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Baraldo, Martina (2018) The role of Raptor in adult skeletal muscle. [Ph.D. thesis]

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Abstract (english)

Skeletal muscle is the largest organ in the body comprising 40% of total body mass. Skeletal muscle mass is the result of an equilibrium between protein synthesis and protein breakdown. When protein synthesis overcomes protein degradation the result is muscle hypertrophy with increased fiber size. Better understanding of the signaling pathways controlling muscle mass and function is of great importance. Indeed so far there are no therapeutic approaches that can prevent or reduce muscle wasting, as seen in aging and muscular dystrophy. While various studies have identified important regulators of adult skeletal muscle mass, little is known about how these pathways can modulate muscle function. One of the main pathways regulating skeletal muscle is the Akt-mTOR pathway. Under anabolic conditions, mTOR is activated, leading to increased protein synthesis through the phosphorylation of S6K1 and 4EBP1. On the other hand, mTOR activation can also lead to the inhibition of protein degradation through the phosphorylation of Ulk1, which is involved in the autophagosome formation.
mTOR assembles into two distinct multiprotein complexes, namely the rapamycin-sensitive complex mTORC1 and the rapamycin-insensitive complex mTORC2. While mTORC2 is mainly involved in cytoskeleton reorganization, mTORC1 plays a role in cell growth and protein synthesis. One of the key members of the mTORC1 is a 150kDa protein called Raptor, which has been shown to be able to recruit mTOR substrates S6K1 and 4EBP1 on mTORC1, promoting their phosphorylation (Hara et al., 2002) (Kim et al., 2002).
Mice lacking Raptor only in skeletal muscle from birth show a pronounced myopathy leading to premature death (Bentzinger et al., 2008). However, treating adult mice with the specific mTORC1 inhibitor rapamycin does not lead to a myopathic phenotype and even improves muscle physiology in aged mice (Harrison et al., 2009). So, we wondered what happens if Raptor is deleted in adult skeletal muscle.
We, therefore, generated an inducible muscle-specific Raptor knock-out mouse line (HSA-Raptor ko).
One month of Raptor deletion in adult muscle does not affect muscle mass or muscle morphology. In addition, also muscle force production is comparable between control and knock-out animals, confirming that at this time point there are no myopathies.
Since in literature it has been reported that deletion of Raptor from birth leads to premature death around 5-6 months of age, we decided to monitor mice lifespan and body weight for a longer period after deletion. We observed that body weight during these months is unchanged between wt and Raptor ko mice, so we decided to sacrifice mice 7 months after the beginning of the treatment to assess muscle histology.
At this time point, muscles from Raptor ko mice showed signs of a muscle myopathy, with centronucleated fibers, a high number of small and large muscle fibers, central structures and inflammation. In addition, we observed that Raptor knock-out muscles show a huge amount of spontaneous fibrillation spikes at rest, suggesting the presence of denervated fibers. Furthermore, mitochondrial membrane potential and respiratory chain complex activity are impaired upon Raptor deletion. These features result in compromised muscle performance and exercise intolerance.
Moreover, while metabolic characteristics upon Raptor deletion shift from oxidative to glycolytic fibers with glycogen accumulation, structural properties reveal the opposite behaviour, with a shift from fast- to slow- twitch fibers. This is likely linked to the increased activity of calcineurin- NFAT pathway seen in Raptor ko muscles.
Since understanding the key players in the regulation of muscle mass can be of therapeutic interest, we wanted to understand the role of Raptor during Akt-induced hypertrophy. So, we generate an inducible muscle- specific Akt-Raptor ko mouse line.
Akt overexpression results in a strong increase in cross-sectional area of muscle fibers, which is only partially reduced upon Raptor deletion. Moreover, fiber hypertrophy is completely blunted when Akt-Raptor ko mice are treated with the mTORC1 inhibitor, rapamycin.
We also found that Akt-Raptor ko mice are significantly weaker than controls, meaning that Akt-induced hypertrophy in the absence of Raptor is not functional anymore. In addition, this effect is not reverted by rapamycin administration, as seen in Akt-S6K1 knock-out mice (Marabita et al., 2016).

