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WO2024088066A1 - Marqueur de diagnostic de sarcopénie et son utilisation - Google Patents

Marqueur de diagnostic de sarcopénie et son utilisation Download PDF

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Publication number
WO2024088066A1
WO2024088066A1 PCT/CN2023/124108 CN2023124108W WO2024088066A1 WO 2024088066 A1 WO2024088066 A1 WO 2024088066A1 CN 2023124108 W CN2023124108 W CN 2023124108W WO 2024088066 A1 WO2024088066 A1 WO 2024088066A1
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protein
sarcopenia
sample
oxidized
subject
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Chinese (zh)
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朱大海
武日茂
李虎
张勇
符祥
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Bioisland Laboratory
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/978—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
    • G01N2333/98—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5) acting on amide bonds in linear amides (3.5.1)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/10—Musculoskeletal or connective tissue disorders

Definitions

  • the present invention belongs to the field of biological detection, and specifically relates to diagnostic markers for sarcopenia and applications thereof.
  • Sarcopenia is an aging-related disease caused by a progressive systemic loss of muscle mass and muscle function. Sarcopenia increases the risk of falls and fractures, reduces patients' ability to live in daily life, and is associated with heart disease, respiratory diseases, and cognitive impairment. It can lead to motor dysfunction, decreased quality of life, loss of independent living ability, or long-term need for care from others, and increased risk of death.
  • sarcopenia also increases the risk of hospitalization, increases the cost of care during hospitalization, and increases hospitalization expenses. Therefore, sarcopenia not only seriously reduces the quality of life of the elderly, but also increases the economic burden on family and social care for the elderly.
  • the diagnosis of sarcopenia also mainly relies on clinical criteria, including case screening through the SARC-F (Simple 5-item rating scale, including Strength, Assistance in walking, Rise from a chair, Climb stairs and Falls) scale, muscle strength test, muscle mass test and creatine dilution test.
  • SARC-F questionnaire method consists of a 5-item questionnaire, which is self-reported by patients and obtains the characteristics of sarcopenia from the signs reported by patients themselves. Patients respond based on their perception of limited strength, walking ability, ability to stand up from a chair and climb stairs, and the experience of falling.
  • the SARC-F scale is self-reported by patients, the results will be affected by the patients' subjective conclusions about adverse results.
  • the present disclosure provides a biomarker for sarcopenia and related applications thereof.
  • a reagent for detecting a biomarker in preparing a diagnostic reagent for sarcopenia, wherein the biomarker comprises Parkinson's disease-associated deglycosylation (DJ-1) protein.
  • DJ-1 Parkinson's disease-associated deglycosylation
  • the 46th, 53rd, 106th and/or 121st cysteine residues of the DJ-1 protein are Acids are oxidizing forms.
  • the cysteine at position 46, 53, 106 and/or 121 of the DJ-1 protein is oxidized.
  • the cysteine at position 46 of the DJ-1 protein is oxidized.
  • the cysteine at position 53 of the DJ-1 protein is oxidized.
  • the cysteine at position 106 of the DJ-1 protein is oxidized.
  • the cysteine at position 121 of the DJ-1 protein is oxidized.
  • the diagnostic reagent is used to detect the level of the biomarker in a sample from a subject.
  • the sample is selected from a blood sample, a serum sample, a plasma sample, a saliva sample and a urine sample, or an extract of any of the samples mentioned above.
  • the sample is a blood sample, more preferably a serum sample or a plasma sample.
  • the control sample can be a sample from a healthy person.
  • the subject when the expression level (i.e., expression amount) of the DJ-1 protein in the sample from the subject is significantly higher than that in the control sample, the subject is judged to suffer from sarcopenia or to have a high risk of suffering from sarcopenia.
