TY - JOUR T1 - Increasing Muscle Hypertrophy with a Natural Product Designed to Inhibit SIRT1 JF - bioRxiv DO - 10.1101/2022.06.27.497838 SP - 2022.06.27.497838 AU - Suraj Pathak AU - Marita Wallace AU - Sonia Athalye AU - Simon Schenk AU - Henning T. Langer AU - Keith Baar Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/06/29/2022.06.27.497838.abstract N2 - 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.Competing Interest StatementThe inhibition of SIRT1 and enhanced muscle hypertrophy (U.S. patent number 9,480,675) and the natural product cocktail described in this manuscript (U.S. patent number 11,312,695) have been patented. Both patents have been licensed by Advanced Muscle Technologies (AMT). AMT provided funds for the studies described in this manuscript, paid KB as a consultant, and provided shares to SS and KB. ER -