Exercise induction of key transcriptional regulators of metabolic adaptation in muscle is preserved in type 2 diabetes

Context: Type 2 diabetes (T2D) is characterized by insulin resistance in skeletal muscle. Regular exercise improves insulin sensitivity, mitochondrial function and energy metabolism. Thus, an impaired response to exercise may contribute to insulin resistance.

Objective: We hypothesized that key transcriptional regulators of metabolic adaptation to exercise show an attenuated response in skeletal muscle in T2D.

Patients and Design: Skeletal muscle biopsies were obtained from 13 patients with T2D and 14 age and weight-matched controls before, immediately after 1-h acute exercise (70% VO_2max), and 3-h into recovery to examine mRNA expression of key transcription factors and downstream targets and activity of key upstream kinases underlying the metabolic adaptation to exercise.

Results: Acute exercise increased gene expression of the nuclear hormone receptor 4A (NR4A) subfamily (∼4-36-fold) and other key transcription factors including ATF3, EGR1, JUNB, SIK1, PPARA and PPARG (∼1.5-12-fold), but with no differences between groups. The expression of NR4A1 (∼8-fold) and NR4A3 (∼75-fold) was further increased 3-h into recovery, whereas most muscle transcripts sustained elevated or returned to basal levels, again with no differences between groups. Muscle expression of HKII and SLC2A4, and HKII protein content were reduced in patients with T2D. The phosphorylation of p38 MAPK, Erk1/2, CaMKII and CREB was equally increased in response to exercise and/or recovery in both groups.

Conclusion: Acute exercise elicits a pronounced and overall similar increase in expression of key transcription factors and activation of key upstream kinases involved in muscle metabolic adaptation to exercise in patients with T2D and weight-matched controls.