  • expression level i.e., expression amount
  • the subject when the expression level of DJ-1 protein in which one or more of cysteines at positions 46, 53, 106 and 121 are oxidized in the sample from the subject is significantly higher than that in the control sample, the subject is judged to suffer from sarcopenia or to have a high risk of suffering from sarcopenia. In a preferred embodiment, when the expression level of DJ-1 protein in which cysteines at positions 46 and/or 106 are oxidized in the sample from the subject is significantly higher than that in the control sample, the subject is judged to suffer from sarcopenia or to have a high risk of suffering from sarcopenia.
  • the expression level of the DJ-1 protein at the transcription or protein level in a sample can be detected.
  • the detection can be any type of detection method used in the field of diagnostics.
  • the detection can include immunoassays, such as radioimmunoassays (RIA), chemiluminescence and fluorescence immunoassays, enzyme-linked immunosorbent assays (ELISA), Luminex-based bead arrays, protein microarray assays, and rapid detection methods (e.g., immunochromatographic strip tests), etc.
  • the detection can include polymerase chain reaction (PCR), such as quantitative PCR (qPCR), real-time quantitative PCR (RT-PCR), etc.
  • a method for diagnosing sarcopenia comprising: providing a sample from a subject; and determining the level of the above-mentioned biomarker in the sample.
  • the method further includes: comparing the level of the biomarker from the sample with the level of the biomarker in the control sample. When the level of the biomarker from the sample is significantly higher, it can be determined that the subject suffers from sarcopenia or has a high risk of suffering from sarcopenia.
  • the subject is a human or non-human organism. In a preferred embodiment, the subject is a human.
  • a marker for diagnosing sarcopenia wherein the biomarker comprises Parkinson's Deglycosylation associated with disease (DJ-1) protein.
  • DJ-1 Parkinson's Deglycosylation associated with disease
  • the cysteine at position 46, position 53, position 106 and/or position 121 of the DJ-1 protein is reduced.
  • the cysteine at position 46, 53, 106 and/or 121 of the DJ-1 protein is oxidized.
  • the cysteine at position 46 of the DJ-1 protein is oxidized.
  • the cysteine at position 53 of the DJ-1 protein is oxidized.
  • the cysteine at position 106 of the DJ-1 protein is oxidized.
  • the cysteine at position 121 of the DJ-1 protein is oxidized.
  • FIG. 1 shows the oxidation status of cysteine at positions 46, 53, 106, and 121 of DJ-1 protein of young and old mice according to one embodiment.
  • Figure 2 shows the expression of DJ-1 protein, Cys46 oxidized DJ-1 protein and Cys106 oxidized DJ-1 protein in young mice and old mice according to one embodiment.
  • Figure 2A shows the results of western blotting;
  • Figure 2B is the grayscale statistics result of western blotting.
  • FIG3 shows the grayscale statistical results of DJ-1 protein immunoblotting in the serum of female sarcopenia patients and elderly women of the same age group according to one embodiment.
  • FIG4 shows the grayscale statistical results of DJ-1 protein immunoblotting in the serum of male sarcopenia patients and elderly men of the same age group according to one embodiment.
  • FIG. 5 shows the grayscale statistical results of immunoblotting of the oxidized DJ-1 protein at Cys 46 in the serum of female sarcopenia patients and elderly women of the same age group according to one embodiment.
  • FIG. 6 shows the grayscale statistical results of immunoblotting of the oxidized DJ-1 protein at Cys 46 in the serum of male sarcopenia patients and elderly men of the same age group according to one embodiment.
  • FIG. 7 shows the grayscale statistical results of immunoblotting of the oxidized DJ-1 protein at Cys 106 in the serum of female sarcopenia patients and elderly women of the same age group according to one embodiment.
  • FIG. 8 shows the grayscale statistical results of immunoblotting of the oxidized DJ-1 protein at Cys 106 in the serum of male sarcopenia patients and elderly men of the same age group according to one embodiment.
