{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:07:34Z","timestamp":1792714054921,"version":"4.5.0"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Skeletal Muscle"],"published-print":{"date-parts":[[2013,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Skeletal muscle mass is determined by the balance between protein synthesis and degradation. Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of protein translation and has been implicated in the control of muscle mass. Inactivation of mTORC1 by skeletal muscle-specific deletion of its obligatory component raptor results in smaller muscles and a lethal dystrophy. Moreover, raptor-deficient muscles are less oxidative through changes in the expression PGC-1\u03b1, a critical determinant of mitochondrial biogenesis. These results suggest that activation of mTORC1 might be beneficial to skeletal muscle by providing resistance to muscle atrophy and increasing oxidative function. Here, we tested this hypothesis by deletion of the mTORC1 inhibitor tuberous sclerosis complex (TSC) in muscle fibers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>Skeletal muscles of mice with an acute or a permanent deletion of raptor or TSC1 were examined using histological, biochemical and molecular biological methods. Response of the muscles to changes in mechanical load and nerve input was investigated by ablation of synergistic muscles or by denervation .<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Genetic deletion or knockdown of raptor, causing inactivation of mTORC1, was sufficient to prevent muscle growth and enhance muscle atrophy. Conversely, short-term activation of mTORC1 by knockdown of TSC induced muscle fiber hypertrophy and atrophy-resistance upon denervation, in both fast\n                      <jats:italic>tibialis anterior<\/jats:italic>\n                      (TA) and slow\n                      <jats:italic>soleus<\/jats:italic>\n                      muscles. Surprisingly, however, sustained activation of mTORC1 by genetic deletion of\n                      <jats:italic>Tsc1<\/jats:italic>\n                      caused muscle atrophy in all but\n                      <jats:italic>soleus<\/jats:italic>\n                      muscles. In contrast, oxidative capacity was increased in all muscles examined. Consistently, TSC1-deficient\n                      <jats:italic>soleus<\/jats:italic>\n                      muscle was atrophy-resistant whereas TA underwent normal atrophy upon denervation. Moreover, upon overloading,\n                      <jats:italic>plantaris<\/jats:italic>\n                      muscle did not display enhanced hypertrophy compared to controls. Biochemical analysis indicated that the atrophy response of muscles was based on the suppressed phosphorylation of PKB\/Akt via feedback inhibition by mTORC1 and subsequent increased expression of the E3 ubiquitin ligases\n                      <jats:italic>MuRF1<\/jats:italic>\n                      and\n                      <jats:italic>atrogin-1\/MAFbx<\/jats:italic>\n                      . In contrast, expression of both E3 ligases was not increased in\n                      <jats:italic>soleus<\/jats:italic>\n                      muscle suggesting the presence of compensatory mechanisms in this muscle.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study shows that the mTORC1- and the PKB\/Akt-FoxO pathways are tightly interconnected and differentially regulated depending on the muscle type. These results indicate that long-term activation of the mTORC1 signaling axis is not a therapeutic option to promote muscle growth because of its strong feedback induction of the E3 ubiquitin ligases involved in protein degradation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/2044-5040-3-6","type":"journal-article","created":{"date-parts":[[2013,3,6]],"date-time":"2013-03-06T04:20:02Z","timestamp":1362543602000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":155,"title":["Differential response of skeletal muscles to mTORC1 signaling during atrophy and hypertrophy"],"prefix":"10.1186","volume":"3","author":[{"given":"C