The cochaperone BAG3 coordinates protein synthesis and autophagy under mechanical strain through spatial regulation of mTORC1

Biochimica et Biophysica Acta - Molecular Cell Research

Volumn 1864, Issue 1, 2017, Pages 62-75

  Kathage, Barbara ^a   Gehlert, Sebastian ^b   Ulbricht, Anna ^a   Lüdecke, Laura ^a   Tapia, Victor E ^c   Orfanos, Zacharias ^a   Wenzel, Daniela ^d   Bloch, Wilhelm ^b   Volkmer, Rudolf ^c   Fleischmann, Bernd K ^d   Fürst, Dieter O ^a   Höhfeld, Jörg ^a  

^a UNIVERSITY OF BONN   (Germany)

^b GERMAN SPORT UNIVERSITY COLOGNE   (Germany)

^c CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^d UNIVERSITY HOSPITAL BONN   (Germany)

Author keywords

Autophagy; Chaperones; Mechanical strain; Protein synthesis; Proteostasis; Signaling

Indexed keywords

BAG3 PROTEIN; CHAPERONE; FILAMIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; PROLINE RICH PROTEIN; TUBERIN; TUBEROUS SCLEROSIS 1 PROTEIN; UNCLASSIFIED DRUG; APOPTOSIS REGULATORY PROTEIN; BAG3 PROTEIN, HUMAN; HYBRID PROTEIN; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MULTIPROTEIN COMPLEX; PROTEIN BINDING; SIGNAL TRANSDUCING ADAPTOR PROTEIN; TARGET OF RAPAMYCIN KINASE; TUBEROUS SCLEROSIS COMPLEX 1 PROTEIN; TUMOR SUPPRESSOR PROTEIN;

ADULT; ANIMAL CELL; ARTICLE; AUTOPHAGY; CELL DAMAGE; CELL STRESS; CLINICAL ARTICLE; CONTROLLED STUDY; CYTOPLASM; CYTOSKELETON; HUMAN; HUMAN CELL; IN VITRO STUDY; MALE; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN SYNTHESIS; PROTEIN UNFOLDING; RAT; REGULATORY MECHANISM; STRESS FIBER; STRESS STRAIN RELATIONSHIP; ACTIN FILAMENT; AMINO ACID SEQUENCE; ANIMAL; BIOMECHANICS; CELL LINE; CYTOLOGY; ESCHERICHIA COLI; GENE EXPRESSION; GENE EXPRESSION REGULATION; GENETICS; MECHANICAL STRESS; METABOLISM; MOLECULAR CLONING; MOUSE; SIGNAL TRANSDUCTION; SKELETAL MUSCLE; SMOOTH MUSCLE CELL; ULTRASTRUCTURE;

ACTIN CYTOSKELETON; ADAPTOR PROTEINS, SIGNAL TRANSDUCING; AMINO ACID SEQUENCE; ANIMALS; APOPTOSIS REGULATORY PROTEINS; AUTOPHAGY; BIOMECHANICAL PHENOMENA; CELL LINE; CLONING, MOLECULAR; ESCHERICHIA COLI; FILAMINS; GENE EXPRESSION; GENE EXPRESSION REGULATION; HUMANS; MICE; MULTIPROTEIN COMPLEXES; MUSCLE, SKELETAL; MYOCYTES, SMOOTH MUSCLE; PROTEIN BINDING; PROTEIN BIOSYNTHESIS; RATS; RECOMBINANT FUSION PROTEINS; SIGNAL TRANSDUCTION; STRESS, MECHANICAL; TOR SERINE-THREONINE KINASES; TUMOR SUPPRESSOR PROTEINS;

EID: 84994201292     PISSN: 01674889     EISSN: 18792596     Source Type: Journal    
DOI: 10.1016/j.bbamcr.2016.10.007     Document Type: Article

References (72)

