PGC-14 gene expression is suppressed by the IL-6-MEK-ERK 1/2 MAPK signalling axis and altered by resistance exercise, obesity and muscle injury.
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AIM: PGC-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. METHODS: IL-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. RESULTS: In IL-6 knockout mice, Pgc14mRNA was ~sevenfold greater than wild type. In C2C12 cells, Pgc14mRNA was suppressed ~70% by IL-6. Suppression of Pgc14 by IL-6 was prevented by MEK-ERK-MAPK inhibition. RE led to ~260% greater Pgc14mRNA content in lean rats. However, obese Zucker rats exhibited ~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 ~50% lower Pgc14mRNA and ~fivefold greater ERK-MAPK phosphorylation than young despite unchanged Il-6mRNA. During muscle regeneration, Pgc14 content is ~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. CONCLUSION: Our 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.