Abstract (italian)

I muscoli scheletrici costituiscono il 40% di tutto l’organismo. Il tessuto muscolare è un tessuto molto plastico e dinamico che si adatta in relazione ai diversi stimoli. La massa muscolare è il risultato di un equilibrio tra sintesi e degradazione proteica: una maggior sintesi delle proteine muscolari porta infatti ad ipertrofia mentre una maggior degradazione associata ad una ridotta sintesi ha come conseguenza uno stato atrofico del muscolo. Una migliore conoscenza delle vie di segnale che regolano la crescita e la funzione muscolare diventano di particolare importanza terapeutica per prevenire la perdita di massa associata sia all’invecchiamento, che a diverse patologie, quali ad esempio distrofie e sclerosi. Una delle vie maggiormente implicate nella regolazione della crescita muscolare è la via Akt-mTOR.
In condizioni anaboliche, mTOR è attivo e promuove la sintesi proteica attraverso la fosforilazione di S6K1 e 4EBP1. Inoltre, mTOR va anche a bloccare la degradazione proteica attraverso l’inibizione di una proteina che partecipa alla formazione dell’autofagosoma, Ulk1.
mTOR esiste sotto forma di due complessi multiproteici: mTORC1, implicato nella crescita cellulare, e mTORC2, che regola la riorganizzazione del citoscheletro. Uno dei componenti principali di mTORC1 è la proteina Raptor, che è in grado di reclutare i substrati di mTORC1, quali ad esempio S6K1 e 4EBP1, promuovendone la fosforilazione (Hara et al., 2002) (Kim et al., 2002).
Topi in cui Raptor è assente nel muscolo scheletrico dalla nascita sviluppano una severa miopatia, risultante in una morte prematura degli animali (Bentzinger et al., 2008). Tuttavia, il trattamento di topi adulti con rapamicina, che inibisce selettivamente mTORC1, non porta a patologie muscolari e, anzi, migliora la fisiologia del muscolo di topi anziani (Harrison et al., 2009).
Considerando questi risultati contradditori, ci siamo chiesti quale sia il ruolo di Raptor nel muscolo adulto. Abbiamo, quindi, generato un modello murino in cui Raptor viene deleto nel muscolo scheletrico in maniera inducibile.
Un mese di delezione di Raptor non ha effetti sulla morfologia o sulla funzionalità del muscolo. Considerando che in letteratura i topi knock-out per Raptor dalla nascita muoiono attorno ai 5-6 mesi, abbiamo deciso di monitorare il peso corporeo e la durata della vita per un periodo di tempo maggiore. Abbiamo notato che, durante questi mesi, il peso rimane invariato tra i topi controllo e i topi knock-out; abbiamo, quindi, deciso di sacrificare gli animali 7 mesi dopo l’inizio del trattamento per controllare l’istologia del muscolo.
A questo punto, i muscoli dei topi Raptor ko mostrano segni miopatici, con fibre centronucleate, fibre atrofiche e ipertrofiche, strutture centrali e infiammazione. Inoltre, abbiamo notato che i muscoli knock-out presentano fibrillazioni spontanee e quindi attività elettrica a riposo, suggerendo la presenza di fibre denervate. La delezione di Raptor, inoltre, ha portato ad una severa depolarizzazione mitocondriale e ad una ridotta attività di alcuni complessi della catena respiratoria. Tutti questi effetti sono facilmente collegabili alla significativa debolezza muscolare osservata in questi topi.
Dal momento che una più approfondita conoscenza dei mediatori maggiormente implicati nella crescita muscolare può essere di interesse terapeutico, abbiamo deciso di generare una nuova linea murina in cui Akt viene espresso e Raptor deleto solo nel muscolo scheletrico in maniera inducibile al fine di valutare quale sia il ruolo di Raptor nella crescita indotta dall’overespressione di Akt. Nei topi Akt-Raptor ko, l’ipertrofia delle fibre muscolari è solo parzialmente ridotta in confronto a quella osservata nei topi Akt. Incredibilmente, il trattamento con rapamicina significativamente diminuisce la crescita indotta da Akt, anche in assenza di Raptor. Inoltre, i topi Akt-Raptor ko mostrano una ridotta forza muscolare, suggerendo che l’ipertrofia dipendente da Akt in assenza di Raptor non è più funzionale. Quest’effetto non è normalizzato neanche
dalla somministrazione di rapamicina, com’era stato visto nei topi Akt- S6K1 ko (Marabita et al., 2016).

