Evidence of a Muscle–Brain Axis by Quantification of the Neurotrophic Myokine METRNL (Meteorin-Like Protein) in Human Cerebrospinal Fluid and Serum
Abstract
:1. Introduction
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- to quantify the protein concentrations of the neurotrophic adipo-myokine METRNL by ELISA in paired serum and CSF samples from a well- characterized cohort of patients (n = 260) with various diseases who underwent neurological evaluation, including lumbar puncture in a single and tertiary care centre;
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- to correlate serum/CSF METRNL levels with anthropometric parameters, routine laboratory parameters and neurological and internal medicine diseases;
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- to obtain insight into the basal and inducible regulation of BBB function with respect to the migration of METRNL by providing novel and specific CSF/serum ratios and classical Reibergrams;
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- to provide evidence whether or not METRNL fulfils the biochemical and physiological conditions to act as a mediator of the muscle–brain axis.
2. Materials and Methods
2.1. Study Population
2.2. Measurement of CSF and Serum Parameters
2.3. High-Sensitive Quantification of METRNL in Serum and CSF
2.4. Statistics
3. Results
3.1. Characteristics of the Study Population and Concentrations of METRNL in Serum and CSF
3.2. Correlation of Serum and CSF METRNL Concentrations with Numerical Standard Variables
3.3. CSF Concentrations and CSF/Serum Ratios of METRNL Significantly Increase with Biochemical Parameters Blood–Brain Barrier (BBB) Dysfunction
3.4. Detailed Evaluation of Classical Reibergrams for the Quantitative Description of BBB Dysfunction
3.5. Correlation of Serum and CSF METRNL Levels with Respect to the Metabolic Syndrome Complex
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Study Population (n = 260) | |
---|---|
Age (years) [range] | 50.5 ± 17.5 [18–90] |
Males n (%) | 107 (41.2) |
Females n (%) | 153 (58.8) |
Meteorin-like | |
METRNL in serum (pg/mL) [range] | 801.2 ± 378.3 [203.1–2685.1] |
METRNL in cerebrospinal fluid (pg/mL) [range] | 1007.2 ± 624.2 [230.0–4275.3] |
METRNL CSF/serum ratio [range] | 1.4 ± 0.8 [0.2–6.7] |
Anthropometric parameters | |
Mean BMI (kg/m²) ° | 26.5 ± 5.0 [17.4–47.7] |
BMI < 25.0 kg/m² n (%) | 126 (48.5) |
BMI ≥ 25.0 kg/m² n (%) | 128 (49.2) |
Neurological diseases/Clinical subgroups | |
Infectious CNS disease n (%) | 13 (5.0) |
Multiple sclerosis n (%) | 40 (15.4) |
Vascular disease n (%) | 22 (8.5) |
Epilepsie n (%) | 26 (10.0) |
Headache/facial pain n (%) | 23 (8.8) |
Neuropathy/cranial nerve palsy n (%) | 46 (17.7) |
Others * n (%) | 90 (34.6) |
* consisting of dementia (8), psychiatric disorders (12), normal pressure hydrocephalus (8), and patients undergoing spinal puncture for exclusion of other diseases (53) | |
Serum METRNL | |
Males | 745.3 ± 350.9 * |
Females | 840.2 ± 392.8 * (p = 0.031) |
BMI < 25 | 774.7 ± 343.8 |
BMI ≥ 25 | 827.3 ± 411.3 |
Diabetes mellitus | 945.0 ± 565.3 |
Non-Diabetes | 784.3 ± 343.6 |
Hypertension | 835.9 ± 433.7 |
Normotension | 778.5 ± 330.5 |
Smoker | 783.2 ± 320.9 |
Non-Smoker | 807.1 ± 389.9 |
CSF METRNL | |
Males | 1071.2 ± 603.4 |
Females | 962.4 ± 636.5 |
BMI < 25 | 970.9 ± 637.4 |
BMI ≥ 25 | 1041.6 ± 606.8 |
Diabetes mellitus | 1128.1 ± 569.1 |
Non-Diabetes | 993.9 ± 630.7 |
Hypertension | 1117.5 ± 673.1 * |
Normotension | 929.6 ± 575.2 * (p = 0.023) |
