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Cited by 381Muscle Physiology and DisordersPI3K/AKT/mTOR signaling in cancerMuscle metabolism and nutrition

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Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy

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Risson, Valérie, Mazelin, Laetitia, Roceri, Mila, Sanchez, Hervé, Moncollin, Vincent, Corneloup, Claudine, Richard-Bulteau, Hélène, Vignaud, Alban, Baas, Dominique, Defour, Aurélia, Freyssenet, Damien, Tanti, Jean-François, Le-Marchand-Brustel, Yannick, Ferrier, Bernard, Conjard-Duplany, Agnès, Romanino, Klaas, Bauché, Stéphanie, Hantaï, Daniel, Mueller, Matthias, Kozma, Sara C., Thomas, George, Rüegg, Markus A., Ferry, Arnaud, Pende, Mario, Bigard, Xavier, Koulmann, Nathalie, Schaeffer, Laurent, Gangloff, Yann-Gaël·2009·Journal of Cell Biology
DOI 10.1083/jcb.200903131PMC PMC2806319
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Abstract

Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent.

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Figures

Figure 1. Muscle-specific inactivation of mTOR. (A) mTORflox and mTOR− mice were generated as described in Materials and methods. (B) PCR analysis of Cre-mediated recombination of the mTORflox allele (p2/p3) showing that the deleted mTOR allele (p1/p3) was exclusively detected in skeletal muscles of mTOR− mice. C, control; −, mTOR−. (C) Growth curves of mTOR− and control female mice (n = 15 mice). (D) Morphology of 22-wk-old female mTOR− mice. (E) Survival curve of mTOR− and control mice (n = 20). **, P < 0.01. Data indicate mean ± SD.
Figure 1. Muscle-specific inactivation of mTOR. (A) mTORflox and mTOR− mice were generated as described in Materials and methods. (B) PCR analysis of Cre-mediated recombination of the mTORflox allele (p2/p3) showing that the deleted mTOR allele (p1/p3) was exclusively detected in skeletal muscles of mTOR− mice. C, control; −, mTOR−. (C) Growth curves of mTOR− and control female mice (n = 15 mice). (D) Morphology of 22-wk-old female mTOR− mice. (E) Survival curve of mTOR− and control mice (n = 20). **, P < 0.01. Data indicate mean ± SD.CC BY-NC-SA · PubMed Central
Figure 2. mTOR− mice develop a progressive MD. (A) Analysis of the mean fiber CSA in TA and soleus muscles from 6-wk-old mice (n = 4). (B) H&E-stained transverse sections of TA, soleus, and diaphragm (DIA) muscles from control and mTOR− mice. Degeneration with phagocytosis and mononuclear cell infiltration (green arrows), variation in fiber size with small atrophic fibers (yellow arrows), interfiber connective tissue (thin arrows), regenerated muscle fibers with centrally located nuclei (black arrows), fibrosis (asterisk), and fatty infiltration (red arrows) are shown. Adipogenic differentiation was confirmed by oil red O staining as shown in the inset. Bar, 50 µm. (C) Percentage of centrally nucleated fibers (CNF) increases with age in mTOR− muscles. (D) Relative mRNA levels of MyH8, IGF-II, and myogenin in mTOR− muscles from 6-wk-old mice. (E–G) Graphs show the percentage distribution of MHC isoforms I, 2B, 2X, and 2A in soleus (E), TA (F), and PLA (G) muscles from 6-wk-old control and mTOR− mice. (C–G) n = 5 sample sets. *, P < 0.05; **, P < 0.01; ***, P < 0.001. Data indicate mean ± SEM.