EPrint type:Ph.D. thesis
Tutor:Blaauw, Bert
Ph.D. course:Ciclo 30 > Corsi 30 > SCIENZE BIOMEDICHE SPERIMENTALI
Data di deposito della tesi:10 January 2018
Anno di Pubblicazione:08 January 2018
Key Words:mTOR, Raptor, skeletal muscle, myopathy
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/09 Fisiologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:10598
Depositato il:08 Nov 2018 11:02
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Alain, T., Morita, M., Fonseca, B.D., Yanagiya, A., Siddiqui, N., Bhat, M., Zammit, D., Marcus, V., Metrakos, P., Voyer, L.A., et al. (2012). eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies. Cancer Res 72, 6468-6476. Cerca con Google

Amthor, H., Macharia, R., Navarrete, R., Schuelke, M., Brown, S.C., Otto, A., Voit, T., Muntoni, F., Vrbova, G., Partridge, T., et al. (2007). Lack of myostatin results in excessive muscle growth but impaired force generation. Proc Natl Acad Sci U S A 104, 1835-1840. Cerca con Google

Barrett K.E., Boitano S., Barman S.M., Brooks H.L. (2010). Chapther 5 – Excitable tissue: muscle, in “Ganong’s review of medical physiology” twenty-third edition. Cerca con Google

Bdolah, Y., Segal, A., Tanksale, P., Karumanchi, S.A., and Lecker, S.H. (2007). Atrophy-related ubiquitin ligases atrogin-1 and MuRF- 1 are associated with uterine smooth muscle involution in the postpartum period. Am J Physiol Regul Integr Comp Physiol 292, R971-976. Cerca con Google

Beals, C.R., Sheridan, C.M., Turck, C.W., Gardner, P., and Crabtree, G.R. (1997). Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 275, 1930-1934. Cerca con Google

Bentzinger, C.F., Romanino, K., Cloetta, D., Lin, S., Mascarenhas, J.B., Oliveri, F., Xia, J., Casanova, E., Costa, C.F., Brink, M., et al. (2008). Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab 8, 411-424. Cerca con Google

Bjorkoy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A., Stenmark, H., and Johansen, T. (2005). p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171, 603-614. Cerca con Google

Blaauw, B., Canato, M., Agatea, L., Toniolo, L., Mammucari, C., Masiero, E., Abraham, R., Sandri, M., Schiaffino, S., and Reggiani, C. (2009). Inducible activation of Akt increases skeletal muscle mass and force without satellite cell activation. FASEB J 23, 3896-3905. Cerca con Google

Blaauw, B., Mammucari, C., Toniolo, L., Agatea, L., Abraham, R., Sandri, M., Reggiani, C., and Schiaffino, S. (2008). Akt activation prevents the force drop induced by eccentric contractions in dystrophin-deficient skeletal muscle. Hum Mol Genet 17, 3686-3696. Cerca con Google

Bodine, S.C., Latres, E., Baumhueter, S., Lai, V.K., Nunez, L., Clarke, B.A., Poueymirou, W.T., Panaro, F.J., Na, E., Dharmarajan, K., et al. (2001a). Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294, 1704-1708. Cerca con Google

Bodine, S.C., Stitt, T.N., Gonzalez, M., Kline, W.O., Stover, G.L., Bauerlein, R., Zlotchenko, E., Scrimgeour, A., Lawrence, J.C., Glass, D.J., et al. (2001b). Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 3, 1014-1019. Cerca con Google

