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Molecular Mechanisms and Novel Therapeutic Approaches to Rhabdomyolysis-Induced Acute Kidney Injury.Kidney & Blood Pressure Research 2015Rhabdomyolysis is a syndrome caused by injury to skeletal muscle that usually leads to acute kidney injury (AKI). Rhabdomyolysis has been linked to different conditions,... (Review)
Review
Rhabdomyolysis is a syndrome caused by injury to skeletal muscle that usually leads to acute kidney injury (AKI). Rhabdomyolysis has been linked to different conditions, including severe trauma and intense physical exercise. Myoglobin-induced renal toxicity plays a key role in rhabdomyolysis-associated kidney damage by increasing oxidative stress, inflammation, endothelial dysfunction, vasoconstriction, and apoptosis. New drugs that target the harmful effects of myoglobin have been recently developed, and some have been proven to be successful in animal models of acute renal failure secondary to rhabdomyolysis. This review aims to provide a comprehensive and updated overview of the pathological mechanisms of renal damage and describes new therapeutic approaches to this condition based on novel compounds that target key pathways involved in myoglobin-mediated kidney damage.
Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Humans; Iron Chelating Agents; Muscle, Skeletal; Myoglobin; Oxidative Stress; Rhabdomyolysis
PubMed: 26512883
DOI: 10.1159/000368528 -
International Journal of Environmental... Aug 2022The aim of this study was to determine if 1 h after a cycling race, changes in plasma creatine kinase activity (CK) and myoglobin concentrations (MB) differ between...
The aim of this study was to determine if 1 h after a cycling race, changes in plasma creatine kinase activity (CK) and myoglobin concentrations (MB) differ between mountain bike and road cyclists and if these changes show any correlation with race performance. Male mountain bike cyclists ( = 11) under 23 years old and male road cyclists ( = 14), also under 23 years old, were studied following one of their respective races. The cyclists had blood drawn 2 h before and 1 h after the race to assess CK and MB, then the change in pre- and post-race difference was calculated (ΔCK and ΔMB). Each cyclist's performance time was recorded and the time difference from the winner was calculated (T). The cyclists' aerobic capacity was assessed during the incremental test, which determines maximal oxygen uptake and maximal aerobic power. It was observed that 1 h after the cycling race, CK ( = 0.001, = 0.40, = 15.6) and MB ( = 0.000, = 0.43, = 17.2) increased, compared to pre-race values. Post-race CK increased only in road cyclists, while post-race MB increased only in mountain bike cyclists. Smaller T were found for lower ΔMB in road cyclists but for higher ΔCK in mountain bike cyclists.
Topics: Adult; Bicycling; Creatine Kinase; Exercise Tolerance; Humans; Male; Myoglobin; Young Adult
PubMed: 35954814
DOI: 10.3390/ijerph19159456 -
Advanced Science (Weinheim,... Nov 2022The surface of a carboxylate-enriched octuple mutant of Bacillus subtilis lipase A (8M) is chemically anionized to produce core (8M)-shell (cationic polymer surfactants)...
The surface of a carboxylate-enriched octuple mutant of Bacillus subtilis lipase A (8M) is chemically anionized to produce core (8M)-shell (cationic polymer surfactants) bionanoconjugates in protein liquid form, which are termed anion-type biofluids. The resultant lipase biofluids exhibit a 2.5-fold increase in hydrolytic activity when compared with analogous lipase biofluids based on anionic polymer surfactants. In addition, the applicability of the anion-type biofluid using Myoglobin (Mb) that is well studied in anion-type solvent-free liquid proteins is evaluated. Although anionization resulted in the complete unfolding of Mb, the active α-helix level is partially recovered in the anion-type biofluids, and the effect is accentuated in the cation-type Mb biofluids. These highly active anion-type solvent-free liquid enzymes exhibit increased thermal stability and provide a new direction in solvent-free liquid protein research.
