essential element for almost all organisms on Earth. It is necessary for a number of crucial processes such as hemoglobin and myoglobin transport and storage... (Review)
Review
Iron is an essential element for almost all organisms on Earth. It is necessary for a number of crucial processes such as hemoglobin and myoglobin transport and storage of oxygen in mammals; electron transfer support in a variety of iron-sulfur protein or cytochrome reactions; and activation and catalysis of reactions of a wide range of substrate like alkanes, olefins, and alcohols. Living organisms adopted iron as the main metal to carry out all of these functions due to the rich coordination chemistry of its two main redox states, Fe and Fe , and because of its abundance in the Earth's crust and oceans. This paper presents an overview of the coordination chemistry of iron that makes it suitable for a large variety of functions within biological systems. Despite iron's chemical advantages, organisms were forced to manage with some drawbacks: Fe insolubility and the formation of toxic radicals, especially the hydroxyl radical. Iron chemistry within biology is an example of how organisms evolved by creating molecular machinery to overcome these difficulties and perform crucial processes with extraordinary elegance and efficiency. © 2017 IUBMB Life, 69(6):382-388, 2017.
Topics: Biological Transport; Coordination Complexes; Eukaryota; Hemoglobins; Hydroxyl Radical; Iron; Iron-Sulfur Proteins; Myoglobin; Oxidation-Reduction; Oxygen; Prokaryotic Cells
PubMed: 28150902
DOI: 10.1002/iub.1602 -
Frontiers in Immunology 2023To investigate the characteristics of cardiac involvement due to Immune-mediated Necrotizing Myopathy (IMNM).
OBJECTIVE
To investigate the characteristics of cardiac involvement due to Immune-mediated Necrotizing Myopathy (IMNM).
METHODS
Patients diagnosed with Immune-mediated Necrotizing Myopathy (IMNM) who attended the Department of Neurology and the Department of Rheumatology and Immunology at the First Medical Center of the PLA General Hospital between February 2011 and June 2022 were collected. Clinicopathological diagnosis of IMNM was performed according to the criteria established by the European Neuromuscular Center (ENMC). All patients underwent muscle biopsy and Myositis-specific antibodies (MSAs) testing. Information included age, gender, disease duration, intramuscular and extramuscular manifestations, laboratory findings (including creatine kinase, lactate dehydrogenase levels, troponin T, myoglobin and atrial natriuretic peptide), electromyography, skeletal muscle pathology and immunohistochemical staining.
RESULTS
A total of 57 patients were included in this study. Of the serological tests, 56.1% (32/57) were positive for SRP, 21.1% (12/57) were positive for HMGCR and 22.8% (13/57) were seronegative. Thirty patients (52.6%, 30/57) presented with varying degrees of cardiac involvement. We performed ECG in 23 patients and found 6 patients with arrhythmia (26.1%), 12 patients with myocardial ischemia (52.2%), and 7 patients with acute coronary syndrome (ST elevation and non-ST elevation myocardial infarction) (30.4%), and 4 patients with left axis deviation or left ventricular high voltage, suggesting left ventricular hypertrophy (17.4%). Cardiac ultrasound was performed in 14 patients and 3 showed pericardial effusion (21.4%); Decreased left ventricular ejection fraction and atrial enlargement were 2 each; 8 showed a decrease in left ventricular diastolic function (57.1%). In addition, one patient had myocardial edema.
CONCLUSION
Cardiac involvement is not uncommon in IMNM. However, besides clearly statistically significant differences in the disease course, and in the values of troponin T and myoglobin, our data did not show any statistically significant difference in other features of cardiac involvement between patients with different subtypes of IMNM.
Topics: Humans; Myoglobin; Stroke Volume; Troponin T; Autoantibodies; Necrosis; Ventricular Function, Left; Myositis; Autoimmune Diseases; Soft Tissue Injuries
PubMed: 36926343
DOI: 10.3389/fimmu.2023.1094611 -
Scientific Reports Sep 2022Immunity with SARS-CoV-2 infection during the acute phase is not sufficiently well understood to differentiate mild from severe cases and identify prognostic markers. We...
Immunity with SARS-CoV-2 infection during the acute phase is not sufficiently well understood to differentiate mild from severe cases and identify prognostic markers. We evaluated the immune response profile using a total of 71 biomarkers in sera from patients with SARS-CoV-2 infection, confirmed by RT-PCR and controls. We correlated biological marker levels with negative control (C) asymptomatic (A), nonhospitalized (mild cases-M), and hospitalized (severe cases-S) groups. Among angiogenesis markers, we identified biomarkers that were more frequently elevated in severe cases when compared to the other groups (C, A, and M). Among cardiovascular diseases, there were biomarkers with differences between the groups, with D-dimer, GDF-15, and sICAM-1 higher in the S group. The levels of the biomarkers Myoglobin and P-Selectin were lower among patients in group M compared to those in groups S and A. Important differences in cytokines and chemokines according to the clinical course were identified. Severe cases presented altered levels when compared to group C. This study helps to characterize biological markers related to angiogenesis, growth factors, heart disease, and cytokine/chemokine production in individuals infected with SARS-CoV-2, offering prognostic signatures and a basis for understanding the biological factors in disease severity.
Topics: Biomarkers; COVID-19; Chemokines; Cytokines; Growth Differentiation Factor 15; Humans; Myoglobin; P-Selectin; SARS-CoV-2
PubMed: 36163447
DOI: 10.1038/s41598-022-20062-5 -
Journal of the American College of... Apr 2023Peripheral arterial disease (PAD) causes leg muscle damage due to inadequate perfusion and increases cardiovascular events and mortality 2- to 3-fold. It is unclear if...
BACKGROUND
Peripheral arterial disease (PAD) causes leg muscle damage due to inadequate perfusion and increases cardiovascular events and mortality 2- to 3-fold. It is unclear if PAD is a biomarker for high-risk cardiovascular disease or if skeletal muscle injury harms arterial health. The objective of this work is to test if serum myoglobin levels (myoglobinemia) are a marker of PAD, and if so, whether myoglobin impairs vascular health.
STUDY DESIGN
Patient blood samples were collected from PAD and control (no PAD) patients and interrogated for myoglobin concentrations and nitric oxide bioavailability. Patient mortality over time was captured from the medical record. Myoglobin activity was tested on endothelial cells and arterial function.
RESULTS
Myoglobin is a biomarker for symptomatic PAD and was inversely related to nitric oxide bioavailability; 200 ng/mL myoglobin in vitro increased endothelial cell permeability in vitro and decreased nitrate bioavailability. Ex vivo, 100 ng/mL myoglobin increased vascular tone in naive murine aortas approximately 1.5 times, impairing absolute vessel relaxation. In vivo, we demonstrated that myoglobinemia caused impaired flow-mediated dilation in a porcine model. Patients presenting with myoglobin levels of 100 ng/mL or greater had significantly more deaths than those with myoglobin levels of less than 100 ng/mL.
CONCLUSIONS
Using a combination of patient data, in vitro, ex vivo, and in vivo testing, we found that myoglobin is a biomarker for symptomatic PAD and a potent regulator of arterial health that can increase vascular tone, increase vascular permeability, and cause endothelial dysfunction, all of which may contribute to the vulnerability of PAD patients to cardiovascular events and death.
Topics: Animals; Mice; Swine; Endothelial Cells; Nitric Oxide; Myoglobin; Peripheral Arterial Disease; Biomarkers
PubMed: 36656266
DOI: 10.1097/XCS.0000000000000554