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Fumo, A.R. ; Dreher, S. ; Morigny, P. ; Ji, H. ; Terron Exposito, R. ; Samanci, T.F. ; More, T.* ; Ruoff, L.* ; Tissink, J.J.* ; Yubero, C.P.* ; Alfaro, A.J. ; von Toerne, C. ; Hauck, S.M. ; Nusser, S.H.A.* ; Czigany, Z.* ; Dyar, K.A. ; Herzig, S. ; Diaz, M.B. ; Zeigerer, A.* ; Hiller, K.* ; Wirtz, T.H.* ; Weigert, C. ; Rohm, M.

Hepatokines lipocalin 2 and osteopontin drive muscle atrophy in MASH.

Mol. Metab. 110:102391 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
A bidirectional relationship exists between metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), and sarcopenia, with each worsening the prevalence and prognosis of the other. Hepatokines have recently been shown to affect skeletal muscle metabolism and function, both in the context of MASLD and wasting diseases. We here explored the possibility of targeting hepatokines to counteract MASLD-induced sarcopenia. Integrating mouse and human liver transcriptomics with muscle proteomics from MCD-and GAN-diet induced murine MASH models with sarcopenia, we identified three MASH-induced hepatokines, namely LCN2, LGALS3 and OPN. These hepatokines were elevated in the circulation of mouse MASH models with sarcopenia and in sarcopenic patients with advanced chronic liver disease. C2C12 myotubes treated with liver-secreted proteins as well as recombinant LCN2 and LGALS3 exhibited atrophy. Stable isotope tracing and mitochondrial respiration showed that liver-secreted proteins altered mitochondrial metabolism in C2C12 myotubes, which was recapitulated in primary human myotubes. Human 3D skeletal muscle organoids treated with recombinant proteins exhibited functional impairment. Virus-mediated knockdown of LCN2 in liver of mice with MASH improved muscle function and myotube size, whereas virus-mediated overexpression of LCN2 in the liver aggravated MASH-induced myotube atrophy. Targeting hepatokines may therefore be a feasible future therapeutic strategy against sarcopenia. (c) 2026 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Skeletal-muscle; Methylation; Signatures
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Zeitschrift Molecular Metabolism
Quellenangaben Band: 110, Heft: , Seiten: , Artikelnummer: 102391 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Institute of Diabetes Research and Metabolic Diseases (IDM)
CF Metabolomics & Proteomics (CF-MPC)
Förderungen German Centers for Health Research (DZG) innovation fund
German Center for Cardiovascular Research (DZHK) excellence grant
EFSD/Novo Nordisk Foundation Future Leaders Award
German Diabetes Center (DZD) Next grant
Helmholtz Association-Initiative and Networking Fund as part of the International Helmholtz Research School for Diabetes