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PGC-1α and PGC-1β regulate protein synthesis in C2C12 myotubes

E.L. Brown, P. Sepulveda, C.R. Wright, R. Snow and A.P. Russell, Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Highway, Burwood, VIC 3125, Australia.

Skeletal muscle atrophy is characterised by increased rates of protein degradation and/or decreased rates of protein synthesis. Overexpression of peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) or PGC-1β can attenuate muscle atrophy, and this has been attributed to a decrease in protein degradation (Brault, Jespersen & Goldberg, 2010; Sandri et al., 2006).

This study investigated the role of PGC-1α and PGC-1β in protein synthesis in C2C12 myotubes. Myotubes were infected with GFP, PGC-1α, or PGC-1β adenoviruses, and protein synthesis was measured at basal levels and with dexamethasone treatment, by the uptake of [3H]-tyrosine.

PGC-1α or PGC-1β overexpression resulted in a 25-28% increase in protein synthesis. Dexamethasone decreased protein synthesis by 15% in the GFP-infected myotubes. However, overexpression of PGC-1α or PGC-1β was able to prevent the dexamethasone-induced decrease. Treatment with LY294, an inhibitor of PI3K/Akt, did not prevent the PGC-1α or PGC-1β driven increase in protein synthesis. This effect was therefore independent of Akt, a major kinase involved in muscle growth.

Another potential mechanism for the PGC-1α and PGC-1β driven increase in protein synthesis may be via their regulation of microRNAs (miRNAs). The expression of miR-1 and miR-133a, two miRNAs that are thought to play a role in muscle hypertrophy, were downregulated by PGC-1α or PGC-1β overexpression. Further studies will determine if these two miRNAs are involved in the regulation of protein synthesis with PGC-1α and PGC-1β overexpression.

Brault JJ, Jespersen JG & Goldberg AL. (2010) Peroxisome proliferator-activated receptor γ coactivator 1α or 1β overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. Journal of Biological Chemistry 285, 19460-71.

Sandri M, Lin J, Handschin C, Yang W, Arany ZP, Lecker SH, Goldberg AL & Spiegelman BM. (2006). PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proceedings of the National Academy of Sciences USA 103, 16260-16265.