Increasing Muscle Hypertrophy with a Natural Product Designed to Inhibit SIRT1

Muscle mass and strength are predictors of longevity. We have previously identified a series of molecular brakes that slow muscle growth in response to stress. One potential stress that we hypothesized would limit muscle growth is caloric stress through the activation of SIRT1. We therefore identified natural product inhibitors of SIRT1 and tested their effects on load-induced increases in muscle fiber cross-sectional area (fCSA) using an incomplete factorial design. Supplying varying amounts of three natural products for the full two-week period of overload resulted in increases in fCSA that varied from -2 to 113%. Using these data, we produced a model that predicted the optimal combination and concentration of each natural product and validated this model in a separate cohort of animals. Following two weeks of overload, fCSA in the optimal group increased 62%, whereas in the placebo fCSA increased only 3%. The greater increase in fCSA was not the result of an increase in ribosomal mass. In fact, the optimal group showed significantly less of the 5 external transcribed spacer, a marker of 47S ribosomal RNA synthesis, and a trend for decreased total RNA. In spite of the lower ribosome mass, the increase in protein synthesis was similar, suggesting that the natural product cocktail may be increasing ribosomal efficiency rather than capacity. These data suggest that inhibition of SIRT1, together with exercise, may be useful in increasing muscle fCSA.