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Castagnaro, Silvia (2015) Extracellular collagen type VI has prosurvival and autophagy instructive properties in mouse embryonic fibroblasts. [Tesi di dottorato]

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Abstract (inglese)

Collagen VI is a major protein of the extracellular matrix with a broad distribution in many tissues, including skeletal muscle and connective tissues. It is composed of three distinct alpha chains, α1, α2 and α3(VI), ecoded by separate genes. Mutations of collagen VI genes in humans cause several muscle diseases, such as Bethlem myopathy and Ullrich congenital muscular dystrophy. Collagen VI null (Col6a1–/–) mice display a myopathic phenotype characterized by mitochondrial dysfunction, spontaneous apoptosis and autophagic impairments in myofibers. These findings indicate that collagen VI has a key role for skeletal muscle homeostasis.
Before starting my PhD, I participated to a project aimed at investigating the effects of physical exercise on wild type and Col6a1–/– skeletal muscle. This work demonstrated for the first time that exercise is able to activate the autophagic response in muscle. Moreover, this study revealed that physical exercise it is detrimental for Col6a1–/– muscles.
I decided to focus my main PhD work on investigating the role of collagen VI in fibroblasts, which are the major cell type responsible for the secretion and extracellular deposition of this protein, and elucidating the consequences on fibroblasts due to ablation of collagen VI. In patients affected by Bethlem myopathy and Ullrich congenital muscular dystrophy, the mutated forms of collagen VI are produced and retained by fibroblasts, suggesting a potential contribution for this cell type in the onset and progression of muscle defects.
To assess how lack of collagen VI impacts on fibroblast functions, I generated stable mouse embryonic fibroblast (MEF) lines from wild type and Col6a1–/– mice and showed that collagen VI is necessary for autophagy regulation and has prosurvival properties in fibroblasts. Col6a1–/– MEFs displayed accumulation of LC3 both basally and following autophagy induction. To dissect the autophagic response of these cells, I studied the autophagy flux and the activity of the nutrient sensor kinase mTOR. I found that in Col6a1–/– MEFs the mTORC1 downstream targets, such as 4E-BP1 and S6, are persistently activated under nutrient depletion stimuli, leading to autophagy inhibition in starving cells. Furthermore, Col6a1–/– MEFs presented a general energy imbalance, leading to over-activation of the AMP-activated protein kinase. These signalling defects lead to massive accumulation of autophagosomes inside Col6a1–/– fibroblasts, due to a compromised autophagosome-lysosome fusion in association with the presence of enlarged lysosomes and LAMP-2 protein depletion. These lysosomal defects are also associated with aberrant localization and activity of TFEB, a master transcription factor for lysosome biogenesis and autophagy regulation.
In addition, Col6a1–/– MEFs showed increased susceptibility to cell death, especially under nutrient stress, that ended with activation of the intrinsic pathway of apoptosis. This phenotype was specifically rescued by culturing cells onto purified collagen VI provided as an adhesive substrate . Lack of collagen VI also influenced the organization of the mitochondrial network, which has a key role in cell survival. Mitochondria of Col6a1–/– MEFs exhibited increased fragmented morphology, associated with Parkin translocation and defective mitophagy.
These findings show that fibroblasts play a relevant role in the development of the pathophysiological defects of collagen VI null mice, a finding that provide a thus far undisclosed and valuable information for the diagnosis and therapy of inherited diseases associated with collagen VI gene mutations. Moreover, they reveal for the first time a direct effect of collagen VI on the regulation of autophagy and associated mechanisms in this cell type.

Abstract (italiano)