Florian","family":"Bentzinger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaas","family":"Romanino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perrine","family":"Castets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maitea","family":"Guridi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Summermatter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Handschin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel A","family":"Tintignac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael N","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus A","family":"R\u00fcegg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,3,6]]},"reference":[{"key":"68_CR1","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1152\/physiol.00041.2007","volume":"23","author":"M Sandri","year":"2008","unstructured":"Sandri M: Signaling in muscle atrophy and hypertrophy. Physiology (Bethesda). 2008, 23: 160-170. 10.1152\/physiol.00041.2007.","journal-title":"Physiology (Bethesda)"},{"key":"68_CR2","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1146\/annurev-pharmtox-010510-100537","volume":"51","author":"MA Ruegg","year":"2011","unstructured":"Ruegg MA, Glass DJ: Molecular mechanisms and treatment options for muscle wasting diseases. Annu Rev Pharmacol Toxicol. 2011, 51: 373-395. 10.1146\/annurev-pharmtox-010510-100537.","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"68_CR3","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.cell.2006.01.016","volume":"124","author":"S Wullschleger","year":"2006","unstructured":"Wullschleger S, Loewith R, Hall MN: TOR signaling in growth and metabolism. Cell. 2006, 124: 471-484. 10.1016\/j.cell.2006.01.016.","journal-title":"Cell"},{"key":"68_CR4","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","volume":"149","author":"M Laplante","year":"2012","unstructured":"Laplante M, Sabatini DM: mTOR signaling in growth control and disease. Cell. 2012, 149: 274-293. 10.1016\/j.cell.2012.03.017.","journal-title":"Cell"},{"key":"68_CR5","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1038\/ncb1101-1014","volume":"3","author":"SC Bodine","year":"2001","unstructured":"Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, Yancopoulos GD: Akt\/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol. 2001, 3: 1014-1019. 10.1038\/ncb1101-1014.","journal-title":"Nat Cell Biol"},{"key":"68_CR6","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1016\/j.cmet.2007.11.004","volume":"6","author":"J Zhao","year":"2007","unstructured":"Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH, Goldberg AL: FoxO3 coordinately activates protein degradation by the autophagic\/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 2007, 6: 472-483. 10.1016\/j.cmet.2007.11.004.","journal-title":"Cell Metab"},{"key":"68_CR7","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/S1097-2765(04)00211-4","volume":"14","author":"TN Stitt","year":"2004","unstructured":"Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ: The IGF-1\/PI3K\/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell. 2004, 14: 395-403. 10.1016\/S1097-2765(04)00211-4.","journal-title":"Mol Cell"},{"key":"68_CR8","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/S0092-8674(04)00400-3","volume":"117","author":"M Sandri","year":"2004","unstructured":"Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL: Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004, 117: 399-412. 10.1016\/S0092-8674(04)00400-3.","journal-title":"Cell"},{"key":"68_CR9","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1016\/j.cmet.2007.11.001","volume":"6","author":"C Mammucari","year":"2007","unstructured":"Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M: FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 2007, 6: 458-471. 10.1016\/j.cmet.2007.11.001.","journal-title":"Cell Metab"},{"key":"68_CR10","doi-asserted-by":"publisher","first-page":"9295","DOI":"10.1128\/MCB.24.21.9295-9304.2004","volume":"24","author":"KM Lai","year":"2004","unstructured":"Lai KM, Gonzalez M, Poueymirou WT, Kline WO, Na E, Zlotchenko E, Stitt TN, Economides AN, Yancopoulos GD, Glass DJ: Conditional activation of akt in adult skeletal muscle induces rapid hypertrophy. Mol Cell Biol. 2004, 24: 9295-9304. 10.1128\/MCB.24.21.9295-9304.2004.","journal-title":"Mol Cell Biol"},{"key":"68_CR11","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.cmet.2007.11.003","volume":"7","author":"Y Izumiya","year":"2008","unstructured":"Izumiya Y, Hopkins T, Morris C, Sato K, Zeng L, Viereck J, Hamilton JA, Ouchi N, LeBrasseur NK, Walsh K: Fast\/Glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab. 2008, 7: 159-172. 