Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)35-53
Number of pages19
JournalJournal of Cachexia, Sarcopenia and Muscle
Volume10
Issue number1
DOIs
StatePublished - Feb 1 2019

Fingerprint

Muscular Diseases
Sirolimus
Homeostasis
Phosphotransferases
Muscles
Skeletal Muscle
Growth
Glycogen Storage Disease Type V
Glycogen Phosphorylase
Autophagy
Body Composition
Protein Kinases
Down-Regulation
Animal Models
Fats
Body Weight
Clinical Trials

Keywords

  • Body composition
  • Glycogen
  • Mitochondria
  • Myopathy
  • mTOR kinase activity

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Physiology (medical)

Cite this

Zhang, Q., Duplany, A., Moncollin, V., Mouradian, S., Goillot, E., Mazelin, L., ... Gangloff, Y. G. (2019). Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis. Journal of Cachexia, Sarcopenia and Muscle, 10(1), 35-53. https://doi.org/10.1002/jcsm.12336

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis. / Zhang, Qing; Duplany, Agnès; Moncollin, Vincent; Mouradian, Sandrine; Goillot, Evelyne; Mazelin, Laetitia; Gauthier, Karine; Streichenberger, Nathalie; Angleraux, Céline; Chen, Jie; Ding, Shuzhe; Schaeffer, Laurent; Gangloff, Yann Gaël.

In: Journal of Cachexia, Sarcopenia and Muscle, Vol. 10, No. 1, 01.02.2019, p. 35-53.

Research output: Contribution to journalArticle

Zhang, Q, Duplany, A, Moncollin, V, Mouradian, S, Goillot, E, Mazelin, L, Gauthier, K, Streichenberger, N, Angleraux, C, Chen, J, Ding, S, Schaeffer, L & Gangloff, YG 2019, 'Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis' Journal of Cachexia, Sarcopenia and Muscle, vol. 10, no. 1, pp. 35-53. https://doi.org/10.1002/jcsm.12336
Zhang, Qing ; Duplany, Agnès ; Moncollin, Vincent ; Mouradian, Sandrine ; Goillot, Evelyne ; Mazelin, Laetitia ; Gauthier, Karine ; Streichenberger, Nathalie ; Angleraux, Céline ; Chen, Jie ; Ding, Shuzhe ; Schaeffer, Laurent ; Gangloff, Yann Gaël. / Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis. In: Journal of Cachexia, Sarcopenia and Muscle. 2019 ; Vol. 10, No. 1. pp. 35-53.
@article{750c9bf2d068420e840fc87b6c91a294,
title = "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 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.",
keywords = "Body composition, Glycogen, Mitochondria, Myopathy, mTOR kinase activity",
author = "Qing Zhang and Agn{\`e}s Duplany and Vincent Moncollin and Sandrine Mouradian and Evelyne Goillot and Laetitia Mazelin and Karine Gauthier and Nathalie Streichenberger and C{\'e}line Angleraux and Jie Chen and Shuzhe Ding and Laurent Schaeffer and Gangloff, {Yann Ga{\"e}l}",
year = "2019",
month = "2",
day = "1",
doi = "10.1002/jcsm.12336",
language = "English (US)",
volume = "10",
pages = "35--53",
journal = "Journal of Cachexia, Sarcopenia and Muscle",
issn = "2190-5991",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis

AU - Zhang, Qing

AU - Duplany, Agnès

AU - Moncollin, Vincent

AU - Mouradian, Sandrine

AU - Goillot, Evelyne

AU - Mazelin, Laetitia

AU - Gauthier, Karine

AU - Streichenberger, Nathalie

AU - Angleraux, Céline

AU - Chen, Jie

AU - Ding, Shuzhe

AU - Schaeffer, Laurent

AU - Gangloff, Yann Gaël

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

KW - Body composition

KW - Glycogen

KW - Mitochondria

KW - Myopathy

KW - mTOR kinase activity

UR - http://www.scopus.com/inward/record.url?scp=85056791338&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056791338&partnerID=8YFLogxK

U2 - 10.1002/jcsm.12336

DO - 10.1002/jcsm.12336

M3 - Article

VL - 10

SP - 35

EP - 53

JO - Journal of Cachexia, Sarcopenia and Muscle

JF - Journal of Cachexia, Sarcopenia and Muscle

SN - 2190-5991

IS - 1

ER -