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Dreher, Simon I.; Hoeckele, Selina; Huypens, Peter; Irmler, Martin; Hoffmann, Christoph; Jeske, Tim; Hastreiter, Maximilian; Moller, Anja; Birkenfeld, Andreas L.; Haering, Hans-Ulrich; Peter, Andreas; Beckers, Johannes; Hrabe de Angelis, Martin and Weigert, Cora (2021): TGF-beta Induction of miR-143/145 Is Associated to Exercise Response by Influencing Differentiation and Insulin Signaling Molecules in Human Skeletal Muscle. In: Cells, Vol. 10, No. 12, 3443

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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-beta, 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-beta-driven miRNAs on individual exercise response. Non-targeted long and sncRNA sequencing analyses of TGF-beta 1-treated human skeletal muscle cells corroborated the effects of TGF-beta 1 on muscle cell differentiation, the induction of extracellular matrix components, and identified several TGF-beta 1-regulated miRNAs. qPCR validated a potent upregulation of miR-143-3p/145-5p and miR-181a2-5p by TGF-beta 1 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 (& GE;+1.1 or <+1.1, respectively). In skeletal muscle biopsies of low responders, TGF-beta 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-beta 1-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-beta 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-beta and finetuned IRS1 suppression by miR-143-3p.

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