10.1016\/j.cmet.2007.11.003.","journal-title":"Cell Metab"},{"key":"68_CR12","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1038\/ncb1183","volume":"6","author":"E Jacinto","year":"2004","unstructured":"Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN: Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004, 6: 1122-1128. 10.1038\/ncb1183.","journal-title":"Nat Cell Biol"},{"key":"68_CR13","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1016\/j.cub.2004.06.054","volume":"14","author":"DD Sarbassov","year":"2004","unstructured":"Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM: Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004, 14: 1296-1302. 10.1016\/j.cub.2004.06.054.","journal-title":"Curr Biol"},{"key":"68_CR14","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1126\/science.1215135","volume":"335","author":"DW Lamming","year":"2012","unstructured":"Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA: Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012, 335: 1638-1643. 10.1126\/science.1215135.","journal-title":"Science"},{"key":"68_CR15","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1128\/MCB.01405-07","volume":"28","author":"A Kumar","year":"2008","unstructured":"Kumar A, Harris TE, Keller SR, Choi KM, Magnuson MA, Lawrence JC: Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances basal glycogen synthase activity. Mol Cell Biol. 2008, 28: 61-70. 10.1128\/MCB.01405-07.","journal-title":"Mol Cell Biol"},{"key":"68_CR16","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.cmet.2008.10.002","volume":"8","author":"CF Bentzinger","year":"2008","unstructured":"Bentzinger CF, Romanino K, Clo\u00ebtta D, Lin S, Mascarenhas JB, Oliveri F, Xia J, Casanova E, Costa CF, Brink M, Zorzato F, Hall MN, R\u00fcegg MA: Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 2008, 8: 411-424. 10.1016\/j.cmet.2008.10.002.","journal-title":"Cell Metab"},{"key":"68_CR17","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1038\/ncb1101-1009","volume":"3","author":"C Rommel","year":"2001","unstructured":"Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L, Stitt TN, Yancopoulos GD, Glass DJ: Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K\/Akt\/mTOR and PI(3)K\/Akt\/GSK3 pathways. Nat Cell Biol. 2001, 3: 1009-1013. 10.1038\/ncb1101-1009.","journal-title":"Nat Cell Biol"},{"key":"68_CR18","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1152\/japplphysiol.00873.2006","volume":"102","author":"WO Kline","year":"2007","unstructured":"Kline WO, Panaro FJ, Yang H, Bodine SC: Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol. J Appl Physiol. 2007, 102: 740-747.","journal-title":"J Appl Physiol"},{"key":"68_CR19","doi-asserted-by":"publisher","first-page":"5621","DOI":"10.1016\/j.febslet.2006.09.008","volume":"580","author":"M Wan","year":"2006","unstructured":"Wan M, Wu X, Guan KL, Han M, Zhuang Y, Xu T: Muscle atrophy in transgenic mice expressing a human TSC1 transgene. FEBS Lett. 2006, 580: 5621-5627. 10.1016\/j.febslet.2006.09.008.","journal-title":"FEBS Lett"},{"key":"68_CR20","doi-asserted-by":"publisher","first-page":"3258","DOI":"10.1091\/mbc.E10-05-0454","volume":"21","author":"CA Goodman","year":"2010","unstructured":"Goodman CA, Miu MH, Frey JW, Mabrey DM, Lincoln HC, Ge Y, Chen J, Hornberger TA: A phosphatidylinositol 3-kinase\/protein kinase B-independent activation of mammalian target of rapamycin signaling is sufficient to induce skeletal muscle hypertrophy. Mol Biol Cell. 2010, 21: 3258-3268. 10.1091\/mbc.E10-05-0454.","journal-title":"Mol Biol Cell"},{"key":"68_CR21","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1038\/ncb1231","volume":"7","author":"M Ohanna","year":"2005","unstructured":"Ohanna M, Sobering AK, Lapointe T, Lorenzo L, Praud C, Petroulakis E, Sonenberg N, Kelly PA, Sotiropoulos A, Pende M: Atrophy of S6K1(\u2212\/\u2212) skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control. Nat Cell Biol. 2005, 7: 286-294. 