Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice

Simon C. Johnson, Melana E. Yanos, Alessandro Bitto, Anthony Castanza, Arni Gagnidze, Brenda Gonzalez, Kanav Gupta, Jessica Hui, Conner Jarvie, Brittany M. Johnson, Nicolas Letexier, Lanny McCanta, Maya Sangesland, Oliver Tamis, Lauren Uhde, Alex Van Den Ende, Peter S. Rabinovitch, Yousin Suh, Matt Kaeberlein

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Article number247
JournalFrontiers in Genetics
Volume6
Issue numberJUL
DOIs
StatePublished - 2015

Fingerprint

Mitochondrial Diseases
Sirolimus
Weights and Measures
Knockout Mice
Leigh Disease
Intraperitoneal Injections
Weight Gain
Disease Progression

Keywords

  • Aging
  • Mitochondrial disease
  • MTOR
  • Pharmaceutical intervention
  • Rapamycin

ASJC Scopus subject areas

  • Genetics
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Johnson, S. C., Yanos, M. E., Bitto, A., Castanza, A., Gagnidze, A., Gonzalez, B., ... Kaeberlein, M. (2015). Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice. Frontiers in Genetics, 6(JUL), [247]. https://doi.org/10.3389/fgene.2015.00247

Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice. / Johnson, Simon C.; Yanos, Melana E.; Bitto, Alessandro; Castanza, Anthony; Gagnidze, Arni; Gonzalez, Brenda; Gupta, Kanav; Hui, Jessica; Jarvie, Conner; Johnson, Brittany M.; Letexier, Nicolas; McCanta, Lanny; Sangesland, Maya; Tamis, Oliver; Uhde, Lauren; Den Ende, Alex Van; Rabinovitch, Peter S.; Suh, Yousin; Kaeberlein, Matt.

In: Frontiers in Genetics, Vol. 6, No. JUL, 247, 2015.

Research output: Contribution to journalArticle

Johnson, SC, Yanos, ME, Bitto, A, Castanza, A, Gagnidze, A, Gonzalez, B, Gupta, K, Hui, J, Jarvie, C, Johnson, BM, Letexier, N, McCanta, L, Sangesland, M, Tamis, O, Uhde, L, Den Ende, AV, Rabinovitch, PS, Suh, Y & Kaeberlein, M 2015, 'Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice', Frontiers in Genetics, vol. 6, no. JUL, 247. https://doi.org/10.3389/fgene.2015.00247
Johnson, Simon C. ; Yanos, Melana E. ; Bitto, Alessandro ; Castanza, Anthony ; Gagnidze, Arni ; Gonzalez, Brenda ; Gupta, Kanav ; Hui, Jessica ; Jarvie, Conner ; Johnson, Brittany M. ; Letexier, Nicolas ; McCanta, Lanny ; Sangesland, Maya ; Tamis, Oliver ; Uhde, Lauren ; Den Ende, Alex Van ; Rabinovitch, Peter S. ; Suh, Yousin ; Kaeberlein, Matt. / Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice. In: Frontiers in Genetics. 2015 ; Vol. 6, No. JUL.
@article{41fe4f223b974ab4b11ac8b5d92b2fdf,
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.",
keywords = "Aging, Mitochondrial disease, MTOR, Pharmaceutical intervention, Rapamycin",
author = "Johnson, {Simon C.} and Yanos, {Melana E.} and Alessandro Bitto and Anthony Castanza and Arni Gagnidze and Brenda Gonzalez and Kanav Gupta and Jessica Hui and Conner Jarvie and Johnson, {Brittany M.} and Nicolas Letexier and Lanny McCanta and Maya Sangesland and Oliver Tamis and Lauren Uhde and {Den Ende}, {Alex Van} and Rabinovitch, {Peter S.} and Yousin Suh and Matt Kaeberlein",
year = "2015",
doi = "10.3389/fgene.2015.00247",
language = "English (US)",
volume = "6",
journal = "Frontiers in Genetics",
issn = "1664-8021",
publisher = "Frontiers Media S. A.",
number = "JUL",

}

TY - JOUR

T1 - Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice

AU - Johnson, Simon C.

AU - Yanos, Melana E.

AU - Bitto, Alessandro

AU - Castanza, Anthony

AU - Gagnidze, Arni

AU - Gonzalez, Brenda

AU - Gupta, Kanav

AU - Hui, Jessica

AU - Jarvie, Conner

AU - Johnson, Brittany M.

AU - Letexier, Nicolas

AU - McCanta, Lanny

AU - Sangesland, Maya

AU - Tamis, Oliver

AU - Uhde, Lauren

AU - Den Ende, Alex Van

AU - Rabinovitch, Peter S.

AU - Suh, Yousin

AU - Kaeberlein, Matt

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Aging

KW - Mitochondrial disease

KW - MTOR

KW - Pharmaceutical intervention

KW - Rapamycin

UR - http://www.scopus.com/inward/record.url?scp=84940102312&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940102312&partnerID=8YFLogxK

U2 - 10.3389/fgene.2015.00247

DO - 10.3389/fgene.2015.00247

M3 - Article

VL - 6

JO - Frontiers in Genetics

JF - Frontiers in Genetics

SN - 1664-8021

IS - JUL

M1 - 247

ER -