1. [1] Kim, Y.E., Hipp, M.S., Bracher, A., Hayer-Hartl, M., Ulrich Hartl, F., Molecular chaperone functions in protein folding and proteostasis. Annu. Rev. Biochem. 82 (2013), 323–355, 10.1146/annurev-biochem-060208-092442.
2. [2] Laplante, M., Sabatini, D.M., mTOR signaling in growth control and disease. Cell 149 (2012), 274–293, 10.1016/j.cell.2012.03.017.
3. [3] Dibble, C.C., Manning, B.D., Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat. Cell Biol. 15 (2013), 555–564, 10.1038/ncb2763.
4. [4] Betz, C., Hall, M.N., Where is mTOR and what is it doing there?. J. Cell Biol. 203 (2013), 563–574, 10.1083/jcb.201306041.
5. [5] Huang, K., Fingar, D.C., Growing knowledge of the mTOR signaling network. Semin. Cell. Dev. Biol. 36 (2014), 79–90, 10.1016/j.semcdb.2014.09.011.
6. [6] Feng, Y., Yao, Z., Klionsky, D.J., How to control self-digestion: transcriptional, post-transcriptional, and post-translational regulation of autophagy. Trends Cell Biol., 1–10, 2015, 10.1016/j.tcb.2015.02.002.
7. [7] Dunlop, E.A., Tee, A.R., mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Semin. Cell Dev. Biol. 36 (2014), 121–129, 10.1016/j.semcdb.2014.08.006.
8. [8] Xie, Z., Klionsky, D.J., Autophagosome formation: core machinery and adaptations. Nat. Cell Biol. 9 (2007), 1102–1109, 10.1038/ncb1007-1102.
9. [9] Menon, S., Dibble, C.C., Talbott, G., Hoxhaj, G., Valvezan, A.J., Takahashi, H., Cantley, L.C., Manning, B.D., Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156 (2014), 771–785, 10.1016/j.cell.2013.11.049.
10. [10] Dibble, C.C., Elis, W., Menon, S., Qin, W., Klekota, J., Asara, J.M., Finan, P.M., Kwiatkowski, D.J., Murphy, L.O., Manning, B.D., TBC1D7 is a third subunit of the TSC1–TSC2 complex upstream of mTORC1. Mol. Cell 47 (2012), 535–546, 10.1016/j.molcel.2012.06.009.
11. [11] Demetriades, C., Doumpas, N., Teleman, A.A., Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell 156 (2014), 786–799, 10.1016/j.cell.2014.01.024.
12. [12] Huang, J., Manning, B.D., The TSC1–TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J. 412 (2008), 179–190, 10.1042/BJ20080281.
13. [13] Garami, A., Zwartkruis, F.J.T., Nobukuni, T., Joaquin, M., Roccio, M., Stocker, H., Kozma, S.C., Hafen, E., Bos, J.L., Thomas, G., Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11 (2003), 1457–1466, 10.1016/S1097-2765(03)00220-X.
14. [14] Buerger, C., DeVries, B., Stambolic, V., Localization of Rheb to the endomembrane is critical for its signaling function. Biochem. Biophys. Res. Commun. 344 (2006), 869–880, 10.1016/j.bbrc.2006.03.220.
15. [15] Yadav, R.B., Burgos, P., Parker, A.W., Iadevaia, V., Proud, C.G., Allen, R.A., O'Connell, J.P., Jeshtadi, A., Stubbs, C.D., Botchway, S.W., mTOR direct interactions with Rheb-GTPase and raptor: sub-cellular localization using fluorescence lifetime imaging. BMC Cell Biol., 14, 2013, 3, 10.1186/1471-2121-14-3.