  • Sarcopenia is a disease caused by a progressive systemic loss of muscle mass and muscle function associated with aging. Sarcopenia has been officially identified as a muscle disease. According to the 10th edition of the International Classification of Diseases (ICD), its diagnostic code is M62.84. Sarcopenia increases the risk of falls and fractures, reduces the patient's ability to live in daily life, and is associated with heart disease, respiratory disease and cognitive impairment. It can cause patients to have motor dysfunction, a decline in quality of life, loss of independent living ability, or long-term need for care from others, and an increased risk of death. Sarcopenia also increases the risk of hospitalization, increases the cost of care during hospitalization, and increases hospitalization costs.
  • ICD International Classification of Diseases
  • EWGSOP2 European Working Group on Sarcopenia in Older People
  • EWGSOP2 uses low muscle strength as the primary parameter for evaluating sarcopenia. Muscle strength is currently the most reliable indicator for measuring muscle function. When muscle strength is lower than the diagnostic value, it indicates that sarcopenia may exist; low muscle strength and muscle mass lower than the diagnostic value or physical function assessment lower than the diagnostic value can confirm sarcopenia; when low muscle strength, muscle mass and physical function are all lower than the diagnostic value, it is diagnosed as severe sarcopenia.
  • the diagnosis of sarcopenia mainly relies on clinical criteria, and the SARC-F (Simple 5-item Rating Scale, including Strength, Assistance in walking, Rise from a chair, Climb stairs and Falls) scale is used for case screening, and then the diagnosis is made through muscle strength test and muscle mass test.
  • the SARC-F questionnaire method consists of 5 questionnaires, which are self-reported by patients, and the characteristics of sarcopenia are obtained from the signs reported by patients themselves. Patients respond based on their perception of limited strength, walking ability, ability to stand up from a chair and climb stairs, and their experience of falling.
  • Muscle mass can be measured using dual-energy X-ray absorptiometry (DXA) or bioelectrical impedance analysis (Bioelectrical impedance analysis, BAI) to measure the total skeletal muscle mass of the whole body and the skeletal muscle mass of the limbs. The device estimates muscle mass based on the conductivity of the whole body, rather than directly measuring muscle mass.
  • DXA dual-energy X-ray absorptiometry
  • Bioelectrical impedance analysis BAI
  • the SARC-F questionnaire method has low to moderate sensitivity in predicting low muscle strength and is mainly used to detect severe cases.
  • the clinician makes a preliminary judgment through muscle strength test, and then confirms the diagnosis through strength test.
  • his body function has undergone irreversible changes, and there are potential risks.
  • screening and early intervention are carried out before changes in muscle strength and muscle mass occur, it will be more conducive to the control of disease progression.
  • Sarcopenia progresses insidiously and gradually worsens.
  • Early detection, early diagnosis, and early intervention are important links in delaying the development of sarcopenia, improving the quality of life of the elderly and reducing mortality, and are effective means to obtain the maximum health benefits.
  • biomarkers include neuromuscular junctions, muscle protein conversion, behavior-mediated pathways, inflammatory-mediated pathways, redox-related factors, hormones or other anabolic markers, but no relevant biomarkers have appeared yet.
  • Biomarkers can help evaluate the effects of intervention and drug treatment to a certain extent. By testing biomarkers once before and after the intervention, the effect of intervention or treatment can be evaluated by analyzing the changes in biomarkers. The progression of the disease can also be predicted through long-term monitoring of biomarkers, and later intervention and supervision can be actively carried out. On the other hand, biomarkers can be used in drug development and for evaluating the effectiveness of drugs.
  • DJ-1 also known as Parkinson's disease-associated deglycosylation
  • L166P leucine 166
  • DJ-1 protein is a secretory protein and can be detected using blood or serum samples, making clinical detection relatively easy.
  • sarcopenia refers to a disease caused by a progressive systemic decrease in muscle mass and strength associated with aging.
