SREBP-1c (sterol-regulatory-element-binding protein 1c) is a transcription factor that regulates genes associated with glucose and fatty acid metabolism and exhibits responsiveness to insulin and exercise. We have examined the effects of exercise on basal and insulin-mediated changes in the activation (phosphorylation) of the signalling molecules involved in the regulation of SREBP-1c and related them to changes in the expression of SREBP-1c in human skeletal muscle. Eight healthy men performed one-legged cycling for 90 min; 24 h later a hyperinsulinaemic euglycaemic clamp for 4 h was performed. Muscle biopsies were obtained from the rested (control) leg and the exercised leg immediately after exercise and before and after the insulin clamp. Immediately after exercise, phosphorylation of ERK (extracellular-signal-regulated kinase) 1, ERK2 and Akt (protein kinase B) was higher in the exercised than the control leg. SREBP-1c mRNA content was not affected by exercise, whereas its protein level was lower in the exercised than the control leg and returned to pre-exercise levels 24 h later. Similarly, SREBP-1c mRNA content was ∼1.5-fold higher in the exercised than the control leg 24 h after exercise. Insulin infusion up-regulated SREBP-1c mRNA level ∼2-fold, but did not affect its protein level. Phosphorylation of Akt also increased in response to insulin clamp, whereas phospho-ERK1 and -ERK2 levels were unchanged. Neither exercise nor insulin affected STAT3 (signal transducer and activator of transcription 3) or p38 MAPK (mitogen-activated protein kinase) phosphorylation. These findings suggest that exercise-induced changes in muscle SREBP-1c expression might be mediated by the activation of the ERK1/2 pathway, whereas Akt might be a positive regulator of SREBP-1c in human skeletal muscle under insulin-stimulated conditions.

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