Bogdanovich, S., Perkins, K.J., Krag, T.O., Whittemore, L.A., and Khurana, T.S. (2005). Myostatin propeptide-mediated amelioration of dystrophic pathophysiology. FASEB J 19, 543-549. Cerca con Google

Carnio, S., LoVerso, F., Baraibar, M.A., Longa, E., Khan, M.M., Maffei, M., Reischl, M., Canepari, M., Loefler, S., Kern, H., et al. Cerca con Google

(2014). Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging. Cell Rep 8, 1509-1521. Cerca con Google

Castets, P., Lin, S., Rion, N., Di Fulvio, S., Romanino, K., Guridi, M., Frank, S., Tintignac, L.A., Sinnreich, M., and Ruegg, M.A. (2013). Sustained activation of mTORC1 in skeletal muscle inhibits constitutive and starvation-induced autophagy and causes a severe, late- onset myopathy. Cell Metab 17, 731-744. Cerca con Google

Chen, D., and Dou, Q.P. (2010). The ubiquitin-proteasome system as a prospective molecular target for cancer treatment and prevention. Curr Protein Pept Sci 11, 459-470. Cerca con Google

Ciciliot, S., Rossi, A.C., Dyar, K.A., Blaauw, B., and Schiaffino, S. (2013). Muscle type and fiber type specificity in muscle wasting. Int J Biochem Cell Biol 45, 2191-2199. Cerca con Google

Cohen, P., and Frame, S. (2001). The renaissance of GSK3. Nat Rev Mol Cell Biol 2, 769-776. Cerca con Google

Eskelinen, E.L., and Saftig, P. (2009). Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim Biophys Acta 1793, 664-673. Cerca con Google

Flynn, J.M., O'Leary, M.N., Zambataro, C.A., Academia, E.C., Presley, M.P., Garrett, B.J., Zykovich, A., Mooney, S.D., Strong, R., Rosen, C.J., et al. (2013). Late-life rapamycin treatment reverses age- related heart dysfunction. Aging Cell 12, 851-862. Cerca con Google

Frezza, C., Cipolat, S., and Scorrano, L. (2007). Organelle isolation: functional mitochondria from mouse liver, muscle and cultured fibroblasts. Nat Protoc 2, 287-295. Cerca con Google

Fusi, L., Huang, Z., and Irving, M. (2015). The Conformation of Myosin Heads in Relaxed Skeletal Muscle: Implications for Myosin- Based Regulation. Biophys J 109, 783-792. Cerca con Google

Gomes, M.D., Lecker, S.H., Jagoe, R.T., Navon, A., and Goldberg, A.L. (2001). Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci U S A 98, 14440- 14445. Cerca con Google

Goodman, C.A., Frey, J.W., Mabrey, D.M., Jacobs, B.L., Lincoln, H.C., You, J.S., and Hornberger, T.A. (2011a). The role of skeletal muscle mTOR in the regulation of mechanical load-induced growth. J Physiol 589, 5485-5501. Cerca con Google

Goodman, C.A., Mabrey, D.M., Frey, J.W., Miu, M.H., Schmidt, E.K., Pierre, P., and Hornberger, T.A. (2011b). Novel insights into the regulation of skeletal muscle protein synthesis as revealed by a new nonradioactive in vivo technique. FASEB J 25, 1028-1039. Cerca con Google

Grumati, P., Coletto, L., Sabatelli, P., Cescon, M., Angelin, A., Bertaggia, E., Blaauw, B., Urciuolo, A., Tiepolo, T., Merlini, L., et al. (2010). Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med 16, 1313-1320. Cerca con Google

Guertin, D.A., Stevens, D.M., Thoreen, C.C., Burds, A.A., Kalaany, N.Y., Moffat, J., Brown, M., Fitzgerald, K.J., and Sabatini, D.M. (2006). Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11, 859-871. Cerca con Google

Hara, K., Maruki, Y., Long, X., Yoshino, K., Oshiro, N., Hidayat, S., Tokunaga, C., Avruch, J., and Yonezawa, K. (2002). Raptor, a Cerca con Google

binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177-189. Cerca con Google

