Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults

Adam R. Konopka, Jaime L. Laurin, Hayden M. Schoenberg, Justin J. Reid, William M. Castor, Christopher A. Wolff, Robert V. Musci, Oscar D. Safairad, Melissa A. Linden, Laurie M. Biela, Susan M. Bailey, Karyn L. Hamilton, Benjamin F. Miller

Research output: Contribution to journalArticle

Abstract

Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise-induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double-blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24-hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole-body insulin sensitivity and VO 2 max after AET. In the metformin group, there was no overall change in whole-body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration. The change in whole-body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET-induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.

Original languageEnglish (US)
Article numbere12880
JournalAging Cell
Volume18
Issue number1
DOIs
StatePublished - Feb 1 2019

Fingerprint

Metformin
Exercise
Insulin Resistance
Respiration
Mitochondrial Proteins
Skeletal Muscle
Muscle Proteins
Therapeutics
Fasting
Mitochondria

Keywords

  • aging
  • healthspan
  • protein synthesis
  • proteostasis
  • telomere

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Konopka, A. R., Laurin, J. L., Schoenberg, H. M., Reid, J. J., Castor, W. M., Wolff, C. A., ... Miller, B. F. (2019). Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell, 18(1), [e12880]. https://doi.org/10.1111/acel.12880

Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. / Konopka, Adam R.; Laurin, Jaime L.; Schoenberg, Hayden M.; Reid, Justin J.; Castor, William M.; Wolff, Christopher A.; Musci, Robert V.; Safairad, Oscar D.; Linden, Melissa A.; Biela, Laurie M.; Bailey, Susan M.; Hamilton, Karyn L.; Miller, Benjamin F.

In: Aging Cell, Vol. 18, No. 1, e12880, 01.02.2019.

Research output: Contribution to journalArticle

Konopka, AR, Laurin, JL, Schoenberg, HM, Reid, JJ, Castor, WM, Wolff, CA, Musci, RV, Safairad, OD, Linden, MA, Biela, LM, Bailey, SM, Hamilton, KL & Miller, BF 2019, 'Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults', Aging Cell, vol. 18, no. 1, e12880. https://doi.org/10.1111/acel.12880
Konopka, Adam R. ; Laurin, Jaime L. ; Schoenberg, Hayden M. ; Reid, Justin J. ; Castor, William M. ; Wolff, Christopher A. ; Musci, Robert V. ; Safairad, Oscar D. ; Linden, Melissa A. ; Biela, Laurie M. ; Bailey, Susan M. ; Hamilton, Karyn L. ; Miller, Benjamin F. / Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. In: Aging Cell. 2019 ; Vol. 18, No. 1.
@article{0d7b74313dc64519adc583ee01141791,
title = "Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults",
abstract = "Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise-induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double-blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24-hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole-body insulin sensitivity and VO 2 max after AET. In the metformin group, there was no overall change in whole-body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration. The change in whole-body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET-induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.",
keywords = "aging, healthspan, protein synthesis, proteostasis, telomere",
author = "Konopka, {Adam R.} and Laurin, {Jaime L.} and Schoenberg, {Hayden M.} and Reid, {Justin J.} and Castor, {William M.} and Wolff, {Christopher A.} and Musci, {Robert V.} and Safairad, {Oscar D.} and Linden, {Melissa A.} and Biela, {Laurie M.} and Bailey, {Susan M.} and Hamilton, {Karyn L.} and Miller, {Benjamin F.}",
year = "2019",
month = "2",
day = "1",
doi = "10.1111/acel.12880",
language = "English (US)",
volume = "18",
journal = "Aging Cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults

AU - Konopka, Adam R.

AU - Laurin, Jaime L.

AU - Schoenberg, Hayden M.

AU - Reid, Justin J.

AU - Castor, William M.

AU - Wolff, Christopher A.

AU - Musci, Robert V.

AU - Safairad, Oscar D.

AU - Linden, Melissa A.

AU - Biela, Laurie M.

AU - Bailey, Susan M.

AU - Hamilton, Karyn L.

AU - Miller, Benjamin F.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise-induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double-blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24-hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole-body insulin sensitivity and VO 2 max after AET. In the metformin group, there was no overall change in whole-body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration. The change in whole-body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET-induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.

AB - Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise-induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double-blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24-hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole-body insulin sensitivity and VO 2 max after AET. In the metformin group, there was no overall change in whole-body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration. The change in whole-body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET-induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.

KW - aging

KW - healthspan

KW - protein synthesis

KW - proteostasis

KW - telomere

UR - http://www.scopus.com/inward/record.url?scp=85058225554&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058225554&partnerID=8YFLogxK

U2 - 10.1111/acel.12880

DO - 10.1111/acel.12880

M3 - Article

C2 - 30548390

AN - SCOPUS:85058225554

VL - 18

JO - Aging Cell

JF - Aging Cell

SN - 1474-9718

IS - 1

M1 - e12880

ER -