The impact of a 48-h fast on SIRT1 and GCN5 in human skeletal muscle.

The present study examined the impact of a 48 h fast on the expression and activation status of SIRT1 and GCN5, the relationship between SIRT1/GCN5 and the gene expression of PGC-1 alpha, and the PGC-1 alpha target PDK4 in the skeletal muscle of 10 lean healthy men (age, 22.0 +/- 1.5 years; peak oxygen uptake, 47.2 +/- 6.7 mL/(min.kg)). Muscle biopsies and blood samples were collected 1 h postprandial (Fed) and following 48 h of fasting (Fasted). Plasma insulin (Fed, 80.8 +/- 47.9 pmol/L; Fasted, not detected) and glucose (Fed, 4.36 +/- 0.86; Fasted, 3.74 +/- 0.25 mmol/L, p = 0.08) decreased, confirming participant adherence to fasting. Gene expression of PGC-1 alpha decreased (p < 0.05, -24%), while SIRT1 and PDK4 increased (p < 0.05, + 11% and + 1023%, respectively), and GCN5 remained unchanged. No changes were observed for whole-muscle protein expression of SIRT1, GCN5, PGC-1 alpha, or COX IV. Phosphorylation of SIRT1, AMPK alpha, ACC, p38 MAPK, and PKA substrates as well as nuclear acetylation status was also unaltered. Additionally, nuclear SIRT1 activity, GCN5, and PGC-1 alpha content remained unchanged. Preliminary findings derived from regression analysis demonstrate that changes in nuclear GCN5 and SIRT1 activity/phosphorylation may contribute to the control of PGC-1 alpha, but not PDK4, messenger RNA expression following fasting. Collectively, and in contrast with previous animal studies, our data are inconsistent with the altered activation status of SIRT1 and GCN5 in response to 48 h of fasting in human skeletal muscle.