16. [16] Zhang, J., Kim, J., Alexander, A., Cai, S., Tripathi, D.N., Dere, R., Tee, A.R., Tait-Mulder, J., Di Nardo, A., Han, J.M., Kwiatkowski, E., Dunlop, E.A., Dodd, K.M., Folkerth, R.D., Faust, P.L., Kastan, M.B., Sahin, M., Walker, C.L., A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nat. Cell Biol. 15 (2013), 1186–1196, 10.1038/ncb2822.
17. [17] Feng, Y., He, D., Yao, Z., Klionsky, D.J., The machinery of macroautophagy. Cell Res. 24 (2014), 24–41, 10.1038/cr.2013.168.
18. [18] Khaminets, A., Behl, C., Dikic, I., Ubiquitin-dependent and independent signals in selective autophagy. Trends Cell Biol. 26 (2015), 6–16, 10.1016/j.tcb.2015.08.010.
19. [19] Kirkin, V., McEwan, D.G., Novak, I., Dikic, I., A role for ubiquitin in selective autophagy. Mol. Cell 34 (2009), 259–269, 10.1016/j.molcel.2009.04.026.
20. [20] Ulbricht, A., Höhfeld, J., Tension-induced autophagy: may the chaperone be with you. Autophagy 9 (2013), 920–922, 10.4161/auto.24213.
21. [21] Behl, C., Breaking BAG: the co-chaperone BAG3 in health and disease. Trends Pharmacol. Sci., 2016, 10.1016/j.tips.2016.04.007.
22. [22] Kettern, N., Dreiseidler, M., Tawo, R., Höhfeld, J., Chaperone-assisted degradation: multiple paths to destruction. Biol. Chem. 391 (2010), 481–489, 10.1515/bc.2010.058.
23. [23] Bandyopadhyay, U., Sridhar, S., Kaushik, S., Kiffin, R., Cuervo, A.M., Identification of regulators of chaperone-mediated autophagy. Mol. Cell 39 (2010), 535–547, 10.1016/j.molcel.2010.08.004.
24. [24] Ulbricht, A., Arndt, V., Höhfeld, J., Chaperone-assisted proteostasis is essential for mechanotransduction in mammalian cells. Commun. Integr. Biol. 6 (2013), 1–7, 10.4161/cib.24925.
25. [25] Arndt, V., Dick, N., Tawo, R., Dreiseidler, M., Wenzel, D., Hesse, M., Fürst, D.O., Saftig, P., Saint, R., Fleischmann, B.K., Hoch, M., Höhfeld, J., Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr. Biol. 20 (2010), 143–148, 10.1016/j.cub.2009.11.022.
26. [26] Carra, S., Seguin, S.J., Lambert, H., Landry, J., HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy. J. Biol. Chem. 283 (2008), 1437–1444, 10.1074/jbc.M706304200.
27. [27] Gamerdinger, M., Hajieva, P., Kaya, A.M., Wolfrum, U., Hartl, F.U., Behl, C., Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3. EMBO J. 28 (2009), 889–901, 10.1038/emboj.2009.29.
28. [28] Ulbricht, A., Eppler, F.J., Tapia, V.E., Van Der Ven, P.F.M., Hampe, N., Hersch, N., Vakeel, P., Stadel, D., Haas, A., Saftig, P., Behrends, C., Fürst, D.O., Volkmer, R., Hoffmann, B., Kolanus, W., Höhfeld, J., Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy. Curr. Biol. 23 (2013), 430–435, 10.1016/j.cub.2013.01.064.
29. [29] Kaushik, S., Cuervo, A.M., Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 22 (2012), 407–417, 10.1016/j.tcb.2012.05.006.
30. [30] Gamerdinger, M., Kaya, A.M., Wolfrum, U., Clement, A.M., Behl, C., BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins. EMBO Rep. 12 (2011), 149–156, 10.1038/embor.2010.203.
31. [31] Lei, Z., Brizzee, C., Johnson, G.V.W., BAG3 facilitates the clearance of endogenous tau in primary neurons. Neurobiol. Aging 36 (2015), 241–248.
