PGC-14 gene expression is suppressed by the IL-6MEKERK 1/2 MAPK signalling axis and altered by resistance exercise, obesity and muscle injury

AimPGC-14 is a novel regulator of muscle hypertrophy; however, there is limited understanding of the regulation of its expression and role in many (patho)physiological conditions. Therefore, our purpose was to elicit signalling mechanisms regulating gene expression of Pgc14 and examine its response to (patho)physiological stimuli associated with altered muscle mass. MethodsIL-6 knockout mice and pharmacological experiments in C2C12 myocytes were used to identify regulation of Pgc14 transcription. To examine Pgc14 gene expression in (patho)physiological conditions, obese and lean Zucker rats with/without resistance exercise (RE), ageing mice and muscle regeneration from injury were examined. ResultsIn IL-6 knockout mice, Pgc14mRNA was similar to sevenfold greater than wild type. In C2C12 cells, Pgc14mRNA was suppressed similar to 70% by IL-6. Suppression of Pgc14 by IL-6 was prevented by MEK-ERK-MAPK inhibition. RE led to similar to 260% greater Pgc14mRNA content in lean rats. However, obese Zucker rats exhibited similar to 270% greater Pgc14mRNA than lean, sedentary with no further augmentation by RE. No difference was seen in IL-6mRNA or ERK-MAPK phosphorylation in Zucker rats. Aged mice demonstrated similar to 50% lower Pgc14mRNA and similar to fivefold greater ERK-MAPK phosphorylation than young despite unchanged Il-6mRNA. During muscle regeneration, Pgc14 content is similar to 30% and IL-6mRNA >threefold of uninjured controls 3days following injury; at 5days, Pgc14 was >twofold greater in injured mice with no difference in IL-6mRNA. ConclusionOur findings reveal a novel mechanism suppressing Pgc14 gene expression via IL-6-ERK-MAPK and suggest this signalling axis may inhibit Pgc14 in some, but not all, (patho)physiological conditions.