Topics: Solvents; Lipase; Surface-Active Agents; Hydrolysis; Polymers; Myoglobin
PubMed: 35988154
DOI: 10.1002/advs.202202359 -
JCI Insight Oct 2022BACKGROUNDDuring aging, there is a functional decline in the pool of muscle stem cells (MuSCs) that influences the functional and regenerative capacity of skeletal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUNDDuring aging, there is a functional decline in the pool of muscle stem cells (MuSCs) that influences the functional and regenerative capacity of skeletal muscle. Preclinical evidence has suggested that nicotinamide riboside (NR) and pterostilbene (PT) can improve muscle regeneration, e.g., by increasing MuSC function. The objective of this study was to investigate if supplementation with NR and PT (NRPT) promotes skeletal muscle regeneration after muscle injury in elderly individuals by improved recruitment of MuSCs.METHODSThirty-two elderly individuals (55-80 years of age) were randomized to daily supplementation with either NRPT (1,000 mg NR and 200 mg PT) or matched placebo. Two weeks after initiation of supplementation, skeletal muscle injury was induced by electrically induced eccentric muscle work. Skeletal muscle biopsies were obtained before, 2 hours after, and 2, 8, and 30 days after injury.RESULTSA substantial skeletal muscle injury was induced by the protocol and associated with release of myoglobin and creatine kinase, muscle soreness, tissue edema, and a decrease in muscle strength. MuSC content, proliferation, and cell size revealed a large demand for recruitment after injury, but this was not affected by NRPT. Furthermore, histological analyses of muscle fiber area, central nuclei, and embryonic myosin heavy chain showed no NRPT supplementation effect.CONCLUSIONDaily supplementation with 1,000 mg NR and 200 mg PT is safe but does not improve recruitment of the MuSC pool or other measures of muscle recovery in response to injury or subsequent regeneration in elderly individuals.TRIAL REGISTRATIONClinicalTrials.gov NCT03754842.FUNDINGNovo Nordisk Foundation (NNF17OC0027242) and Novo Nordisk Foundation CBMR.
Topics: Aged; Creatine Kinase, MM Form; Dietary Supplements; Humans; Muscle, Skeletal; Muscular Diseases; Myoglobin; Myosin Heavy Chains; Niacinamide; Pyridinium Compounds; Stilbenes
PubMed: 35998039
DOI: 10.1172/jci.insight.158314 -
The Journal of Sports Medicine and... Dec 2023Monitoring muscle damage in athletes assists not only coaches to adjust the training workload but also medical staff to prevent injury. Measuring blood myoglobin...
BACKGROUND
Monitoring muscle damage in athletes assists not only coaches to adjust the training workload but also medical staff to prevent injury. Measuring blood myoglobin concentration can help evaluate muscle damage. The novel portable device utilized in this study allows for easy on-site measurement of myoglobin, providing real-time data on the player's muscle damage. This study investigated the relationship between external load (global positioning system parameters) and internal loads (myoglobin concentration and creatine kinase activity) in 15 male professional football players before and after a match.
METHODS
Whole blood samples from participants' fingertips were collected before the match (baseline) and at 2, 16, and 40 h after the match. Myoglobin concentrations were measured using the IA-100 compact immunoassay system. Creatine kinase concentrations were measured in a clinical laboratory, and match loads were monitored using a global positioning system device.
RESULTS
The mean myoglobin concentration was significantly higher at 2 h than at the other time points (P<0.05), and decreased to baseline levels within 16 h post-match. The mean creatine kinase concentration increased after the match but did not reach a significant level. Muscle damage monitored by myoglobin after football match-play was strongly associated with acceleration/deceleration metrics rather than the sprint/high-speed running distance.
CONCLUSIONS
Our findings indicate that myoglobin is a more sensitive marker of muscle damage than creatine kinase after football match-play. Monitoring myoglobin in athletes can aid in determining their recovery status from the previous training load and help practitioners manage the training load.
Topics: Humans; Male; Acceleration; Athletic Performance; Creatine Kinase; Deceleration; Geographic Information Systems; Muscles; Myoglobin; Soccer
PubMed: 37712927
DOI: 10.23736/S0022-4707.23.15203-0 -
PloS One 2022Myoglobin (MB) is known to bind and deliver oxygen in striated muscles at high expression levels. MB is also expressed at much reduced levels in mammary epithelial...
