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Dreher, S.I.* ; Höckele, S. ; Huypens, P. ; Irmler, M. ; Hoffmann, C.* ; Jeske, T. ; Hastreiter, M. ; Moller, A. ; Birkenfeld, A.L. ; Häring, H.-U. ; Peter, A. ; Beckers, J. ; Hrabě de Angelis, M. ; Weigert, C.

Tgf-β induction of mir-143/145 is associated to exercise response by influencing differentiation and insulin signaling molecules in human skeletal muscle.

Cells 10:3443 (2021)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Physical training improves insulin sensitivity and can prevent type 2 diabetes (T2D). However, approximately 20% of individuals lack a beneficial outcome in glycemic control. TGF-β, identified as a possible upstream regulator involved in this low response, is also a potent regulator of microRNAs (miRNAs). The aim of this study was to elucidate the potential impact of TGF-β-driven miRNAs on individual exercise response. Non-targeted long and sncRNA sequencing analyses of TGF-β1-treated human skeletal muscle cells corroborated the effects of TGF-β1 on muscle cell differentiation, the induction of extracellular matrix components, and identified several TGF-β1-regulated miRNAs. qPCR validated a potent upregulation of miR-143-3p/145-5p and miR-181a2-5p by TGF-β1 in both human myoblasts and differentiated myotubes. Healthy subjects who were overweight or obese participated in a supervised 8-week endurance training intervention (n = 40) and were categorized as responder or low responder in glycemic control based on fold change ISIMats (≥+1.1 or <+1.1, respectively). In skeletal muscle biopsies of low responders, TGF-β signaling and miR-143/145 cluster levels were induced by training at much higher rates than among responders. Target-mining revealed HDACs, MYHs, and insulin signaling components INSR and IRS1 as potential miR-143/145 cluster targets. All these targets were down-regulated in TGF-β1-treated myotubes. Transfection of miR-143-3p/145-5p mimics in differentiated myotubes validated MYH1, MYH4, and IRS1 as miR-143/145 cluster targets. Elevated TGF-β signaling and miR-143/145 cluster induction in skeletal muscle of low responders might obstruct improvements in insulin sensitivity by training in two ways: by a negative impact of miR-143-3p on muscle cell fusion and myofiber functionality and by directly impairing insulin signaling via a reduction in INSR by TGF-β and finetuned IRS1 suppression by miR-143-3p.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Deus ; Exercise ; Insulin Sensitivity ; Irs1 ; Mir-143 ; Mir-145 ; Tgf-β1 ; Training Response; Transforming-growth-factor; Endurance Exercise; Expression; Cells; Suppression; Sensitivity; Activation; Inhibitor; Phenotype; Micrornas
ISSN (print) / ISBN 2073-4409
e-ISSN 2073-4409
Zeitschrift Cells
Quellenangaben Band: 10, Heft: 12, Seiten: , Artikelnummer: 3443 Supplement: ,
Verlag MDPI
Verlagsort Basel
Nichtpatentliteratur Publikationen
Institut(e) Institute of Diabetes Research and Metabolic Diseases (IDM)
Institute of Experimental Genetics (IEG)
Institute of Bioinformatics and Systems Biology (IBIS)
Institute of Computational Biology (ICB)
Förderungen medical faculty of the University of Tubingen
German Federal Ministry of Education and Research (BMBF)
Helmholtz Alliance 'Aging and Metabolic Programming, AMPro'