Evidence of a Muscle–Brain Axis by Quantification of the Neurotrophic Myokine METRNL (Meteorin-Like Protein) in Human Cerebrospinal Fluid and Serum

Martin Berghoff,Alexandra Höpfinger,Andreas Schäffler,Ranjithkumar Rajendran,Thomas Karrasch,Andreas Schmid

doi:10.3390/jcm10153271

Martin Berghoff, Alexandra Höpfinger + Show 4 more

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https://doi.org/10.3390/jcm10153271

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Abstract

Data on the quantification of the potentially neurotrophic adipo-myokine METRNL (Meteorin-like protein) in human cerebrospinal fluid (CSF) are lacking and migration of this secreted protein across the blood–brain barrier (BBB) is uncertain. In the present pilot study, METRNL concentrations were quantified by ELISA in paired serum and CSF samples of 260 patients (107 males, 153 females) undergoing neurological evaluation. METRNL was abundant in serum (801.2 ± 378.3 pg/mL) and CSF (1007.2 ± 624.2 pg/mL) with a CSF/serum ratio of 1.4 ± 0.8. Serum METRNL levels were significantly correlated (rho = +0.521) to those in CSF. CSF METRNL concentrations were significantly correlated (rho = +0.480) with albumin CSF/serum ratios. The CSF/serum ratios of METRNL and albumin were positively correlated in Reibergram analysis (rho = 0.498), indicating that raising CSF concentrations of METRNL are mediated by increasing BBB dysfunction. The CSF concentrations of METRNL strongly increased in a stepwise manner along with increasing BBB dysfunction from grade 0 to grade 3 and with rising CSF cell count. CSF/serum ratio of METRNL also increased from grade 0 (1.2 ± 0.7) to grade 3 (3.0 ± 0.2). Furthermore, CSF levels were positively correlated with age. In conclusion, METRNL is a secreted and neurotrophic myokine that crosses over the BBB. CSF concentrations of METRNL increase with BBB dysfunction.

Highlights

The hypothesis of a “fat–brain axis” [1,2] is that adipocyte-specific secretory hormones, proteins and peptides are released by white adipocytes (“adipokines”) or brown adipocytes (“batokines”) into the circulation, cross over the blood–brain barrier (BBB), appear in cerebrospinal fluid (CSF) and regulate central nervous system functions such as appetite, satiety, sympathetic neural outflow, temperature, energy expenditure, pituitary and hypothalamic function, stress reaction, energy appeal reaction and others [3,4,5]
Wcohnecnenctoramtipoanrsedantodobthyerspadecipifoickicnaelscu[1la,6ti–o8n], tohfisthraetiroelwataisveelxytehnisgivhely CSF(~/s1e0r0u-mtora1t0i0o0o-ffo1ld.4) ±hi0g.8h.eWr thheann croamtiopsarceadlcutolaotethderfoardaipdoipkoinneesct[i1n,6(–08.7], ×thi1s0r−a3t)i,orwesaisstin ext(e4n.4siv×el1y0−(~31),0a0d- itpos1in00(02-7fo×ld1)0h−i3g)h, eRrBtPh4an(8r.2at×ios10c−al3c)u, plartoegdrafonrualidnip(1o6n.3ec×tin10(0−.37),×cl1u0s−3t)e,rin res(is2t9i.n6(×4.410×−130)−,3)P,EaDdiFps(4in2.(327××1100−−33)),RoBr PC4T(R8P.2-3× (1101−30),×pr1o0g−r3a)n. uBlainse(d16o.3n×th1e0s−e3),ccallucustleartiinons, (29t.6he×h1i0g−h3),bPasEaDl Fpe(r4m2.e3a×bi1li0t−y3)o, fotrhCeTBRBPB-3fo(r1M10E×TR10N−3L). eBxapsleadinosnththeehsieghcaclocunlcaetniotrnast,iothnes of higthhibsaasdalippoe-rmmyeoakbiilniteyinofCthSFe,BwBhBicfhoraMreEsTimRNilaLr etoxpthlaeinrsestpheechtiivgehsceornucmenctorantcioenntsraotfiothniss. It adipo-myokine in CSF, which are similar to the respective serum concentrations. It is of high clinical interest why the myokine METRNL has such a high BBB permeability when is of high clinical interest why the myokine METRNL has such a high BBB permeability when compared to classical adipokines mentioned above
We found a highly significant increase in CSF METRNL levels along with increasing grades of BBB dysfunction and with rising CSF cell count

Summary

Introduction

The hypothesis of a “fat–brain axis” [1,2] is that adipocyte-specific secretory hormones, proteins and peptides are released by white adipocytes (“adipokines”) or brown adipocytes (“batokines”) into the circulation, cross over the blood–brain barrier (BBB), appear in cerebrospinal fluid (CSF) and regulate central nervous system functions such as appetite, satiety, sympathetic neural outflow, temperature, energy expenditure, pituitary and hypothalamic function, stress reaction, energy appeal reaction and others [3,4,5]. The concept of a muscle–brain axis [9,10] has been discussed recently due to the fact that myocytes represent secretory cells releasing “myokines” [9,10,11] or “adipomyokines” such as myonectin, myostatin, IL-6, IL-8, IL-15, FGF-21, irisin, and sclerostin [12]. Exerciseinduced release of lipolytic myokines such as irisin and IL-6 increase thermogenesis via browning of adipose tissue [10]

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