Harrison, D.E., Strong, R., Sharp, Z.D., Nelson, J.F., Astle, C.M., Flurkey, K., Nadon, N.L., Wilkinson, J.E., Frenkel, K., Carter, C.S., et al. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392-395. Cerca con Google

Hay, N., and Sonenberg, N. (2004). Upstream and downstream of mTOR. Genes Dev 18, 1926-1945. Cerca con Google

He, C., Bassik, M.C., Moresi, V., Sun, K., Wei, Y., Zou, Z., An, Z., Loh, J., Fisher, J., Sun, Q., et al. (2012). Exercise-induced BCL2- regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511-515. Cerca con Google

Hilioti, Z., Gallagher, D.A., Low-Nam, S.T., Ramaswamy, P., Gajer, P., Kingsbury, T.J., Birchwood, C.J., Levchenko, A., and Cunningham, K.W. (2004). GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs. Genes Dev 18, 35-47. Cerca con Google

Irwin, W.A., Bergamin, N., Sabatelli, P., Reggiani, C., Megighian, A., Merlini, L., Braghetta, P., Columbaro, M., Volpin, D., Bressan, G.M., et al. (2003). Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat Genet 35, 367-371. Cerca con Google

Ju, J.S., Varadhachary, A.S., Miller, S.E., and Weihl, C.C. (2010). Quantitation of "autophagic flux" in mature skeletal muscle. Autophagy 6, 929-935. Cerca con Google

Kang, S.A., Pacold, M.E., Cervantes, C.L., Lim, D., Lou, H.J., Ottina, K., Gray, N.S., Turk, B.E., Yaffe, M.B., and Sabatini, D.M. (2013). mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science 341, 1236566. Cerca con Google

Khan, N.A., Nikkanen, J., Yatsuga, S., Jackson, C., Wang, L., Pradhan, S., Kivela, R., Pessia, A., Velagapudi, V., and Suomalainen, A. (2017). mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression. Cell Metab 26, 419-428 e415. Cerca con Google

Kim, D.H., Sarbassov, D.D., Ali, S.M., King, J.E., Latek, R.R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D.M. (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163-175. Cerca con Google

Kim, J., Kundu, M., Viollet, B., and Guan, K.L. (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13, 132-141. Cerca con Google

Kingsbury, T.J., and Cunningham, K.W. (2000). A conserved family of calcineurin regulators. Genes Dev 14, 1595-1604. Cerca con Google

Light, N., and Champion, A.E. (1984). Characterization of muscle epimysium, perimysium and endomysium collagens. Biochem J 219, 1017-1026. Cerca con Google

Liu, C.W., Li, X., Thompson, D., Wooding, K., Chang, T.L., Tang, Z., Yu, H., Thomas, P.J., and DeMartino, G.N. (2006). ATP binding and ATP hydrolysis play distinct roles in the function of 26S proteasome. Mol Cell 24, 39-50. Cerca con Google

Lopez, R.J., Mosca, B., Treves, S., Maj, M., Bergamelli, L., Calderon, J.C., Bentzinger, C.F., Romanino, K., Hall, M.N., Ruegg, M.A., et al. (2015). Raptor ablation in skeletal muscle decreases Cav1.1 Cerca con Google

expression and affects the function of the excitation-contraction coupling supramolecular complex. Biochem J 466, 123-135. Cerca con Google

Lowe, D.A., Surek, J.T., Thomas, D.D., and Thompson, L.V. (2001). Electron paramagnetic resonance reveals age-related myosin structural changes in rat skeletal muscle fibers. Am J Physiol Cell Physiol 280, C540-547. Cerca con Google

Luo, Y., Liu, L., Wu, Y., Singh, K., Su, B., Zhang, N., Liu, X., Shen, Y., and Huang, S. (2015). Rapamycin inhibits mSin1 phosphorylation independently of mTORC1 and mTORC2. Oncotarget 6, 4286-4298. Cerca con Google

Mammucari, C., Milan, G., Romanello, V., Masiero, E., Rudolf, R., Del Piccolo, P., Burden, S.J., Di Lisi, R., Sandri, C., Zhao, J., et al. (2007). FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6, 458-471. Cerca con Google

