Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis
Abstract Background The protein kinase mechanistic target of rapamycin (mTOR) controls cellular growth and metabolism. Although balanced mTOR signalling is required for proper muscle homeostasis, partial mTOR inhibition by rapamycin has beneficial effects on various muscle disorders and age‐related...
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Wiley
2019-02-01
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Series: | Journal of Cachexia, Sarcopenia and Muscle |
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Online Access: | https://doi.org/10.1002/jcsm.12336 |
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doaj-481283996c1a43f4bda9799c846af817 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Qing Zhang Agnès Duplany Vincent Moncollin Sandrine Mouradian Evelyne Goillot Laetitia Mazelin Karine Gauthier Nathalie Streichenberger Céline Angleraux Jie Chen Shuzhe Ding Laurent Schaeffer Yann‐Gaël Gangloff |
spellingShingle |
Qing Zhang Agnès Duplany Vincent Moncollin Sandrine Mouradian Evelyne Goillot Laetitia Mazelin Karine Gauthier Nathalie Streichenberger Céline Angleraux Jie Chen Shuzhe Ding Laurent Schaeffer Yann‐Gaël Gangloff Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis Journal of Cachexia, Sarcopenia and Muscle mTOR kinase activity Myopathy Mitochondria Glycogen Body composition |
author_facet |
Qing Zhang Agnès Duplany Vincent Moncollin Sandrine Mouradian Evelyne Goillot Laetitia Mazelin Karine Gauthier Nathalie Streichenberger Céline Angleraux Jie Chen Shuzhe Ding Laurent Schaeffer Yann‐Gaël Gangloff |
author_sort |
Qing Zhang |
title |
Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis |
title_short |
Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis |
title_full |
Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis |
title_fullStr |
Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis |
title_full_unstemmed |
Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis |
title_sort |
lack of muscle mtor kinase activity causes early onset myopathy and compromises whole‐body homeostasis |
publisher |
Wiley |
series |
Journal of Cachexia, Sarcopenia and Muscle |
issn |
2190-5991 2190-6009 |
publishDate |
2019-02-01 |
description |
Abstract Background The protein kinase mechanistic target of rapamycin (mTOR) controls cellular growth and metabolism. Although balanced mTOR signalling is required for proper muscle homeostasis, partial mTOR inhibition by rapamycin has beneficial effects on various muscle disorders and age‐related pathologies. Besides, more potent mTOR inhibitors targeting mTOR catalytic activity have been developed and are in clinical trials. However, the physiological impact of loss of mTOR catalytic activity in skeletal muscle is currently unknown. Methods We have generated the mTORmKOKI mouse model in which conditional loss of mTOR is concomitant with expression of kinase inactive mTOR in skeletal muscle. We performed a comparative phenotypic and biochemical analysis of mTORmKOKI mutant animals with muscle‐specific mTOR knockout (mTORmKO) littermates. Results In striking contrast with mTORmKO littermates, mTORmKOKI mice developed an early onset rapidly progressive myopathy causing juvenile lethality. More than 50% mTORmKOKI mice died before 8 weeks of age, and none survived more than 12 weeks, while mTORmKO mice died around 7 months of age. The growth rate of mTORmKOKI mice declined beyond 1 week of age, and the animals showed profound alterations in body composition at 4 weeks of age. At this age, their body weight was 64% that of mTORmKO mice (P < 0.001) due to significant reduction in lean and fat mass. The mass of isolated muscles from mTORmKOKI mice was remarkably decreased by 38–56% (P < 0.001) as compared with that from mTORmKO mice. Histopathological analysis further revealed exacerbated dystrophic features and metabolic alterations in both slow/oxidative and fast/glycolytic muscles from mTORmKOKI mice. We show that the severity of the mTORmKOKI as compared with the mild mTORmKO phenotype is due to more robust suppression of muscle mTORC1 signalling leading to stronger alterations in protein synthesis, oxidative metabolism, and autophagy. This was accompanied with stronger feedback activation of PKB/Akt and dramatic down‐regulation of glycogen phosphorylase expression (0.16‐fold in tibialis anterior muscle, P < 0.01), thus causing features of glycogen storage disease type V. Conclusions Our study demonstrates a critical role for muscle mTOR catalytic activity in the regulation of whole‐body growth and homeostasis. We suggest that skeletal muscle targeting with mTOR catalytic inhibitors may have detrimental effects. The mTORmKOKI mutant mouse provides an animal model for the pathophysiological understanding of muscle mTOR activity inhibition as well as for mechanistic investigation of the influence of skeletal muscle perturbations on whole‐body homeostasis. |
topic |
mTOR kinase activity Myopathy Mitochondria Glycogen Body composition |
url |
https://doi.org/10.1002/jcsm.12336 |
work_keys_str_mv |