Myoglobin (MB) is known to bind and deliver oxygen in striated muscles at high expression levels. MB is also expressed at much reduced levels in mammary epithelial cells, where the protein´s function is unclear. In this study, we aim to determine whether MB impacts fatty acid trafficking and facilitates aerobic fatty acid ß-oxidation in mammary epithelial cells. We utilized MB-wildtype versus MB-knockout mice and human breast cancer cells to examine the impact of MB and its oxygenation status on fatty acid metabolism in mouse milk and mammary epithelia. MB deficient cells were generated through CRISPR/Cas9 and TALEN approaches and exposed to various oxygen tensions. Fatty acid profiling of milk and cell extracts were performed along with cell labelling and immunocytochemistry. Our findings show that MB expression in mammary epithelial cells promoted fatty acid oxidation while reducing stearyl-CoA desaturase activity for lipogenesis. In cells and milk product, presence of oxygenated MB significantly elevated indices of limited fatty acid ß-oxidation, i.e., the organelle-bound removal of a C2 moiety from long-chain saturated or monounsaturated fatty acids, thus shifting the composition toward more saturated and shorter fatty acid species. Presence of the globin also increased cytoplasmic fatty acid solubility under normoxia and fatty acid deposition to lipid droplets under severe hypoxia. We conclude that MB can function in mammary epithelia as intracellular O2-dependent shuttle of oxidizable fatty acid substrates. MB's impact on limited oxidation of fatty acids could generate inflammatory mediator lipokines, such as 7-hexadecenoate. Thus, the novel functions of MB in breast epithelia described herein range from controlling fatty acid turnover and homeostasis to influencing inflammatory signalling cascade. Future work is needed to analyse to what extent these novel roles of MB also apply to myocytic cell physiology and malignant cell behaviour, respectively.
Topics: Animals; Cell Extracts; Epithelial Cells; Fatty Acids; Fatty Acids, Monounsaturated; Humans; Inflammation Mediators; Lipid Metabolism; Mammary Glands, Animal; Mice; Myoglobin; Oxygen; Stearoyl-CoA Desaturase; Transcription Activator-Like Effector Nucleases
PubMed: 36223378
DOI: 10.1371/journal.pone.0275725 -
Blood Purification 2022The role of extracorporeal myoglobin removal in the treatment of rhabdomyolysis-associated severe acute kidney injury (AKI) is not yet fully established. High cut-off...
INTRODUCTION
The role of extracorporeal myoglobin removal in the treatment of rhabdomyolysis-associated severe acute kidney injury (AKI) is not yet fully established. High cut-off (HCO) and medium cut-off (MCO) dialysis membrane and cytokine adsorber (CytoSorb®) have been used to this purpose in clinical practice. The data on comparative effectiveness of those methods are scarce.
METHODS
In this single-center retrospective study, we included patients with AKI and concomitant rhabdomyolysis (myoglobin >20,000 μg/L), who underwent at least one extracorporeal myoglobin removal procedure. The main outcome parameter was myoglobin reduction ratio, whereas albumin was assessed as a safety parameter.
RESULTS
We analyzed data for 15 patients, who underwent 28 procedures (13 HCO, 9 MCO, and 6 adsorber). Pre-treatment serum myoglobin levels were similar between the groups and myoglobin reduction was significant in HCO (p = 0.03) and MCO groups (p < 0.01) and borderline significant in adsorber group (p = 0.06). Reduction ratios were comparable between the groups (median 0.64 (inter-quartile range IQR 0.13-0.72), 0.54 (IQR 0.51-0.61) and 0.50 (IQR 0.37-0.62), respectively, p = 0.83). Both pre- and post-procedure serum albumin levels were significantly lower in the MCO group. However, with routine albumin substitution in the HCO group only, serum albumin remained stable during the procedures in all subgroups.
CONCLUSIONS
Novel MCO membrane might represent the optimal mode of treatment of severe rhabdomyolysis-associated AKI, as it allows for efficient removal of myoglobin, avoids albumin supplementation and is associated with lower costs. For patients requiring cytokine removal, the adsorption capsule can simultaneously reduce cytokine and myoglobin levels.
Topics: Humans; Acute Kidney Injury; Cytokines; Myoglobin; Renal Dialysis; Retrospective Studies; Rhabdomyolysis; Serum Albumin
PubMed: 35340002
DOI: 10.1159/000521923 -
Frontiers in Immunology 2023The novel coronavirus disease 2019 (COVID-19) presents with complex pathophysiological effects in various organ systems. Following the COVID-19, there are shifts in...
