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TGFβ contributes to impaired exercise response by suppression of mitochondrial key regulators in skeletal muscle

ABSTRACT: substantial number of people at risk to develop 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 who performed a controlled eight weeks cycling and walking training at 80 % individual VO2max. Participants identified as non-responders in insulin sensitivity (based on Matsuda index) did not differ in pre-intervention parameters compared to high responders. The failure to increase insulin sensitivity after training correlates with impaired up-regulation of mitochondrial fuel oxidation genes in skeletal muscle, and with the suppression of the upstream regulators PGC1α and AMPKα2. The muscle transcriptome of the non-responders is further characterized by an activation of TGFβ and TGFβ target genes, which is associated with increases in inflammatory and macrophage markers. TGFβ1 as inhibitor of mitochondrial regulators and insulin signaling is validated in human skeletal muscle cells. Activated TGFβ1 signaling down-regulates the abundance of PGC1α, AMPKα2, mitochondrial transcription factor TFAM, and of mitochondrial enzymes. Thus, increased TGFβ activity in skeletal muscle can attenuate the improvement of mitochondrial fuel oxidation after training and contribute to the failure to increase insulin sensitivity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE72462 | GEO | 2016/06/29

SECONDARY ACCESSION(S): PRJNA294095

REPOSITORIES: GEO

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TGFÎ² contributes to impaired exercise response by suppression of mitochondrial key regulators in skeletal muscle

Project description:substantial number of people at risk to develop 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 who performed a controlled eight weeks cycling and walking training at 80 % individual VO2max. Participants identified as non-responders in insulin sensitivity (based on Matsuda index) did not differ in pre-intervention parameters compared to high responders. The failure to increase insulin sensitivity after training correlates with impaired up-regulation of mitochondrial fuel oxidation genes in skeletal muscle, and with the suppression of the upstream regulators PGC1Î± and AMPKÎ±2. The muscle transcriptome of the non-responders is further characterized by an activation of TGFÎ² and TGFÎ² target genes, which is associated with increases in inflammatory and macrophage markers. TGFÎ²1 as inhibitor of mitochondrial regulators and insulin signaling is validated in human skeletal muscle cells. Activated TGFÎ²1 signaling down-regulates the abundance of PGC1Î±, AMPKÎ±2, mitochondrial transcription factor TFAM, and of mitochondrial enzymes. Thus, increased TGFÎ² activity in skeletal muscle can attenuate the improvement of mitochondrial fuel oxidation after training and contribute to the failure to increase insulin sensitivity. We performed gene expression microarray analysis on muscle biopsies from humans before and after an eight weeks endurance training intervention

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