Marabita, M., Baraldo, M., Solagna, F., Ceelen, J.J.M., Sartori, R., Nolte, H., Nemazanyy, I., Pyronnet, S., Kruger, M., Pende, M., et al. (2016). S6K1 Is Required for Increasing Skeletal Muscle Force during Hypertrophy. Cell Rep 17, 501-513. Cerca con Google

Masiero, E., Agatea, L., Mammucari, C., Blaauw, B., Loro, E., Komatsu, M., Metzger, D., Reggiani, C., Schiaffino, S., and Sandri, M. (2009). Autophagy is required to maintain muscle mass. Cell Metab 10, 507-515. Cerca con Google

Milan, G., Romanello, V., Pescatore, F., Armani, A., Paik, J.H., Frasson, L., Seydel, A., Zhao, J., Abraham, R., Goldberg, A.L., et al. (2015). Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy. Nat Commun 6, 6670. Cerca con Google

Mizushima, N., and Yoshimori, T. (2007). How to interpret LC3 immunoblotting. Autophagy 3, 542-545. Cerca con Google

Morita, M., Gravel, S.P., Chenard, V., Sikstrom, K., Zheng, L., Alain, T., Gandin, V., Avizonis, D., Arguello, M., Zakaria, C., et al. (2013). mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metab 18, 698-711. Cerca con Google

Morita, M., Prudent, J., Basu, K., Goyon, V., Katsumura, S., Hulea, L., Pearl, D., Siddiqui, N., Strack, S., McGuirk, S., et al. (2017). mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1. Mol Cell 67, 922-935 e925. Cerca con Google

Murgia, M., Serrano, A.L., Calabria, E., Pallafacchina, G., Lomo, T., and Schiaffino, S. (2000). Ras is involved in nerve-activity- dependent regulation of muscle genes. Nat Cell Biol 2, 142-147. Cerca con Google

Nakamura, S., and Yoshimori, T. (2017). New insights into autophagosome-lysosome fusion. J Cell Sci 130, 1209-1216. Cerca con Google

Nandi, D., Tahiliani, P., Kumar, A., and Chandu, D. (2006). The ubiquitin-proteasome system. J Biosci 31, 137-155. Cerca con Google

Patursky-Polischuk, I., Stolovich-Rain, M., Hausner-Hanochi, M., Kasir, J., Cybulski, N., Avruch, J., Ruegg, M.A., Hall, M.N., and Meyuhas, O. (2009). The TSC-mTOR pathway mediates translational activation of TOP mRNAs by insulin largely in a raptor- or rictor- independent manner. Mol Cell Biol 29, 640-649. Cerca con Google

Pette, D., and Heilmann, C. (1979). Some characteristics of sarcoplasmic reticulum in fast- and slow-twitch muscles. Biochem Soc Trans 7, 765-767. Cerca con Google

Pfaffl, M.W. (2001). A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29, e45. Cerca con Google

Pickart, C.M., and Fushman, D. (2004). Polyubiquitin chains: polymeric protein signals. Curr Opin Chem Biol 8, 610-616. Cerca con Google

Risson, V., Mazelin, L., Roceri, M., Sanchez, H., Moncollin, V., Corneloup, C., Richard-Bulteau, H., Vignaud, A., Baas, D., Defour, A., et al. (2009). Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy. J Cell Biol 187, 859-874. Cerca con Google

Rommel, C., Bodine, S.C., Clarke, B.A., Rossman, R., Nunez, L., Stitt, T.N., Yancopoulos, G.D., and Glass, D.J. (2001). Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol 3, 1009- 1013. Cerca con Google

Sacheck, J.M., Hyatt, J.P., Raffaello, A., Jagoe, R.T., Roy, R.R., Edgerton, V.R., Lecker, S.H., and Goldberg, A.L. (2007). Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases. FASEB J 21, 140-155. Cerca con Google

Schiaffino, S., and Mammucari, C. (2011). Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skelet Muscle 1, 4. Cerca con Google