Figure 2. mTOR− mice develop a progressive MD. (A) Analysis of the mean fiber CSA in TA and soleus muscles from 6-wk-old mice (n = 4). (B) H&E-stained transverse sections of TA, soleus, and diaphragm (DIA) muscles from control and mTOR− mice. Degeneration with phagocytosis and mononuclear cell infiltration (green arrows), variation in fiber size with small atrophic fibers (yellow arrows), interfiber connective tissue (thin arrows), regenerated muscle fibers with centrally located nuclei (black arrows), fibrosis (asterisk), and fatty infiltration (red arrows) are shown. Adipogenic differentiation was confirmed by oil red O staining as shown in the inset. Bar, 50 µm. (C) Percentage of centrally nucleated fibers (CNF) increases with age in mTOR− muscles. (D) Relative mRNA levels of MyH8, IGF-II, and myogenin in mTOR− muscles from 6-wk-old mice. (E–G) Graphs show the percentage distribution of MHC isoforms I, 2B, 2X, and 2A in soleus (E), TA (F), and PLA (G) muscles from 6-wk-old control and mTOR− mice. (C–G) n = 5 sample sets. *, P < 0.05; **, P < 0.01; ***, P < 0.001. Data indicate mean ± SEM.CC BY-NC-SA · PubMed Central
Figure 3. Reduced DGC amount and utrophin induction in mTOR− muscles. (A) Soleus, diaphragm, and TA muscle extracts from 6-wk-old mice were immunoblotted with the indicated antibodies to examine dystrophy-related protein levels. Black lines indicate that intervening lanes have been spliced out. (B) Rare Evans blue–positive fibers can be detected in mTOR− diaphragms from 30-wk-old mice. (C) Dystrophin immunostaining (green) and Hoechst staining (blue) on soleus muscle sections from 11-wk-old control and mTOR− mice showing sarcolemmal localization of residual dystrophin. A higher magnification view (inset) shows that dystrophin expression is reduced in noncentronucleated fibers, whereas it is normal in regenerating centronucleated fibers. Bars, 50 µm.
Figure 3. Reduced DGC amount and utrophin induction in mTOR− muscles. (A) Soleus, diaphragm, and TA muscle extracts from 6-wk-old mice were immunoblotted with the indicated antibodies to examine dystrophy-related protein levels. Black lines indicate that intervening lanes have been spliced out. (B) Rare Evans blue–positive fibers can be detected in mTOR− diaphragms from 30-wk-old mice. (C) Dystrophin immunostaining (green) and Hoechst staining (blue) on soleus muscle sections from 11-wk-old control and mTOR− mice showing sarcolemmal localization of residual dystrophin. A higher magnification view (inset) shows that dystrophin expression is reduced in noncentronucleated fibers, whereas it is normal in regenerating centronucleated fibers. Bars, 50 µm.CC BY-NC-SA · PubMed Central
Figure 4. mTOR controls dystrophin expression. (A) Time course for mTOR inactivation, dystrophin down-regulation, and induction of terminal differentiation markers in cultured mTORflox myotubes. The myotubes were transduced by CMV-GFP or CMV-Cre adenovirus on differentiation day 1 (dd1), harvested at a different time point after differentiation, and immunoblotted with the indicated antibodies. (B) Relative mRNA levels of mTOR and the indicated DGC components in mTORflox myotubes transduced by Ad-Cre (n = 3). (C) Relative mRNA levels of mTOR and the indicated dystrophy-related genes in muscles from 6-wk-old mice (n = 5). (D) Detection of mTOR on the dystrophin promoter by ChIP assay. Antibodies against mTOR (lane 1), normal mouse IgG (lane 2), or RNA polymerase 2 (lane 3) were used to immunoprecipitate (IP) a mouse TA chromatin extract. The precipitated DNA was analyzed by PCR using primers for the dystrophin (top) or dysferlin (bottom) promoter. (E, top) Western blot analysis showing the phosphorylation status of S6 protein in C2C12 myotubes in the absence (−) or presence (+) of 20 nM rapamycin or 250 nM Torin1 for 48 h from differentiation day 4. For soleus muscle, C57BL/6 mice were daily injected intraperitoneally with 2.5 mg/kg rapamycin or vehicle for 8 d. (bottom) mRNA levels for the indicated DGC components in C2C12 myotubes and soleus muscle in absence or presence of the indicated mTOR inhibitors. (F) Relative mRNA levels of dystrophin in the TA muscle fibers of mTOR− mice 12 d after in vivo coelectroporation of rat wild-type (wt) or kinase-dead (kd) mTOR and pRNAT-GFP vector. Graphs show means versus pcDNA3-electroporated control (n = 5 mice/group). (G) Western blot analysis showing dystrophin protein levels in soleus muscle from 14-wk-old RAmKO and RImKO mice. *, P < 0.05; **, P < 0.01; ***, P < 0.001. Data indicate mean ± SEM.