BACKGROUND
The novel coronavirus disease 2019 (COVID-19) presents with complex pathophysiological effects in various organ systems. Following the COVID-19, there are shifts in biomarker and cytokine equilibrium associated with altered physiological processes arising from viral damage or aggressive immunological response. We hypothesized that high daily dose methylprednisolone improved the injury biomarkers and serum cytokine profiles in COVID-19 patients.
METHODS
Injury biomarker and cytokine analysis was performed on 50 SARS-Cov-2 negative controls and 101 hospitalized severe COVID-19 patients: 49 methylprednisolone-treated (MP group) and 52 placebo-treated serum samples. Samples from the treated groups collected on days D1 (pre-treatment) all the groups, D7 (2 days after ending therapy) and D14 were analyzed. Luminex assay quantified the biomarkers HMGB1, FABP3, myoglobin, troponin I and NTproBNP. Immune mediators (CXCL8, CCL2, CXCL9, CXCL10, TNF, IFN-γ, IL-17A, IL-12p70, IL-10, IL-6, IL-4, IL-2, and IL-1β) were quantified using cytometric bead array.
RESULTS
At pretreatment, the two treatment groups were comparable demographically. At pre-treatment (D1), injury biomarkers (HMGB1, TnI, myoglobin and FABP3) were distinctly elevated. At D7, HMGB1 was significantly higher in the MP group (p=0.0448) compared to the placebo group, while HMGB1 in the placebo group diminished significantly by D14 (p=0.0115). Compared to healthy control samples, several immune mediators (IL-17A, IL-6, IL-10, MIG, MCP-1, and IP-10) were considerably elevated at baseline (all p≤0.05). At D7, MIG and IP-10 of the MP-group were significantly lower than in the placebo-group (p=0.0431, p=0.0069, respectively). Longitudinally, IL-2 (MP-group) and IL-17A (placebo-group) had increased significantly by D14. In placebo group, IL-2 and IL-17A continuously increased, as IL-12p70, IL-10 and IP-10 steadily decreased during follow-up. The MP treated group had IL-2, IFN-γ, IL-17A and IL-12p70 progressively increase while IL-1β and IL-10 gradually decreased towards D14. Moderate to strong positive correlations between chemokines and cytokines were observed on D7 and D14.
CONCLUSION
These findings suggest MP treatment could ameliorate levels of myoglobin and FABP3, but appeared to have no impact on HMGB1, TnI and NTproBNP. In addition, methylprednisolone relieves the COVID-19 induced inflammatory response by diminishing MIG and IP-10 levels. Overall, corticosteroid (methylprednisolone) use in COVID-19 management influences the immunological molecule and injury biomarker profile in COVID-19 patients.
Topics: Humans; Cytokines; Interleukin-10; HMGB1 Protein; Interleukin-17; Methylprednisolone; Chemokine CXCL10; Interleukin-2; Interleukin-6; Myoglobin; COVID-19; SARS-CoV-2; Interleukin-12
PubMed: 37662953
DOI: 10.3389/fimmu.2023.1229611 -
Medicina (Kaunas, Lithuania) Oct 2022: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection represents a pathology with primary pulmonary involvement and multisystemic impact, including... (Observational Study)
Observational Study
: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection represents a pathology with primary pulmonary involvement and multisystemic impact, including cardiovascular injuries. The present study aimed to assess the value of clinical, biochemical, and imaging factors in COVID-19 patients in determining the severity of myocardial involvement, and to create a model that can be used toevaluate myocardial injury risk based on clinical, biochemical and imaging factors. : We performed an observational cohort study on 150 consecutive patients, evaluating their age, sex, hospitalization period, peripheral oxygen saturation (SpO) in ambient air, systolic and diastolic blood pressure, heart rate, respiratory rate, biochemical markers of cardiac dysfunction (TnI, and NT-proBNP), inflammatory markers (C reactive protein (CRP), fibrinogen, serum ferritin, interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα)), D-dimers, lactate dehydrogenase (LDH), myoglobin and radio-imaging parameters. All patients underwent computerized tomography chest scan in the first two days following admission. : We observed elevated heart and respiratory rates, higher systolic blood pressure, and a lower diastolic blood pressure in the patients with cardiac injury; significant differences between groups were registered in TnI, NT-proBNP, LDH, CRP, and D-dimers. For the radiological parameters, we found proportional correlations with the myocardial injury for the severity of lung disease, number of pulmonary segments with alveolar consolidation, number of pulmonary lobes with pneumonia, crazy paving pattern, type of lung involvement, the extent of fibroatelectatic lesions and the mediastinal adenopathies. : Myocardial injury occurred in 12% of patients in the study group. Ground glass opacities, interstitial interlobular septal thickening (crazy paving pattern), fibroatelectasic lesions and alveolar consolidations on CT scan were correlated with myocardial injury. Routine lung sectional imaging along with non-specific biomarkers (LDH, D-dimers, and CRP) can be further valuable in the characterization of the disease burden, thus impacting patient care.