10.1038\/ncb1231.","journal-title":"Nat Cell Biol"},{"key":"68_CR22","doi-asserted-by":"publisher","first-page":"20808","DOI":"10.1073\/pnas.1111448109","volume":"108","author":"K Romanino","year":"2011","unstructured":"Romanino K, Mazelin L, Albert V, Conjard-Duplany A, Lin S, Bentzinger CF, Handschin C, Puigserver P, Zorzato F, Schaeffer L, Gangloff YG, R\u00fcegg MA: Myopathy caused by mammalian target of rapamycin complex 1 (mTORC1) inactivation is not reversed by restoring mitochondrial function. Proc Natl Acad Sci U S A. 2011, 108: 20808-20813. 10.1073\/pnas.1111448109.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"68_CR23","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1093\/hmg\/11.5.525","volume":"11","author":"DJ Kwiatkowski","year":"2002","unstructured":"Kwiatkowski DJ, Zhang H, Bandura JL, Heiberger KM, Glogauer M, el-Hashemite N, Onda H: A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet. 2002, 11: 525-534. 10.1093\/hmg\/11.5.525.","journal-title":"Hum Mol Genet"},{"key":"68_CR24","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/S1534-5807(03)00118-7","volume":"4","author":"M Schwander","year":"2003","unstructured":"Schwander M, Leu M, Stumm M, Dorchies OM, Ruegg UT, Schittny J, Muller U: Beta1 integrins regulate myoblast fusion and sarcomere assembly. Dev Cell. 2003, 4: 673-685. 10.1016\/S1534-5807(03)00118-7.","journal-title":"Dev Cell"},{"key":"68_CR25","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/sj.embor.7400065","volume":"5","author":"XC Kong","year":"2004","unstructured":"Kong XC, Barzaghi P, Ruegg MA: Inhibition of synapse assembly in mammalian muscle in vivo by RNA interference. EMBO Rep. 2004, 5: 183-188. 10.1038\/sj.embor.7400065.","journal-title":"EMBO Rep"},{"key":"68_CR26","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.nmd.2004.10.013","volume":"15","author":"T Shavlakadze","year":"2005","unstructured":"Shavlakadze T, White JD, Davies M, Hoh JF, Grounds MD: Insulin-like growth factor I slows the rate of denervation induced skeletal muscle atrophy. Neuromuscul Disord. 2005, 15: 139-146. 10.1016\/j.nmd.2004.10.013.","journal-title":"Neuromuscul Disord"},{"key":"68_CR27","doi-asserted-by":"crossref","first-page":"C1561","DOI":"10.1152\/ajpcell.2001.280.6.C1561","volume":"280","author":"D Stockholm","year":"2001","unstructured":"Stockholm D, Herasse M, Marchand S, Praud C, Roudaut C, Richard I, Sebille A, Beckmann JS: Calpain 3 mRNA expression in mice after denervation and during muscle regeneration. Am J Physiol Cell Physiol. 2001, 280: C1561-C1569.","journal-title":"Am J Physiol Cell Physiol"},{"key":"68_CR28","doi-asserted-by":"publisher","first-page":"21908","DOI":"10.1074\/jbc.274.31.21908","volume":"274","author":"SE Dunn","year":"1999","unstructured":"Dunn SE, Burns JL, Michel RN: Calcineurin is required for skeletal muscle hypertrophy. J Biol Chem. 1999, 274: 21908-21912. 10.1074\/jbc.274.31.21908.","journal-title":"J Biol Chem"},{"key":"68_CR29","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1093\/hmg\/7.6.1053","volume":"7","author":"M van Slegtenhorst","year":"1998","unstructured":"van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, Reuser A, Sampson J, Halley D, van der Sluijs P: Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet. 1998, 7: 1053-1057. 10.1093\/hmg\/7.6.1053.","journal-title":"Hum Mol Genet"},{"key":"68_CR30","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/nmeth.1314","volume":"6","author":"EK Schmidt","year":"2009","unstructured":"Schmidt EK, Clavarino G, Ceppi M, Pierre P: SUnSET, a nonradioactive method to monitor protein synthesis. Nat Methods. 2009, 6: 275-277. 10.1038\/nmeth.1314.","journal-title":"Nat Methods"},{"key":"68_CR31","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/S1525-0016(03)00129-1","volume":"8","author":"P Dunant","year":"2003","unstructured":"Dunant P, Larochelle N, Thirion C, Stucka R, Ursu D, Petrof BJ, Wolf E, Lochmuller H: Expression of dystrophin driven by the 1.35-kb MCK promoter ameliorates muscular dystrophy in fast, but not in slow muscles of transgenic mdx mice. Mol Ther. 2003, 8: 80-89. 10.1016\/S1525-0016(03)00129-1.","journal-title":"Mol Ther"},{"key":"68_CR32","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.nmd.2004.06.008","volume":"14","author":"A Briguet","year":"2004","unstructured":"Briguet A, Courdier-Fruh I, Foster M, Meier T, Magyar JP: Histological parameters for the quantitative assessment of muscular dystrophy in the mdx-mouse. Neuromuscul Disord. 2004, 14: 675-682. 