Figure 4. mTOR controls dystrophin expression. (A) Time course for mTOR inactivation, dystrophin down-regulation, and induction of terminal differentiation markers in cultured mTORflox myotubes. The myotubes were transduced by CMV-GFP or CMV-Cre adenovirus on differentiation day 1 (dd1), harvested at a different time point after differentiation, and immunoblotted with the indicated antibodies. (B) Relative mRNA levels of mTOR and the indicated DGC components in mTORflox myotubes transduced by Ad-Cre (n = 3). (C) Relative mRNA levels of mTOR and the indicated dystrophy-related genes in muscles from 6-wk-old mice (n = 5). (D) Detection of mTOR on the dystrophin promoter by ChIP assay. Antibodies against mTOR (lane 1), normal mouse IgG (lane 2), or RNA polymerase 2 (lane 3) were used to immunoprecipitate (IP) a mouse TA chromatin extract. The precipitated DNA was analyzed by PCR using primers for the dystrophin (top) or dysferlin (bottom) promoter. (E, top) Western blot analysis showing the phosphorylation status of S6 protein in C2C12 myotubes in the absence (−) or presence (+) of 20 nM rapamycin or 250 nM Torin1 for 48 h from differentiation day 4. For soleus muscle, C57BL/6 mice were daily injected intraperitoneally with 2.5 mg/kg rapamycin or vehicle for 8 d. (bottom) mRNA levels for the indicated DGC components in C2C12 myotubes and soleus muscle in absence or presence of the indicated mTOR inhibitors. (F) Relative mRNA levels of dystrophin in the TA muscle fibers of mTOR− mice 12 d after in vivo coelectroporation of rat wild-type (wt) or kinase-dead (kd) mTOR and pRNAT-GFP vector. Graphs show means versus pcDNA3-electroporated control (n = 5 mice/group). (G) Western blot analysis showing dystrophin protein levels in soleus muscle from 14-wk-old RAmKO and RImKO mice. *, P < 0.05; **, P < 0.01; ***, P < 0.001. Data indicate mean ± SEM.CC BY-NC-SA · PubMed Central
Figure 5. Signal transduction in mTOR− muscles. (A) Muscle extracts from 6-wk-old mice were immunoblotted with the indicated antibodies to examine mTORC1 and mTORC2 signaling in soleus and TA muscles. Black lines indicate that intervening lanes have been spliced out. (B and C) Immunofluorescence staining for total PKB/Akt (B) and P-PKB/Akt (C; green) and Hoechst staining (blue) on control and mTOR− soleus muscle sections. Bars, 50 µm. (D) Relative mRNA levels of MuRF1 and MAFbx in mTOR− soleus and TA muscles. **, P < 0.01; ***, P < 0.001. Data indicate means versus control ± SEM (n = 5 sample sets).
Figure 5. Signal transduction in mTOR− muscles. (A) Muscle extracts from 6-wk-old mice were immunoblotted with the indicated antibodies to examine mTORC1 and mTORC2 signaling in soleus and TA muscles. Black lines indicate that intervening lanes have been spliced out. (B and C) Immunofluorescence staining for total PKB/Akt (B) and P-PKB/Akt (C; green) and Hoechst staining (blue) on control and mTOR− soleus muscle sections. Bars, 50 µm. (D) Relative mRNA levels of MuRF1 and MAFbx in mTOR− soleus and TA muscles. **, P < 0.01; ***, P < 0.001. Data indicate means versus control ± SEM (n = 5 sample sets).CC BY-NC-SA · PubMed Central
Figure 6. Altered glucose usage and glycogen accumulation in mTOR− muscle. (A) Representative periodic acid Schiff staining of soleus (SOL), PLA, GC, and TA muscle sections from 6-wk-old mice showing glycogen accumulation in mTOR− muscles. Bar, 400 µm. (B) Quantification of muscle glycogen content (n = 5 sample sets). (C and D) GP and glycolytic enzyme activity in soleus (C) and TA (D) muscles (control, n = 5; mTOR−, n = 4). (E) Relative mRNA levels of the indicated glycolytic enzymes in mTOR− muscles (n = 5 sample sets). (F) Quantification of intramuscular glucose-6-phosphate (G6P) in control and mTOR− mice. (G) Quantification of intramuscular lactate in control and mTOR− mice. (H) Enhanced basal glucose uptake in isolated soleus muscle from 5-wk-old control and mTOR− mice (n = 5–6 mice). (F and G) n = 8 sample sets. HK, hexokinase. *, P < 0.05; **, P < 0.01; ***, P < 0.001. Data indicate mean ± SEM.