AT qingzhang lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis AT agnesduplany lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis AT vincentmoncollin lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis AT sandrinemouradian lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis AT evelynegoillot lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis AT laetitiamazelin lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis AT karinegauthier lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis AT nathaliestreichenberger lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis AT celineangleraux lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis AT jiechen lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis AT shuzheding lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis AT laurentschaeffer lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis AT yanngaelgangloff lackofmusclemtorkinaseactivitycausesearlyonsetmyopathyandcompromiseswholebodyhomeostasis |
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doaj-481283996c1a43f4bda9799c846af8172020-11-25T01:06:31ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092019-02-01101355310.1002/jcsm.12336Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasisQing Zhang0Agnès Duplany1Vincent Moncollin2Sandrine Mouradian3Evelyne Goillot4Laetitia Mazelin5Karine Gauthier6Nathalie Streichenberger7Céline Angleraux8Jie Chen9Shuzhe Ding10Laurent Schaeffer11Yann‐Gaël Gangloff12Institut NeuroMyoGene (INMG) Université Lyon 1, CNRS UMR 5310, INSERM U 1217 Lyon FranceInstitut NeuroMyoGene (INMG) Université Lyon 1, CNRS UMR 5310, INSERM U 1217 Lyon FranceInstitut NeuroMyoGene (INMG) Université Lyon 1, CNRS UMR 5310, INSERM U 1217 Lyon FranceInstitut NeuroMyoGene (INMG) Université Lyon 1, CNRS UMR 5310, INSERM U 1217 Lyon FranceInstitut NeuroMyoGene (INMG) Université Lyon 1, CNRS UMR 5310, INSERM U 1217 Lyon FranceInstitut NeuroMyoGene (INMG) Université Lyon 1, CNRS UMR 5310, INSERM U 1217 Lyon FranceInstitut de Génomique Fonctionnelle de Lyon, UMR 5242, CNRS, ENS Lyon Lyon Cedex 07 FranceInstitut NeuroMyoGene (INMG) Université Lyon 1, CNRS UMR 5310, INSERM U 1217 Lyon FranceAniRA PBES Biosciences Gerland ‐ Lyon Sud (UMS3444/US8), ENS Lyon Lyon FranceDepartment of Cell and Developmental Biology University of Illinois at Urbana‐Champaign Urbana IL USAKey Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education East China Normal University Shanghai ChinaInstitut NeuroMyoGene (INMG) Université Lyon 1, CNRS UMR 5310, INSERM U 1217 Lyon FranceInstitut NeuroMyoGene (INMG) Université Lyon 1, CNRS UMR 5310, INSERM U 1217 Lyon FranceAbstract Background The protein kinase mechanistic target of rapamycin (mTOR) controls cellular growth and metabolism. Although balanced mTOR signalling is required for proper muscle homeostasis, partial mTOR inhibition by rapamycin has beneficial effects on various muscle disorders and age‐related pathologies. Besides, more potent mTOR inhibitors targeting mTOR catalytic activity have been developed and are in clinical trials. However, the physiological impact of loss of mTOR catalytic activity in skeletal muscle is currently unknown. Methods We have generated the mTORmKOKI mouse model in which conditional loss of mTOR is concomitant with expression of kinase inactive mTOR in skeletal muscle. We performed a comparative phenotypic and biochemical analysis of mTORmKOKI mutant animals with muscle‐specific mTOR knockout (mTORmKO) littermates. Results In striking contrast with mTORmKO littermates, mTORmKOKI mice developed an early onset rapidly progressive myopathy causing juvenile lethality. More than 50% mTORmKOKI mice died before 8 weeks of age, and none survived more than 12 weeks, while mTORmKO mice died around 7 months of age. The growth rate of mTORmKOKI mice declined beyond 1 week of age, and the animals showed profound alterations in body composition at 4 weeks of age. At this age, their body weight was 64% that of mTORmKO mice (P < 0.001) due to significant reduction in lean and fat mass. The mass of isolated muscles from mTORmKOKI mice was remarkably decreased by 38–56% (P < 0.001) as compared with that from mTORmKO mice. Histopathological analysis further revealed exacerbated dystrophic features and metabolic alterations in both slow/oxidative and fast/glycolytic muscles from mTORmKOKI mice. We show that the severity of the mTORmKOKI as compared with the mild mTORmKO phenotype is due to more robust suppression of muscle mTORC1 signalling leading to stronger alterations in protein synthesis, oxidative metabolism, and autophagy. This was accompanied with stronger feedback activation of PKB/Akt and dramatic down‐regulation of glycogen phosphorylase expression (0.16‐fold in tibialis anterior muscle, P < 0.01), thus causing features of glycogen storage disease type V. Conclusions Our study demonstrates a critical role for muscle mTOR catalytic activity in the regulation of whole‐body growth and homeostasis. We suggest that skeletal muscle targeting with mTOR catalytic inhibitors may have detrimental effects. The mTORmKOKI mutant mouse provides an animal model for the pathophysiological understanding of muscle mTOR activity inhibition as well as for mechanistic investigation of the influence of skeletal muscle perturbations on whole‐body homeostasis.https://doi.org/10.1002/jcsm.12336mTOR kinase activityMyopathyMitochondriaGlycogenBody composition |