10.1016\/j.nmd.2004.06.008.","journal-title":"Neuromuscul Disord"},{"key":"68_CR33","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1113\/jphysiol.1974.sp010645","volume":"241","author":"DA Tonge","year":"1974","unstructured":"Tonge DA: Physiological characteristics of re-innervation of skeletal muscle in the mouse. J Physiol. 1974, 241: 141-153.","journal-title":"J Physiol"},{"key":"68_CR34","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1002\/mus.20749","volume":"35","author":"M Liu","year":"2007","unstructured":"Liu M, Zhang D, Shao C, Liu J, Ding F, Gu X: Expression pattern of myostatin in gastrocnemius muscle of rats after sciatic nerve crush injury. Muscle Nerve. 2007, 35: 649-656. 10.1002\/mus.20749.","journal-title":"Muscle Nerve"},{"key":"68_CR35","doi-asserted-by":"publisher","first-page":"5546","DOI":"10.1523\/JNEUROSCI.5540-06.2007","volume":"27","author":"L Meikle","year":"2007","unstructured":"Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A, Sahin M, Jensen FE, Kwiatkowski DJ: A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci. 2007, 27: 5546-5558. 10.1523\/JNEUROSCI.5540-06.2007.","journal-title":"J Neurosci"},{"key":"68_CR36","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/j.cmet.2009.03.005","volume":"9","author":"H Mori","year":"2009","unstructured":"Mori H, Inoki K, Munzberg H, Opland D, Faouzi M, Villanueva EC, Ikenoue T, Kwiatkowski D, MacDougald OA, Myers MG, Guan KL: Critical role for hypothalamic mTOR activity in energy balance. Cell Metab. 2009, 9: 362-374. 10.1016\/j.cmet.2009.03.005.","journal-title":"Cell Metab"},{"key":"68_CR37","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1093\/hmg\/ddq491","volume":"20","author":"LH Zeng","year":"2011","unstructured":"Zeng LH, Rensing NR, Zhang B, Gutmann DH, Gambello MJ, Wong M: Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum Mol Genet. 2011, 20: 445-454. 10.1093\/hmg\/ddq491.","journal-title":"Hum Mol Genet"},{"key":"68_CR38","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1038\/nature06322","volume":"450","author":"JT Cunningham","year":"2007","unstructured":"Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P: mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007, 450: 736-740. 10.1038\/nature06322.","journal-title":"Nature"},{"key":"68_CR39","doi-asserted-by":"publisher","first-page":"16260","DOI":"10.1073\/pnas.0607795103","volume":"103","author":"M Sandri","year":"2006","unstructured":"Sandri M, Lin J, Handschin C, Yang W, Arany ZP, Lecker SH, Goldberg AL, Spiegelman BM: PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci U S A. 2006, 103: 16260-16265. 10.1073\/pnas.0607795103.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"68_CR40","doi-asserted-by":"publisher","first-page":"19460","DOI":"10.1074\/jbc.M110.113092","volume":"285","author":"JJ Brault","year":"2010","unstructured":"Brault JJ, Jespersen JG, Goldberg AL: Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. J Biol Chem. 2010, 285: 19460-19471. 10.1074\/jbc.M110.113092.","journal-title":"J Biol Chem"},{"key":"68_CR41","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1210\/er.2002-0012","volume":"24","author":"P Puigserver","year":"2003","unstructured":"Puigserver P, Spiegelman BM: Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003, 24: 78-90. 10.1210\/er.2002-0012.","journal-title":"Endocr Rev"},{"key":"68_CR42","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1038\/nature00904","volume":"418","author":"J Lin","year":"2002","unstructured":"Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM: Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature. 2002, 418: 797-801. 10.1038\/nature00904.","journal-title":"Nature"},{"key":"68_CR43","doi-asserted-by":"publisher","first-page":"e369","DOI":"10.1371\/journal.pbio.0040369","volume":"4","author":"CJ Lelliott","year":"2006","unstructured":"Lelliott CJ, Medina-Gomez G, Petrovic N, Kis A, Feldmann HM, Bjursell M, Parker N, Curtis K, Campbell M, Hu P, Zhang D, Litwin SE, Zaha VG, Fountain KT, Boudina S, Jimenez-Linan M, Blount M, Lopez M, Meirhaeghe A, Bohlooly-Y M, Storlien L, Str\u00f6mstedt M, Snaith M, Oresic M, Abel ED, Cannon B, Vidal-Puig A: Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biol. 2006, 4: e369-10.1371\/journal.pbio.0040369.","journal-title":"PLoS Biol"},{"key":"68_CR44","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1152\/ajplegacy.1967.213.5.1193","volume":"213","author":"AL Goldberg","year":"1967","unstructured":"Goldberg AL: Work-induced growth of skeletal muscle in normal and hypophysectomized rats. Am J Physiol. 