Smoker | 915.5 ± 447.0 |
Non-Smoker | 1029.7 ± 655.5 |
Serum METRNL [pg/mL] | CSF METRNL [pg/mL] | |
---|---|---|
Correlation with | ||
Age [years] | n. s. | rho = +0.237 p < 0.001 |
BMI [kg/m2) | n. s. | n. s. |
Serum parameters | ||
METRNL [pg/mL] | - | rho = +0.521 p < 0.001 |
Leukocyte [giga/L] | n. s. | n. s. |
Hemoglobin [g/L] | rho = −0.231 p < 0.001 | n. s. |
CRP [mg/dL] | rho = +0.159 p = 0.011 | n. s. |
ALT [U/L] | n. s. | rho = +0.169 p = 0.009 |
AST [U/L] | n. s. | rho = +0.255 p < 0.001 |
Creatinine [mg/dL] | n. s. | rho = -0.151 p = 0.016 |
Urea [mg/dL] | n. s. | rho = +0.142 p = 0.025 |
Albumin [g/L] | rho = −0.172 p = 0.005 | n. s. |
CSF/serum albumin ratio | n. s. | rho = +0.480 p < 0.001 |
Lipoprotein-Metabolism (triglycerides, LDL cholesterol, HDL cholesterol) | n. s. | n. s. |
Carbohydrate-Metabolism (Glucose or HbA1c) | n. s. | n. s. |
CSF parameters | ||
Total protein [g/L] | n. s. | rho = +0.420 p < 0.001 |
Albumin [g/L] | n. s. | rho = +0.463 p < 0.001 |
IgM [g/L] | n. s. | rho = +0.349 p = 0.003 |
IgG [g/L] | n. s. | rho = +0.357 p < 0.001 |
IgA [g/L] | rho = +0.348 p = 0.003 | rho = +0.430 p < 0.001 |
Lactate [mmol/L] | n. s. | rho = +0.210 p = 0.001 |
Serum METRNL [pg/mL] | CSF METRNL [pg/mL] | C/S METRNL | |
---|---|---|---|
Disease groups | |||
Infectious disease (n = 13) | 935.2 ± 434.6 | 1674.8 ± 1072.0 | 1.8 ± 0.8 |
Multiple Sclerosis (n = 40) | 759.1 ± 367.3 | 909.2 ± 537.1 | 1.3 ± 0.7 |
Vascular disease (n = 22) | 640.2 ± 391.6 | 879.5 ± 599.1 | 1.4 ± 0.6 |
Epilepsy (n = 26) | 758.5 ± 292.8 | 927.6 ± 485.2 | 1.4 ± 1.0 |
Headache/facial pain (n = 23) | 732.5 ± 312.6 | 864.0 ± 450.8 | 1.2 ± 0.4 |
Neuropathy/ cranial nerve palsy (n = 46) | 800.3 ± 347.2 | 1068.7 ± 560.4 | 1.4 ± 0.6 |
Others (n = 90) | 870.2 ± 412.6 | 1013.7 ± 640.3 | 1.3 ± 0.9 |
BBB dysfunction | |||
Grade 0 (n = 206) | 800.4 ± 375.5 | 912.1 ± 545.9 | 1.2 ± 0.7 |
Grade 1 (n = 21) | 765.4 ± 321.8 | 1151.5 ± 588.3 | 1.6 ± 0.7 |
Grade 2 (n = 31) | 827.9 ± 431.8 | 1446.6 ± 749.3 | 1.9 ± 0.8 |
Grade 3 (n = 2) | 842.3 ± 672.1 | 2473.9 ± 1857.2 | 3.0 ± 0.2 |
p < 0.001 | p < 0.001 | ||
CSF cell count/µL | |||
0–5 cells (n = 226) | 784.4 ± 376.8 | 959.5 ± 561.7 | 1.4 ± 0.8 |
>5 cells (n = 34) | 912.9 ± 374.7 | 1324.6 ± 887.4 | 1.4 ± 0.7 |
p = 0.028 | p = 0.035 | ||
Oligoclonal bands | |||
negative (n = 207) | 791.8 ± 375.4 | 1010.6 ± 609.1 | 1.4 ± 0.8 |
positive (n = 41) | 806.9 ± 385.2 | 1070.9 ± 715.4 | 1.4 ± 0.7 |
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Berghoff, M.; Höpfinger, A.; Rajendran, R.; Karrasch, T.; Schmid, A.; Schäffler, A. Evidence of a Muscle–Brain Axis by Quantification of the Neurotrophic Myokine METRNL (Meteorin-Like Protein) in Human Cerebrospinal Fluid and Serum. J. Clin. Med. 2021, 10, 3271. https://doi.org/10.3390/jcm10153271
Berghoff M, Höpfinger A, Rajendran R, Karrasch T, Schmid A, Schäffler A. Evidence of a Muscle–Brain Axis by Quantification of the Neurotrophic Myokine METRNL (Meteorin-Like Protein) in Human Cerebrospinal Fluid and Serum. Journal of Clinical Medicine. 2021; 10(15):3271. https://doi.org/10.3390/jcm10153271
Chicago/Turabian StyleBerghoff, Martin, Alexandra Höpfinger, Ranjithkumar Rajendran, Thomas Karrasch, Andreas Schmid, and Andreas Schäffler. 2021. "Evidence of a Muscle–Brain Axis by Quantification of the Neurotrophic Myokine METRNL (Meteorin-Like Protein) in Human Cerebrospinal Fluid and Serum" Journal of Clinical Medicine 10, no. 15: 3271. https://doi.org/10.3390/jcm10153271