32. [32] Crippa, V., Galbiati, M., Boncoraglio, A., Rusmini, P., Onesto, E., Giorgetti, E., Cristofani, R., Zito, A., Poletti, A., Motoneuronal and muscle-selective removal of ALS-related misfolded proteins. Biochem. Soc. Trans. 41 (2013), 1598–1604, 10.1042/BST20130118.
33. [33] Homma, S., Iwasaki, M., Shelton, G.D., Engvall, E., Reed, J.C., Takayama, S., BAG3 deficiency results in fulminant myopathy and early lethality. Am. J. Pathol. 169 (2006), 761–773, 10.2353/ajpath.2006.060250.
34. [34] Selcen, D., Muntoni, F., Burton, B.K., Pegoraro, E., Sewry, C., Bite, A., Engel, A.G., Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Ann. Neurol. 65 (2009), 83–89, 10.1002/ana.21553.
35. [35] Konersman, C.G., Bordini, B.J., Scharer, G., Lawlor, M.W., Zangwill, S., Southern, J.F., Amos, L., Geddes, G.C., Kliegman, R., Collins, M.P., BAG3 myofibrillar myopathy presenting with cardiomyopathy. Neuromuscul. Disord. 25 (2015), 418–422, 10.1016/j.nmd.2015.01.009.
36. [36] Arimura, T., Ishikawa, T., Nunoda, S., Kawai, S., Kimura, A., Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes. Hum. Mutat. 32 (2011), 1481–1491, 10.1002/humu.21603.
37. [37] Ruparelia, A.A., Oorschot, V., Vaz, R., Ramm, G., Bryson-Richardson, R.J., Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency. Acta Neuropathol. 128 (2014), 821–833, 10.1007/s00401-014-1344-5.
38. [38] Ruparelia, A., Vaz, R., Bryson-Richardson, R., Myofibrillar myopathies and the Z-disk associated proteins. INTECH 3 (2012), 317–358, 10.5772/50110.
39. [39] Iwasaki, M., Homma, S., Hishiya, A., Dolezal, S.J., Reed, J.C., Takayama, S., BAG3 regulates motility and adhesion of epithelial cancer cells. Cancer Res. 67 (2007), 10252–10259, 10.1158/0008-5472.CAN-07-0618.
40. [40] Ulbricht, A., Gehlert, S., Leciejewski, B., Schiffer, T., Bloch, W., Höhfeld, J., Induction and adaptation of chaperone-assisted selective autophagy CASA in response to resistance exercise in human skeletal muscle. Autophagy 11 (2015), 538–546, 10.1080/15548627.2015.1017186.
41. [41] Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., Zanconato, F., Le Digabel, J., Forcato, M., Bicciato, S., Elvassore, N., Piccolo, S., Role of YAP/TAZ in mechanotransduction. Nature 474 (2011), 179–183, 10.1038/nature10137.
42. [42] Schmidt, E.K., Clavarino, G., Ceppi, M., Pierre, P., SUnSET, a nonradioactive method to monitor protein synthesis. Nat. Methods 6 (2009), 275–277, 10.1038/nmeth.1314.
43. [43] Arndt, V., Daniel, C., Nastainczyk, W., Alberti, S., Höhfeld, J., BAG-2 acts as an inhibitor of the chaperone-associated ubiquitin ligase CHIP. Mol. Biol. Cell 16 (2005), 5891–5900, 10.1091/mbc.E05-07-0660.
44. [44] Orfanos, Z., Gödderz, M.P.O., Soroka, E., Gödderz, T., Rumyantseva, A., van der Ven, P.F.M., Hawke, T.J., Fürst, D.O., Breaking sarcomeres by in vitro exercise. Sci. Rep., 6, 2016, 19614, 10.1038/srep19614.
45. [45] Ursu, D., Sebille, S., Dietze, B., Freise, D., Flockerzi, V., Melzer, W., Excitation–contraction coupling in skeletal muscle of a mouse lacking the dihydropyridine receptor subunit γ1. J. Physiol. 533 (2001), 367–377, 10.1111/j.1469-7793.2001.0367a.x.
