An IL-6 promoter variant (−174 G/C) augments IL-6 production and alters skeletal muscle transcription in response to exercise in mice

Interleukin-6 (IL-6) is produced and secreted by skeletal muscle cells during exercise and plays an important role in mediating metabolic responses to exercise. The promoter region of the IL-6 gene contains a common genetic variant (-174 G/C, rs1800795), which may alter responses to exercise training. To isolate the impact of this gene variant on exercise-induced IL-6 expression and skeletal muscle transcription responses following exercise, we generated knock-in mice with a GG or variant CC genotype for the murine homolog of rs1800795. The overall gross metabolic phenotype of resting mice was similar between genotypes; however, following acute treadmill running, the variant CC genotype was associated with a greater increase in skeletal muscle <i>Il6</i> mRNA and circulating IL-6. Furthermore, we observed that mice with the variant CC genotype exhibited sex-specific differences in skeletal muscle master metabolism regulatory genes and had greater increases in genes controlling mitochondrial biogenesis in skeletal muscle post exercise. However, there was no effect of genotype on exercise-induced skeletal muscle glycogen depletion, circulating free fatty acids, blood glucose and lactate production, or exercise-responsive gene expression in subcutaneous fat. These findings suggest that the IL-6 promoter variant -174 G/C may result in enhanced skeletal muscle adaptations in response to exercise training and could mean that individuals with the "C" allele may more readily gain improvements in metabolic health in response to exercise training.<b>NEW & NOTEWORTHY</b> Interleukin-6 (IL-6) is produced and secreted by skeletal muscle during exercise and mediates metabolic responses to exercise. A common variant in the IL-6 promoter region (-174G/C) may alter responses to exercise training. Mice with the variant "CC" genotype exhibited higher skeletal muscle IL-6 mRNA and circulating IL-6 levels post exercise, as well as altered skeletal muscle gene transcription. This suggests that this variant might enhance muscle adaptations to exercise, potentially benefiting metabolic health.