1967, 213: 1193-1198.","journal-title":"Am J Physiol"},{"key":"68_CR45","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1152\/jappl.1982.52.2.467","volume":"52","author":"KM Baldwin","year":"1982","unstructured":"Baldwin KM, Valdez V, Herrick RE, MacIntosh AM, Roy RR: Biochemical properties of overloaded fast-twitch skeletal muscle. J Appl Physiol. 1982, 52: 467-472.","journal-title":"J Appl Physiol"},{"key":"68_CR46","doi-asserted-by":"crossref","first-page":"C371","DOI":"10.1152\/ajpcell.1997.273.2.C371","volume":"273","author":"SE Dunn","year":"1997","unstructured":"Dunn SE, Michel RN: Coordinated expression of myosin heavy chain isoforms and metabolic enzymes within overloaded rat muscle fibers. Am J Physiol. 1997, 273: C371-C383.","journal-title":"Am J Physiol"},{"key":"68_CR47","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s00418-009-0585-1","volume":"132","author":"T Tamaki","year":"2009","unstructured":"Tamaki T, Uchiyama Y, Okada Y, Tono K, Nitta M, Hoshi A, Akatsuka A: Multiple stimulations for muscle-nerve-blood vessel unit in compensatory hypertrophied skeletal muscle of rat surgical ablation model. Histochem Cell Biol. 2009, 132: 59-70. 10.1007\/s00418-009-0585-1.","journal-title":"Histochem Cell Biol"},{"key":"68_CR48","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1172\/JCI40373","volume":"120","author":"FS Tedesco","year":"2010","unstructured":"Tedesco FS, Dellavalle A, Diaz-Manera J, Messina G, Cossu G: Repairing skeletal muscle: regenerative potential of skeletal muscle stem cells. J Clin Invest. 2010, 120: 11-19. 10.1172\/JCI40373.","journal-title":"J Clin Invest"},{"key":"68_CR49","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1074\/jbc.M112.399949","volume":"288","author":"PN Quy","year":"2013","unstructured":"Quy PN, Kuma A, Pierre P, Mizushima N: Proteasome-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) is essential for autophagy suppression and muscle remodeling following denervation. J Biol Chem. 2013, 288: 1125-1134. 10.1074\/jbc.M112.399949.","journal-title":"J Biol Chem"},{"key":"68_CR50","doi-asserted-by":"publisher","first-page":"6811","DOI":"10.1073\/pnas.0602282103","volume":"103","author":"Q Yang","year":"2006","unstructured":"Yang Q, Inoki K, Kim E, Guan KL: TSC1\/TSC2 and Rheb have different effects on TORC1 and TORC2 activity. Proc Natl Acad Sci U S A. 2006, 103: 6811-6816. 10.1073\/pnas.0602282103.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"68_CR51","doi-asserted-by":"publisher","first-page":"4104","DOI":"10.1128\/MCB.00289-08","volume":"28","author":"J Huang","year":"2008","unstructured":"Huang J, Dibble CC, Matsuzaki M, Manning BD: The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol. 2008, 28: 4104-4115. 10.1128\/MCB.00289-08.","journal-title":"Mol Cell Biol"},{"key":"68_CR52","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/84839","volume":"27","author":"A Musaro","year":"2001","unstructured":"Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER, Sweeney HL, Rosenthal N: Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet. 2001, 27: 195-200. 10.1038\/84839.","journal-title":"Nat Genet"},{"key":"68_CR53","doi-asserted-by":"publisher","first-page":"9213","DOI":"10.1073\/pnas.142166599","volume":"99","author":"G Pallafacchina","year":"2002","unstructured":"Pallafacchina G, Calabria E, Serrano AL, Kalhovde JM, Schiaffino S: A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification. Proc Natl Acad Sci U S A. 2002, 99: 9213-9218. 10.1073\/pnas.142166599.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"68_CR54","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.cmet.2008.09.003","volume":"8","author":"P Polak","year":"2008","unstructured":"Polak P, Cybulski N, Feige JN, Auwerx J, Ruegg MA, Hall MN: Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab. 2008, 8: 399-410. 