46. [46] Chen, Y., Yang, L.-N., Cheng, L., Tu, S., Guo, S.-J., Le, H.-Y., Xiong, Q., Mo, R., Li, C.-Y., Jeong, J.-S., Jiang, L., Blackshaw, S., Bi, L.-J., Zhu, H., Tao, S.-C., Ge, F., Bcl2-associated athanogene 3 interactome analysis reveals a new role in modulating proteasome activity. Mol. Cell. Proteomics 12 (2013), 2804–2819.
47. [47] Taipale, M., Tucker, G., Peng, J., Krykbaeva, I., Lin, Z.Y., Larsen, B., Choi, H., Berger, B., Gingras, A.C., Lindquist, S., A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell 158 (2014), 434–448, 10.1016/j.cell.2014.05.039.
48. [48] Iwasaki, M., Tanaka, R., Hishiya, A., Homma, S., Reed, J.C., Takayama, S., BAG3 directly associates with guanine nucleotide exchange factor of Rap1, PDZGEF2, and regulates cell adhesion. Biochem. Biophys. Res. Commun. 400 (2010), 413–418, 10.1016/j.bbrc.2010.08.092.
49. [49] Yusko, E.C., Asbury, C.L., Force is a signal that cells cannot ignore. Mol. Biol. Cell 25 (2014), 3717–3725, 10.1091/mbc.E13-12-0707.
50. [50] Schiller, H.B., Fässler, R., Mechanosensitivity and compositional dynamics of cell-matrix adhesions. EMBO Rep. 14 (2013), 509–519, 10.1038/embor.2013.49.
51. [51] Elosegui-Artola, A., Oria, R., Chen, Y., Kosmalska, A., Pérez-González, C., Castro, N., Zhu, C., Trepat, X., Roca-Cusachs, P., Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity. Nat. Cell Biol. 18 (2016), 540–548, 10.1038/ncb3336.
52. [52] Zhang, Y., Gao, X., Saucedo, L.J., Ru, B., Edgar, B.A., Pan, D., Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol. 5 (2003), 578–581, 10.1038/ncb999.
53. [53] Ruvinsky, I., Meyuhas, O., Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem. Sci. 31 (2006), 342–348, 10.1016/j.tibs.2006.04.003.
54. [54] Wippich, F., Bodenmiller, B., Trajkovska, M.G., Wanka, S., Aebersold, R., Pelkmans, L., Dual specificity kinase DYRK3 couples stress granule condensation/ dissolution to mTORC1 signaling. Cell 152 (2013), 791–805, 10.1016/j.cell.2013.01.033.
55. [55] Otte, L., Wiedemann, U., Schlegel, B., Pires, J.R., Beyermann, M., Schmieder, P., Krause, G., Volkmer-Engert, R., Schneider-Mergener, J., Oschkinat, H., WW domain sequence activity relationships identified using ligand recognition propensities of 42 WW domains. Protein Sci. 12 (2003), 491–500, 10.1110/ps.0233203.lytic.
56. [56] Bruce, M.C., Kanelis, V., Fouladkou, F., Debonneville, A., Staub, O., Rotin, D., Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain. Biochem. J. 415 (2008), 155–163, 10.1042/BJ20071708.
57. [57] Sudol, M., Harvey, K.F., Modularity in the hippo signaling pathway. Trends Biochem. Sci. 35 (2010), 627–633, 10.1016/j.tibs.2010.05.010.
58. [58] Merabova, N., Sariyer, I.K., Saribas, A.S., Knezevic, T., Gordon, J., Turco, M.C., Rosati, A., Weaver, M., Landry, J., Khalili, K., WW domain of BAG3 is required for the induction of autophagy in Glioma cells. J. Cell. Physiol. 230 (2015), 831–841, 10.1002/jcp.24811.
59. [59] Demand, J., Alberti, S., Patterson, C., Höhfeld, J., Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Curr. Biol. 11 (2001), 1569–1577, 10.1016/S0960-9822(01)00487-0.