Figure 6. Altered glucose usage and glycogen accumulation in mTOR− muscle. (A) Representative periodic acid Schiff staining of soleus (SOL), PLA, GC, and TA muscle sections from 6-wk-old mice showing glycogen accumulation in mTOR− muscles. Bar, 400 µm. (B) Quantification of muscle glycogen content (n = 5 sample sets). (C and D) GP and glycolytic enzyme activity in soleus (C) and TA (D) muscles (control, n = 5; mTOR−, n = 4). (E) Relative mRNA levels of the indicated glycolytic enzymes in mTOR− muscles (n = 5 sample sets). (F) Quantification of intramuscular glucose-6-phosphate (G6P) in control and mTOR− mice. (G) Quantification of intramuscular lactate in control and mTOR− mice. (H) Enhanced basal glucose uptake in isolated soleus muscle from 5-wk-old control and mTOR− mice (n = 5–6 mice). (F and G) n = 8 sample sets. HK, hexokinase. *, P < 0.05; **, P < 0.01; ***, P < 0.001. Data indicate mean ± SEM.CC BY-NC-SA · PubMed Central
Figure 7. Impaired oxidative metabolism in mTOR− soleus muscle. (A) mTOR− soleus muscle is paler than control muscle. (B) Succinate dehydrogenase histochemical staining demonstrating alterations of oxidative metabolism in mTOR− soleus muscle from 6-wk-old mice. Oxidative and glycolytic fibers are indicated by red and yellow arrows, respectively. Bar, 100 µm. (C) Decreased citrate synthase (CS) activity in mTOR− soleus muscle (n = 5 sample sets). (D) Relative mRNA levels of genes involved in oxidative energy production in mTOR− soleus muscle (n = 5 sample sets). (E) Western blot analysis showing reduced protein levels for myoglobin, cytochrome c (cytc), and respiratory chain components (CI–CV) in mTOR− soleus muscle. Equal protein loading was controlled by measuring total protein content and Coomassie blue staining. (F) Effect of mTOR depletion on mitochondrial respiration in saponin-skinned fibers from soleus muscles from 6-wk-old mice with glutamate and malate as substrates. The following data were measured: basal rate of mitochondrial oxygen consumption in the absence of ADP (Vo), maximal rate of oxygen consumption in the presence of 2 mM ADP (Vmax), and acceptor control ratio (ACR; control, n = 15; mTOR−, n = 8). (G) Effect of mTOR depletion on mitochondria sensitivity for ADP in saponin-skinned fibers from soleus muscles. The apparent Km for ADP was measured in the absence and presence of 20 mM creatine (control, n = 8; mTOR−, n = 5). (H) Intramuscular ATP levels in muscles from control and mTOR− mice (n = 8 sample sets). ##, P < 0.01 (for control with creatine versus control without creatine); **, P < 0.01 (for mTOR− without creatine versus control without creatine). Data indicate mean ± SEM.
Figure 7. Impaired oxidative metabolism in mTOR− soleus muscle. (A) mTOR− soleus muscle is paler than control muscle. (B) Succinate dehydrogenase histochemical staining demonstrating alterations of oxidative metabolism in mTOR− soleus muscle from 6-wk-old mice. Oxidative and glycolytic fibers are indicated by red and yellow arrows, respectively. Bar, 100 µm. (C) Decreased citrate synthase (CS) activity in mTOR− soleus muscle (n = 5 sample sets). (D) Relative mRNA levels of genes involved in oxidative energy production in mTOR− soleus muscle (n = 5 sample sets). (E) Western blot analysis showing reduced protein levels for myoglobin, cytochrome c (cytc), and respiratory chain components (CI–CV) in mTOR− soleus muscle. Equal protein loading was controlled by measuring total protein content and Coomassie blue staining. (F) Effect of mTOR depletion on mitochondrial respiration in saponin-skinned fibers from soleus muscles from 6-wk-old mice with glutamate and malate as substrates. The following data were measured: basal rate of mitochondrial oxygen consumption in the absence of ADP (Vo), maximal rate of oxygen consumption in the presence of 2 mM ADP (Vmax), and acceptor control ratio (ACR; control, n = 15; mTOR−, n = 8). (G) Effect of mTOR depletion on mitochondria sensitivity for ADP in saponin-skinned fibers from soleus muscles. The apparent Km for ADP was measured in the absence and presence of 20 mM creatine (control, n = 8; mTOR−, n = 5). (H) Intramuscular ATP levels in muscles from control and mTOR− mice (n = 8 sample sets). ##, P < 0.01 (for control with creatine versus control without creatine); **, P < 0.01 (for mTOR− without creatine versus control without creatine). Data indicate mean ± SEM.CC BY-NC-SA · PubMed Central
Figure 8. Glucose homeostasis and insulin sensitivity in mTOR− mice. (A) Fasting and fed blood glucose concentrations in mTOR− and control male mice. (B) Fasting and fed serum insulin concentrations in mTOR− and control male mice (n = 7 mice/group). (C) Glucose tolerance test on male mice (n = 15 mice/group). (D) Insulin tolerance test on mTOR− and control mice (n = 8 mice/group). **, P < 0.01. Data indicate mean ± SEM.
