TGF-β contributes to impaired exercise response by suppression of mitochondrial key regulators in skeletal muscle

Anja Böhm, Christoph Hoffmann, Martin Irmler, Patrick Schneeweiss, Günter Schnauder, Corinna Sailer, Vera Schmid, Jens Hudemann, Jürgen Machann, Fritz Schick, Johannes Beckers, Martin Hrabe De Angelis, Harald Staiger, Andreas Fritsche, Norbert Stefan, Andreas M. Nieß, Hans Ulrich Häring, Cora Weigert

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

A substantial number of people at risk of developing type 2 diabetes could not improve insulin sensitivity by physical training intervention.We studied the mechanisms of this impaired exercise response in 20 middle-aged individuals at high risk of developing type 2 diabetes who performed 8 weeks of controlled cycling and walking training at 80% individual VO2 peak. Participants identified as nonresponders in insulin sensitivity (based on the Matsuda index) did not differ in preintervention parameters compared with high responders. The failure to increase insulin sensitivity after training correlates with impaired upregulation of mitochondrial fuel oxidation genes in skeletal muscle, and with the suppression of the upstream regulators PGC1αand AMPKα2. The muscle transcriptomes of the nonresponders are further characterized by the activation of transforming growth factor (TGF)- βand TGF-β target genes, which is associated with increases in inflammatory and macrophage markers. TGF-β1 as inhibitor of mitochondrial regulators and insulin signaling is validated in human skeletal muscle cells. Activated TGF-β1 signaling downregulates the abundance of PGC1α AMPKα, the mitochondrial transcription factor TFAM, and mitochondrial enzymes. Thus, the data suggest that increased TGF-β activity in skeletal muscle can attenuate the improvement of mitochondrial fuel oxidation after training and contribute to the failure to increase insulin sensitivity.

Original languageEnglish
Pages (from-to)2849-2861
Number of pages13
JournalDiabetes
Volume65
Issue number10
DOIs
StatePublished - 1 Oct 2016

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