  • Sarcopenia is a muscle-related disease associated with aging. During the aging process, oxidative free radicals accumulate in the body, changing the redox state of cells, and reducing redox homeostasis, leading to skeletal muscle dysfunction. Based on this, the accumulation of oxidized proteins in cells may serve as a molecular marker for sarcopenia.
  • the present invention uses redox protein spectrum technology to compare and analyze the different redox proteins in the skeletal muscle tissue of young and old mice, and screens and identifies DJ-1 protein as a biomarker for sarcopenia for early screening and diagnosis.
  • DJ-1 protein has multiple cysteines, for example, human DJ-1 protein has three cysteine residues, namely Cys46, Cys53 and Cys106; mouse DJ-1 has four cysteine residues, namely Cys46, Cys53, Cys106 and Cys121. It is known that these cysteine residues of DJ-1 protein can be oxidized in response to cellular oxidative stress.
  • Cysteine can form 3 different oxidized forms, cysteine-sulfenic acid (Cys-SOH), cysteine-sulfinic acid (Cys-SO 2 H) and cysteine-sulfonic acid (Cys-SO 3 H). It has been reported that DJ-1 can regulate transcription factors by oxidizing Cys106, showing an antioxidant defense effect. DJ-1 is known to be associated with Parkinson's disease and cancer, but no studies have shown the relationship between DJ-1 and sarcopenia.
  • DJ-1 and its cysteine (Cys) oxidized form are highly correlated with sarcopenia, and can be used as marker molecules to accurately diagnose sarcopenia or screen for sarcopenia in its early stages.
  • the "oxidized form" of cysteine herein means that the cysteine at the corresponding site in the DJ-1 protein is oxidized to form sulfinic acid and sulfonic acid forms.
  • the present invention uses redox mass spectrometry to compare secretory proteins with significant differences in the bones of young and old mice, and unexpectedly finds that DJ-1 and oxidized DJ-1 (Cys46/Cys106) levels are significantly increased in the serum of sarcopenia patients. Therefore, they can be used as potential molecular markers for sarcopenia and can be used for early prevention and screening of sarcopenia, monitoring of disease progression, and monitoring and evaluation during later drug or physical interventions.
  • diagnosis refers to the process of determining and/or identifying a possible disease of a subject, i.e., the diagnostic process, and also refers to the opinion obtained by the procedure, i.e., the diagnostic opinion. Therefore, it can also be regarded as an attempt to classify the condition of a subject into separate and distinct categories in order to make medical decisions about treatment and prognosis. It should be understood that in a preferred embodiment, the process is performed in vitro, i.e., not on the human or animal body.
  • subject refers to a living human or non-human organism.
  • the subject is preferably a human subject.
  • test samples refers to a body fluid sample obtained for diagnosis, prognosis or evaluation of a target subject (e.g., a patient).
  • Preferred test samples include blood, serum, plasma, urine and saliva.
  • certain test samples may be more easily analyzed after a fractionation or purification step, such as separation of whole blood into serum or plasma components.
  • the level of a biomarker in a sample is "significantly" higher than that in a control sample, which is determined by statistical significance level analysis. Statistical significance is usually determined by comparing samples from multiple subjects and determining confidence intervals and/or p-values. Preferably, when compared to the control, the p-value for the biomarker level of the sample to be tested is 0.05 or less, preferably 0.01 or less, more preferably 0.001 or less, then the biomarker level is judged to be significantly higher than the control sample, with a significant difference.
  • protein reduction mass spectrometry was used to compare and analyze the proteins with significant changes in skeletal muscle tissue of young (3 months old) and old (22 months old) mice, and then a joint analysis was performed with the disease database (Gene Card/Disgenet) and the secretome database (https://www.proteinatlas.org/humanproteome/blood+protein/secretome#predicting_secreted_proteins).