Topics: Humans; COVID-19; SARS-CoV-2; Interleukin-6; Tumor Necrosis Factor-alpha; C-Reactive Protein; Myoglobin; Lung; Biomarkers; Lactate Dehydrogenases; Ferritins; Retrospective Studies
PubMed: 36295594
DOI: 10.3390/medicina58101436 -
Biochemistry. Biokhimiia Dec 2016In addition to reversible O2 binding, respiratory proteins of the globin family, hemoglobin (Hb) and myoglobin (Mb), participate in redox reactions with various metal... (Review)
Review
In addition to reversible O2 binding, respiratory proteins of the globin family, hemoglobin (Hb) and myoglobin (Mb), participate in redox reactions with various metal complexes, including biologically significant ones, such as those of copper and iron. HbO and MbO are present in cells in large amounts and, as redox agents, can contribute to maintaining cell redox state and resisting oxidative stress. Divalent copper complexes with high redox potentials (E, 200-600 mV) and high stability constants, such as [Cu(phen)], [Cu(dmphen)], and CuDTA oxidize ferrous heme proteins by the simple outer-sphere electron transfer mechanism through overlapping π-orbitals of the heme and the copper complex. Weaker oxidants, such as Cu2+, CuEDTA, CuNTA, CuCit, CuATP, and CuHis (E ≤ 100-150 mV) react with HbO and MbO through preliminary binding to the protein with substitution of the metal ligands with protein groups and subsequent intramolecular electron transfer in the complex (the site-specific outer-sphere electron transfer mechanism). Oxidation of HbO and MbO by potassium ferricyanide and Fe(3) complexes with NTA, EDTA, CDTA, ATP, 2,3-DPG, citrate, and pyrophosphate PP proceeds mainly through the simple outer-sphere electron transfer mechanism via the exposed heme edge. According to Marcus theory, the rate of this reaction correlates with the difference in redox potentials of the reagents and their self-exchange rates. For charged reagents, the reaction may be preceded by their nonspecific binding to the protein due to electrostatic interactions. The reactions of LbO with carboxylate Fe complexes, unlike its reactions with ferricyanide, occur via the site-specific outer-sphere electron transfer mechanism, even though the same reagents oxidize structurally similar MbO and cytochrome b via the simple outer-sphere electron transfer mechanism. Of particular biological interest is HbO and MbO transformation into met-forms in the presence of small amounts of metal ions or complexes (catalysis), which, until recently, had been demonstrated only for copper compounds with intermediate redox potentials. The main contribution to the reaction rate comes from copper binding to the "inner" histidines, His97 (0.66 nm from the heme) that forms a hydrogen bond with the heme propionate COO group, and the distal His64. The affinity of both histidines for copper is much lower than that of the surface histidines residues, and they are inaccessible for modification with chemical reagents. However, it was found recently that the high-potential Fe(3) complex, potassium ferricyanide (400 mV), at a 5 to 20% of molar protein concentration can be an efficient catalyst of MbO oxidation into metMb. The catalytic process includes binding of ferrocyanide anion in the region of the His119 residue due to the presence there of a large positive local electrostatic potential and existence of a "pocket" formed by Lys16, Ala19, Asp20, and Arg118 that is sufficient to accommodate [Fe(CN)]. Fast, proton-assisted reoxidation of the bound ferrocyanide by oxygen (which is required for completion of the catalytic cycle), unlike slow [Fe(CN)] oxidation in solution, is provided by the optimal location of neighboring protonated His113 and His116, as it occurs in the enzyme active site.
Topics: Animals; Copper; Hemoglobins; Humans; Iron Compounds; Myoglobin; Oxidation-Reduction
PubMed: 28260494
DOI: 10.1134/S0006297916130101