Figure 8. Glucose homeostasis and insulin sensitivity in mTOR− mice. (A) Fasting and fed blood glucose concentrations in mTOR− and control male mice. (B) Fasting and fed serum insulin concentrations in mTOR− and control male mice (n = 7 mice/group). (C) Glucose tolerance test on male mice (n = 15 mice/group). (D) Insulin tolerance test on mTOR− and control mice (n = 8 mice/group). **, P < 0.01. Data indicate mean ± SEM.CC BY-NC-SA · PubMed Central

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Authors
Risson, V., Mazelin, L., Roceri, M., Sanchez, H., Moncollin, V., Corneloup, C., Richard-Bulteau, H., Vignaud, A., Baas, D., Defour, A., Freyssenet, D., Tanti, J.-F., Le-Marchand-Brustel, Y., Ferrier, B., Conjard-Duplany, A., Romanino, K., Bauché, S., Hantaï, D., Mueller, M., Kozma, S. C., Thomas, G., Rüegg, M. A., Ferry, A., Pende, M., Bigard, X., Koulmann, N., Schaeffer, L., & Gangloff, Y.-G.
Affiliations
  • École Normale Supérieure de Lyon (FR)
  • Inserm (FR)
  • Service de Santé des Armées (FR)
  • Department of Human Factors, Research Center of the Health of the Military, La Tronche 38702, France 3
  • Université Pierre-et-Marie-Curie (FR)
  • Université de Lyon (FR)
  • Institut National de la Santé et de la Recherche Médicale, Unité 895, Centre Méditerranéen de Médecine Moléculaire, F-06204 Nice, France 6
  • Lyon 1 Université (FR)
  • Métabolomique et Maladies Métaboliques, Institut National de la Santé et de la Recherche Médicale, Unité 820, Faculté de Médecine R.T.H. Laennec, Université Claude Bernard Lyon 1, 69372 Lyon Cedex 08, France 8
  • University of Basel (CH)
  • Institut National de la Santé et de la Recherche Médicale, Université Pierre et Marie Curie, Unité Mixte de Recherche 975, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France 10
  • Novartis (Switzerland) (CH)
  • University of Cincinnati (US)
Corresponding author
  • Schaeffer, Laurent
  • Gangloff, Yann-Gaël
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2009-12-14
Volume
187
Issue
6
Pages
859-874
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.200903131
PMC
PMC2806319
OpenAlex
W2164316354
Cited by
381
References
52
Citations by year
2026: 8 · 2025: 14 · 2024: 17 · 2023: 15 · 2022: 26 · 2021: 31 · 2020: 28 · 2019: 25 · 2018: 23 · 2017: 31 · 2016: 28 · 2015: 22 · 2014: 28 · 2013: 27 · 2012: 26
FWCI
7.78
Type
journal article
Language
en
Open access
Locations
  • The Journal of Cell Biology (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • edoc (University of Basel) (acceptedVersion)
  • HAL (submittedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
Funders
Agence Nationale de la Recherche (ANR-06-BLAN-0354)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
Keywords
mTOR, mTORC1, mTORC2, raptors, Rictor, muscle myopathies, dystrophin, oxidative metabolism, mitochondrial regulation, glycogen accumulation, glucose uptake, glucose homeostasis, rapamycin resistance, kinase-independent signaling
MeSH terms
Regulatory-Associated Protein of mTOR, Rapamycin-Insensitive Companion of mTOR Protein, Age Factors, Animals, Carrier Proteins, Cells, Cultured, Energy Metabolism, Enzyme Activation, Female, Glucose, Glycogen, Mice, Inbred C57BL, Mitochondria, Muscle, Muscle Contraction, Muscular Dystrophy, Animal, Mutation, Oxidation-Reduction, Severity of Illness Index, Transduction, Genetic, Dystrophin, Phosphotransferases (Alcohol Group Acceptor), Electroporation, Mice, Knockout, Muscle, Skeletal, Sirolimus, Adaptor Proteins, Signal Transducing, Utrophin, Proto-Oncogene Proteins c-akt, Mice, Rats, TOR Serine-Threonine Kinases

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