title: Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice.
abstract: Rapamycin extends lifespan and attenuates age-related pathologies in mice when administered through diet at 14 parts per million (PPM). Recently, we reported that daily intraperitoneal injection of rapamycin at 8 mg/kg attenuates mitochondrial disease symptoms and progression in the Ndufs4 knockout mouse model of Leigh Syndrome. Although rapamycin is a widely used pharmaceutical agent dosage has not been rigorously examined and no dose-response profile has been established. Given these observations we sought to determine if increased doses of oral rapamycin would result in more robust impact on mTOR driven parameters. To test this hypothesis, we compared the effects of dietary rapamycin at doses ranging from 14 to 378 PPM on developmental weight in control and Ndufs4 knockout mice and on health and survival in the Ndufs4 knockout model. High dose rapamycin was well tolerated, dramatically reduced weight gain during development, and overcame gender differences. The highest oral dose, approximately 27-times the dose shown to extend murine lifespan, increased survival in Ndufs4 knockout mice similarly to daily rapamycin injection without observable adverse effects. These findings have broad implications for the effective use of rapamycin in murine studies and for the translational potential of rapamycin in the treatment of mitochondrial disease. This data, further supported by a comparison of available literature, suggests that 14 PPM dietary rapamycin is a sub-optimal dose for targeting mTOR systemically in mice. Our findings suggest that the role of mTOR in mammalian biology may be broadly underestimated when determined through treatment with rapamycin at commonly used doses.
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA ; Department of Genetics, Albert Einstein College of Medicine New York, NY, USA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Johnson
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA ; Department of Psychology, University of Washington Seattle, WA, USA.
authors.forename: Melana E
authors.initials: ME
authors.lastname: Yanos
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bitto
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Castanza
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Arni
authors.initials: A
authors.lastname: Gagnidze
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine New York, NY, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Gonzalez
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Kanav
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hui
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Conner
authors.initials: C
authors.lastname: Jarvie
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Brittany M
authors.initials: BM
authors.lastname: Johnson
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Letexier
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Lanny
authors.initials: L
authors.lastname: McCanta
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Sangesland
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Tamis
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Uhde
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Van Den Ende
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine New York, NY, USA.
authors.forename: Yousin
authors.initials: Y
authors.lastname: Suh
authors.affiliation: Department of Pathology, University of Washington Seattle, WA, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
keywords: aging; mTOR; mitochondrial disease; pharmaceutical intervention; rapamycin