TGF-β Contributes to Impaired Exercise Response by Suppression of Mitochondrial Key Regulators in Skeletal Muscle.
Study Goal
The researchers aimed to investigate why some individuals at high risk of type 2 diabetes fail to improve insulin sensitivity after physical training interventions involving cycling and walking.
Results Summary
The study found that nonresponders to insulin sensitivity improvement after training exhibited impaired upregulation of mitochondrial fuel oxidation genes and suppression of regulators like PGC1α and AMPKα2, linked to increased TGF-β activity in skeletal muscle. This suggests TGF-β signaling may hinder mitochondrial and insulin sensitivity improvements post-exercise.
Population
Middle-aged individuals at high risk of developing type 2 diabetes.
Effective Dosage
Training at 80% individual Vo2 peak (specific frequency not mentioned).
Duration
8 weeks.
Interactions
None mentioned.
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
8 weeks of controlled cycling and walking training at 80% individual Vo2 peak | no change | insulin sensitivity | a substantial number of people at risk of developing type 2 diabetes | - | could not improve | #1 |
8 weeks of controlled cycling and walking training at 80% individual Vo2 peak | no change | insulin sensitivity after training | nonresponders in insulin sensitivity (based on the Matsuda index) | - | the failure to increase | #2 |
8 weeks of controlled cycling and walking training at 80% individual Vo2 peak | no change | mitochondrial fuel oxidation genes in skeletal muscle | nonresponders in insulin sensitivity | - | correlates with impaired upregulation | #3 |
8 weeks of controlled cycling and walking training at 80% individual Vo2 peak | decrease | the upstream regulators PGC1α and AMPKα2 | nonresponders in insulin sensitivity | - | correlates with the suppression | #4 |
- | increase | transforming growth factor (TGF)-β and TGF-β target genes | the muscle transcriptomes of the nonresponders | - | are further characterized by the activation | #5 |
- | increase | inflammatory and macrophage markers | the muscle transcriptomes of the nonresponders | - | is associated with increases | #6 |
Activated TGF-β1 signaling | decrease | PGC1α, AMPKα2, the mitochondrial transcription factor TFAM, and mitochondrial enzymes | human skeletal muscle cells | - | downregulates the abundance | #7 |
increased TGF-β activity in skeletal muscle | decrease | mitochondrial fuel oxidation after training | - | - | can attenuate the improvement | #8 |
increased TGF-β activity in skeletal muscle | no change | insulin sensitivity | - | - | contribute to the failure to increase | #9 |
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 PGC1α and AMPKα2. The muscle transcriptomes of the nonresponders are further characterized by the activation of transforming growth factor (TGF)-β and 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, AMPKα2, 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.