60. [60] Smith, M.C., Scaglione, K.M., Assimon, V.A., Patury, S., Thompson, A.D., Dickey, C.A., Southworth, D.R., Paulson, H.L., Gestwicki, J.E., Zuiderweg, E.R.P., The E3 ubiquitin ligase CHIP and the molecular chaperone Hsc70 form a dynamic, tethered complex. Biochemistry 52 (2013), 5354–5364, 10.1021/bi4009209.
61. [61] Graf, C., Stankiewicz, M., Nikolay, R., Mayer, M.P., Insights into the conformational dynamics of the E3 ubiquitin ligase CHIP in complex with chaperones and E2 enzymes. Biochemistry 49 (2010), 2121–2129, 10.1021/bi901829f.
62. [62] Yang, Z., Lu, Y., Liu, J., Wang, Y., Zhao, X., The chaperone-like activity of rat HspB8/Hsp22 and dynamic molecular transition related to oligomeric architectures in vitro. Protein Pept. Lett. 19 (2012), 353–359.
63. [63] Jiang, J., Ballinger, C.A., Wu, Y., Dai, Q., Cyr, D.M., Höhfeld, J., Patterson, C., CHIP is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation. J. Biol. Chem. 276 (2001), 42938–42944, 10.1074/jbc.M101968200.
64. [64] Itakura, E., Mizushima, N., p62 targeting to the autophagosome formation site requires self-oligomerization but not LC3 binding. J. Cell Biol. 192 (2011), 17–27, 10.1083/jcb.201009067.
65. [65] Ciuffa, R., Lamark, T., Tarafder, A.K., Guesdon, A., Rybina, S., Hagen, W.J.H., Johansen, T., Sachse, C., The selective autophagy receptor p62 forms a flexible filamentous helical scaffold. Cell Rep. 11 (2015), 748–758, 10.1016/j.celrep.2015.03.062.
66. [66] Hornberger, T.A., Mechanotransduction and the regulation of mTORC1 signaling in skeletal muscle. Int. J. Biochem. Cell Biol. 43 (2011), 1267–1276, 10.1016/j.biocel.2011.05.007.
67. [67] Gehlert, S., Suhr, F., Gutsche, K., Willkomm, L., Kern, J., Jacko, D., Knicker, A., Schiffer, T., Wackerhage, H., Bloch, W., High force development augments skeletal muscle signalling in resistance exercise modes equalized for time under tension. Pflugers Arch. 467 (2015), 1343–1356, 10.1007/s00424-014-1579-y.
68. [68] Schiaffino, S., Dyar, K.A., Ciciliot, S., Blaauw, B., Sandri, M., Mechanisms regulating skeletal muscle growth and atrophy. FEBS J. 280 (2013), 4294–4314, 10.1111/febs.12253.
69. [69] Ogasawara, R., Fujita, S., Hornberger, T.A., Kitaoka, Y., Makanae, Y., Nakazato, K., Naokata, I., The role of mTOR signalling in the regulation of skeletal muscle mass in a rodent model of resistance exercise. Sci. Rep., 6, 2016, 31142, 10.1038/srep31142.
70. [70] Goodman, C.A., The role of mTORC1 in regulating protein synthesis and skeletal muscle mass in response to various mechanical stimuli. Rev. Physiol. Biochem. Pharmacol. 166 (2014), 43–95, 10.1007/112_2013_17.
71. [71] Egerman, M.A., Glass, D.J., Signaling pathways controlling skeletal muscle mass. Crit. Rev. Biochem. Mol. Biol. 49 (2014), 59–68, 10.3109/10409238.2013.857291.
72. [72] Jacobs, B.L., Goodman, C.A., Hornberger, T.A., The mechanical activation of mTOR signaling: an emerging role for late endosome/lysosomal targeting. J. Muscle Res. Cell Motil. 35 (2014), 11–21, 10.1007/s10974-013-9367-4.