Schiaffino, S., and Reggiani, C. (1996). Molecular diversity of myofibrillar proteins: gene regulation and functional significance. Physiol Rev 76, 371-423. Cerca con Google

Schiaffino, S., and Reggiani, C. (2011). Fiber types in mammalian skeletal muscles. Physiol Rev 91, 1447-1531. Cerca con Google

Schiaffino, S., Sandri, M., and Murgia, M. (2007). Activity- dependent signaling pathways controlling muscle diversity and plasticity. Physiology (Bethesda) 22, 269-278. Cerca con Google

Schmidt, E.K., Clavarino, G., Ceppi, M., and Pierre, P. (2009). SUnSET, a nonradioactive method to monitor protein synthesis. Nat Methods 6, 275-277. Cerca con Google

Schuler, M., Ali, F., Metzger, E., Chambon, P., and Metzger, D. (2005). Temporally controlled targeted somatic mutagenesis in skeletal muscles of the mouse. Genesis 41, 165-170. Cerca con Google

Sehgal, S.N. (1998). Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 31, 335-340. Cerca con Google

Settembre, C., De Cegli, R., Mansueto, G., Saha, P.K., Vetrini, F., Visvikis, O., Huynh, T., Carissimo, A., Palmer, D., Klisch, T.J., et al. (2013). TFEB controls cellular lipid metabolism through a starvation- induced autoregulatory loop. Nat Cell Biol 15, 647-658. Cerca con Google

Settembre, C., Di Malta, C., Polito, V.A., Garcia Arencibia, M., Vetrini, F., Erdin, S., Erdin, S.U., Huynh, T., Medina, D., Colella, P., et al. (2011). TFEB links autophagy to lysosomal biogenesis. Science 332, 1429-1433. Cerca con Google

Shea, L., and Raben, N. (2009). Autophagy in skeletal muscle: implications for Pompe disease. Int J Clin Pharmacol Ther 47 Suppl 1, S42-47. Cerca con Google

Shende, P., Plaisance, I., Morandi, C., Pellieux, C., Berthonneche, C., Zorzato, F., Krishnan, J., Lerch, R., Hall, M.N., Ruegg, M.A., et al. (2011). Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice. Circulation 123, 1073-1082. Cerca con Google

Spinazzi, M., Casarin, A., Pertegato, V., Salviati, L., and Angelini, C. (2012). Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells. Nat Protoc 7, 1235- 1246. Cerca con Google

Tezze, C., Romanello, V., Desbats, M.A., Fadini, G.P., Albiero, M., Favaro, G., Ciciliot, S., Soriano, M.E., Morbidoni, V., Cerqua, C., et al. (2017). Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence. Cell Metab 25, 1374-1389 e1376. Cerca con Google

Wang, X., Yue, P., Tao, H., and Sun, S.Y. (2017). Inhibition of p70S6K does not mimic the enhancement of Akt phosphorylation by rapamycin. Heliyon 3, e00378. Cerca con Google

Winbanks, C.E., Chen, J.L., Qian, H., Liu, Y., Bernardo, B.C., Beyer, C., Watt, K.I., Thomson, R.E., Connor, T., Turner, B.J., et al. (2013). The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass. J Cell Biol 203, 345-357. Cerca con Google

Xu, P., Duong, D.M., Seyfried, N.T., Cheng, D., Xie, Y., Robert, J., Rush, J., Hochstrasser, M., Finley, D., and Peng, J. (2009). Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell 137, 133-145. Cerca con Google

Yang, Z., Huang, J., Geng, J., Nair, U., and Klionsky, D.J. (2006). Atg22 recycles amino acids to link the degradative and recycling functions of autophagy. Mol Biol Cell 17, 5094-5104. Cerca con Google

Yao, T.P. (2010). The role of ubiquitin in autophagy- dependent protein aggregate processing. Genes Cancer 1, 779-786. Cerca con Google

Zhao, J., Brault, J.J., Schild, A., Cao, P., Sandri, M., Schiaffino, S., Lecker, S.H., and Goldberg, A.L. (2007). FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 6, 472- 483. Cerca con Google

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