  • the protein reduction mass spectrometry experiment includes the following steps. First, the tibialis anterior muscle of mice was collected and protein was extracted using 4% sodium deoxycholate (SDC) detergent (Thermo Scientific TM ). The protein concentration was detected by the Pierce TM BCA protein assay kit (Thermo Fisher Scientific), and the protein concentration of each sample was diluted to 2 mg/mL using 4% SDC detergent. 1 mg (0.5 mL of whole protein extract) was taken for protein reduction state determination.
  • SDC sodium deoxycholate
  • Iodoacetamide alkyne was added at a final concentration of 0.1 mM and reacted at room temperature for 1 hour; Diazo Biotin-Azide, 10 mM vitamin C, 2.5 mM THPTA (tris (3-hydroxypropyltriazolemethyl) amine) and 0.5 mM copper sulfate were added at a final concentration of 0.2 mM and reacted at room temperature for 2 hours.
  • the protein was purified by acetone precipitation and digested with trypsin at 37 °C. After digestion, the reduced cysteine peptides were enriched using streptavidin-agarose beads, and the enriched peptides were eluted using 100 mM sodium thiosulfite.
  • the peptides were analyzed using an Orbitrap Eclipse three-in-one high-resolution mass spectrometer (Thermo Fisher), and the mass spectrometry results were qualitatively and quantitatively analyzed using MaxQuant.
  • Protein reduction mass spectrometry was performed on the tibialis anterior muscles of 3-month-old (young) and 22-month-old (old) mice, and proteins with increased oxidation sites in the skeletal muscle of old mice were identified through bioinformatics analysis (e.g., using Hiplot or Sangerbox 3.0). Then, the intersection was taken with the disease database (Gene Card/Disgenet) and the secretory proteome database. The secretory protein DJ-1 protein with increased oxidation state in old mice was screened out.
  • the DJ-1 protein of mouse skeletal muscle (Genbank No: NP_065594.2) has four cysteine (Cys) oxidation sites, namely the 46th, 53rd, 106th and 121st amino acids.
  • This example focuses on the DJ-1 protein and the oxidation status of Cys at positions 46 and 106.
  • the DJ-1 protein (Proteintech, Western blotting was performed with primary antibodies against DJ-1 protein oxidized at position 46 (oxDJ-1(Cys46), homemade) and DJ-1 protein oxidized at position 106 (oxDJ-1(Cys106), Merk, #MABN1773), and goat anti-mouse IgG secondary antibody (Biosharp, BL001A) or goat anti-rabbit IgG secondary antibody (Biosharp, BL003A).
  • the results showed that the amounts of DJ-1 protein, DJ-1 protein oxidized at position 46 and DJ-1 protein oxidized at position 106 in the serum of old mice were significantly higher than those in young mice (Figure 2A).
  • DJ-1 protein, oxidized DJ-1 protein at position 46 and oxidized DJ-1 protein at position 106 can be used as molecular markers for sarcopenia in human subjects.
  • 20 serum samples were collected from normal elderly people aged 80 to 100 years old (female grip strength>18kg, male grip strength>28kg), including 12 male samples and 8 female samples.
  • 30 serum samples of sarcopenia patients (female grip strength ⁇ 18kg, male grip strength ⁇ 28kg), including 16 male samples and 14 female samples.
  • Figure 3 shows the grayscale statistical results of female DJ-1 protein immunoblotting, showing that the DJ-1 level in the serum of female sarcopenia patients is significantly higher than that of normal elderly women.
  • Figure 4 shows the grayscale statistical results of male DJ-1 protein immunoblotting, also showing that the DJ-1 level in the serum of male sarcopenia patients is significantly higher than that of normal male serum of the same age group.

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Abstract

Utilisation d'un réactif pour détecter un biomarqueur comprenant une protéine déglycase liée à la maladie de Parkinson (DJ -1) dans la préparation d'un réactif de diagnostic de sarcopénie.
PCT/CN2023/124108 2022-10-28 2023-10-11 Marqueur de diagnostic de sarcopénie et son utilisation Ceased WO2024088066A1 (fr)

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CN119446501A (zh) * 2025-01-09 2025-02-14 四川大学 一种肌少症辅助诊疗方法及系统

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CN110809718A (zh) * 2017-06-21 2020-02-18 韩国生命工学研究院 利用血液生物标志物诊断肌肉衰弱相关疾病的方法和试剂盒
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119446501A (zh) * 2025-01-09 2025-02-14 四川大学 一种肌少症辅助诊疗方法及系统

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