10.1016\/j.cmet.2008.09.003.","journal-title":"Cell Metab"},{"key":"68_CR55","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1161\/CIRCULATIONAHA.110.977066","volume":"123","author":"P Shende","year":"2011","unstructured":"Shende P, Plaisance I, Morandi C, Pellieux C, Berthonneche C, Zorzato F, Krishnan J, Lerch R, Hall MN, R\u00fcegg MA, Pedrazzini T, Brink M: Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice. Circulation. 2011, 123: 1073-1082. 10.1161\/CIRCULATIONAHA.110.977066.","journal-title":"Circulation"},{"key":"68_CR56","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1083\/jcb.200903131","volume":"187","author":"V Risson","year":"2009","unstructured":"Risson V, Mazelin L, Roceri M, Sanchez H, Moncollin V, Corneloup C, Richard-Bulteau H, Vignaud A, Baas D, Defour A, Freyssenet D, Tanti JF, Le-Marchand-Brustel Y, Ferrier B, Conjard-Duplany A, Romanino K, Bauch\u00e9 S, Hanta\u00ef D, Mueller M, Kozma SC, Thomas G, R\u00fcegg MA, Ferry A, Pende M, Bigard X, Koulmann N, Schaeffer L, Gangloff YG: Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy. J Cell Biol. 2009, 187: 859-874. 10.1083\/jcb.200903131.","journal-title":"J Cell Biol"},{"key":"68_CR57","doi-asserted-by":"publisher","first-page":"2197","DOI":"10.1172\/JCI44774","volume":"121","author":"M G\u00f6del","year":"2011","unstructured":"G\u00f6del M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S, Debreczeni-M\u00f3r A, Lindenmeyer MT, Rastaldi MP, Hartleben G, Wiech T, Fornoni A, Nelson RG, Kretzler M, Wanke R, Pavenst\u00e4dt H, Kerjaschki D, Cohen CD, Hall MN, R\u00fcegg MA, Inoki K, Walz G, Huber TB: Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest. 2011, 121: 2197-2209. 10.1172\/JCI44774.","journal-title":"J Clin Invest"},{"key":"68_CR58","doi-asserted-by":"publisher","first-page":"E1013","DOI":"10.1152\/ajpendo.00262.2009","volume":"297","author":"H Mori","year":"2009","unstructured":"Mori H, Inoki K, Opland D, Munzberg H, Villanueva EC, Faouzi M, Ikenoue T, Kwiatkowski DJ, Macdougald OA, Myers MG, Guan KL: Critical roles for the TSC-mTOR pathway in beta-cell function. Am J Physiol Endocrinol Metab. 2009, 297: E1013-E1022. 10.1152\/ajpendo.00262.2009.","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"68_CR59","doi-asserted-by":"publisher","first-page":"2181","DOI":"10.1172\/JCI44771","volume":"121","author":"K Inoki","year":"2011","unstructured":"Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida S, Blattner SM, Ikenoue T, R\u00fcegg MA, Hall MN, Kwiatkowski DJ, Rastaldi MP, Huber TB, Kretzler M, Holzman LB, Wiggins RC, Guan KL: mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest. 2011, 121: 2181-2196. 10.1172\/JCI44771.","journal-title":"J Clin Invest"},{"key":"68_CR60","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.cmet.2006.12.003","volume":"5","author":"Z Arany","year":"2007","unstructured":"Arany Z, Lebrasseur N, Morris C, Smith E, Yang W, Ma Y, Chin S, Spiegelman BM: The transcriptional coactivator PGC-1beta drives the formation of oxidative type IIX fibers in skeletal muscle. Cell Metab. 2007, 5: 35-46. 10.1016\/j.cmet.2006.12.003.","journal-title":"Cell Metab"},{"key":"68_CR61","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.cmet.2010.11.008","volume":"12","author":"C Zechner","year":"2010","unstructured":"Zechner C, Lai L, Zechner JF, Geng T, Yan Z, Rumsey JW, Collia D, Chen Z, Wozniak DF, Leone TC, Kelly DP: Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity. Cell Metab. 2010, 12: 633-642. 10.1016\/j.cmet.2010.11.008.","journal-title":"Cell Metab"}],"container-title":["Skeletal Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/2044-5040-3-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T18:51:23Z","timestamp":1630522283000},"score":1,"resource":{"primary":{"URL":"https:\/\/skeletalmusclejournal.biomedcentral.com\/articles\/10.1186\/2044-5040-3-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,3,6]]},"references-count":61,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,12]]}},"alternative-id":["68"],"URL":"https:\/\/doi.org\/10.1186\/2044-5040-3-6","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.717990746.793473239","asserted-by":"object"}]},"ISSN":["2044-5040"],"issn-type":[{"value":"2044-5040","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,3,6]]},"assertion":[{"value":"3 October 2012","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 February 2013","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 March 2013","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"6"}}