Il collagene VI è una proteina della matrice extracellulare con caratteristiche uniche, presente ed abbondante in numerosi tessuti, come in muscolo scheletrico e i tessuti connettivi. Si compone di tre diverse catene, chiamate α1, α2 e α3(VI), codificate da geni distinti. Mutazioni a carico dei geni per il collagene VI nell’uomo sono causa di diverse patologie muscolari, quali la miopatia di Bethlem e la distrofia muscolare congenita di Ullrich. Il modello murino privo di collagene VI (Col6a1–/–), generato nostro laboratorio, sviluppa un fenotipo miopatico caratterizzato da disfunzione mitocondriale, insorgenza di apoptosi e difetti di autofagia nelle miofibre muscolari. Il collagene VI risulta in sostanza fondamentale per l'omeostasi generale del muscolo scheletrico.
Al termine della laurea specialistica, ho partecipato ad un primo progetto volto a studiare gli effetti dell'esercizio fisico sul muscolo scheletrico di topi wild-type e Col6a1–/–. Questo lavoro ha dimostrato per la prima volta che l'esercizio fisico è in grado di attivare l'autofagia nel muscolo; in secondo luogo che l'esercizio fisico è dannoso per il muscolo dei topi Col6a1–/–, già soggetti a problemi di attivazione dell'autofagia, escludendone un possibile utilizzo come strategia terapeutica.
In seguito ho deciso di focalizzare il mio lavoro di dottorato sullo studio delle alterazioni insorgenti nei fibroblasti privi di collagene VI e sugli effetti diretti di questa proteina sulla regolazione dell'autofagia. Il fibroblasto è il principale tipo cellulare che produce collagene VI. Inoltre, in pazienti distrofici con patologie correlate a mutazioni del collagene VI, le varianti mutate di collagene VI vengono prodotte proprio dai fibroblasti e ritenute all'interno del loro citoplasma, suggerendo così un contributo primario dei fibroblasti nella patogenesi muscolare.
Per indagare più a fondo il contributo di queste cellule, ho generato delle linee cellulari di fibroblasti embrionali murini (MEF) da topi wild-type e Col6a1–/– e ho dimostrato come il collagene VI sia necessario per una corretta attivazione di autofagia e per la sopravvivenza dei fibroblasti. Per analizzare la risposta autofagica di queste cellule, ho studiato il flusso autofagico e l'attività della protein chinasi mTOR, uno dei principali sensori cellulari di risposta ai nutrienti. Nei MEF Col6a1–/–, i target a valle di mTORC1, 4E-BP1 ed S6, risultano costantemente attivati anche in seguito a stimoli di induzione di autofagia, ad indicare un'inibizione a valle della via autofagica. Tuttavia, nei MEF Col6a1–/– è presente uno squilibrio energetico generale, che porta all'iper-attivazione della protein chinasi attivata da AMP (AMPK), che a sua volta è implicata nell'induzione di autofagia. Le analisi relative al fattore di trascrizione TFEB, che svolge un ruolo chiave nella biogenesi e funzionalità lisosomiale, dimostrano inoltre un'alterata localizzazione e attività di questo fattore, ad indicare un'alterata risposta trascrizionale del programma autofagico dei fibroblasti Col6a1–/–. Questa complessa situazione porta infine ad un accumulo intracellulare di autofagosomi nei MEF Col6a1–/–, dovuto alla mancata fusione di autofagosomi e lisosomi, ed associato alla presenza di lisosomi dilatati ed alla diminuzione dei livelli proteici di LAMP-2.
Inoltre i MEF Col6a1–/– hanno dimostrato una maggiore suscettibilità a morte cellulare indotta da stress o induzione di autofagia, tramite attivazione della via intrinseca di apoptosi. È importante evidenziare che questo difetto viene specificatamente recuperato quando i fibroblasti sono coltivati su collagene VI purificato, fornito come substrato. L’assenza del collagene VI nei MEF Col6a1–/– influenza infine l'organizzazione della rete mitocondriale, la quale è nota svolgere un ruolo chiave nella sopravvivenza cellulare. I mitocondri dei MEF Col6a1–/– risultano infatti più frequentemente frammentati rispetto ai wild-type, e questa alterazione potrebbe facilmente essere correlata con una disfunzione mitocondriale. In questo contesto, i mitocondri Col6a1–/– inducono la traslocazione di Parkin e vengono sottoposti ad un'alterata risposta del processo selettivo di mitofagia.
In conclusione, questi risultati dimostrano per la prima volta che i fibroblasti contribuiscono in modo rilevante all’insorgenza e alla progressione dei difetti patofisiologici nei topi Col6a1–/–, fornendo così informazioni preziose e finora ignote per la diagnosi e la terapia delle patologie legate a mutazioni nei geni codificanti per il collagene VI. Inoltre, essi dimostrano che il collagene VI svolge un effetto diretto sulla regolazione dell’autofagia e sui meccanismi ad essa associati in questo tipo cellulare.

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Tipo di EPrint:Tesi di dottorato
Relatore:Bonaldo, Paolo
Dottorato (corsi e scuole):Ciclo 27 > scuole 27 > BIOSCIENZE E BIOTECNOLOGIE > GENETICA E BIOLOGIA MOLECOLARE DELLO SVILUPPO
Data di deposito della tesi:31 Gennaio 2015
Anno di Pubblicazione:Gennaio 2015
Parole chiave (italiano / inglese):Collagen VI; autophagy; apoptosis; mouse embryonic fibroblasts; extracellular matrix
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:7853
Depositato il:12 Nov 2015 14:42
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Alexopoulos, L.G. et al., 2009. Developmental and osteoarthritic changes in Col6a1-knockout mice: biomechanics of type VI collagen in the cartilage pericellular matrix. Arthritis and rheumatism, 60(3), pp.771–9. Cerca con Google

Allamand, V. et al., 2011. ColVI myopathies: where do we stand, where do we go? Skeletal muscle, 1(1), p.30. Cerca con Google

Angelin, A. et al., 2007. Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins. Proceedings of the National Academy of Sciences of the United States of America, 104(3), pp.991–6. Cerca con Google

Avivar-Valderas, A. et al., 2011. PERK integrates autophagy and oxidative stress responses to promote survival during extracellular matrix detachment. Molecular and Cellular Biology, 31(17), pp.3616–29. Cerca con Google

Di Bartolomeo, S. et al., 2010. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. The Journal of cell biology, 191(1), pp.155–68. Cerca con Google

Benato, F. et al., 2013. Ambra1 knockdown in zebrafish leads to incomplete development due to severe defects in organogenesis. Autophagy, 9(4), pp.476–95. Cerca con Google

Bernardi, P. & Bonaldo, P., 2008. Dysfunction of mitochondria and sarcoplasmic reticulum in the pathogenesis of collagen VI muscular dystrophies. Annals of the New York Academy of Sciences, 1147, pp.303–11. Cerca con Google

Bertrand, A.T. et al., 2014. 199th ENMC international workshop: FHL1 related myopathies, June 7-9, 2013, Naarden, The Netherlands. Neuromuscular Disorders, 24(5), pp.453–462. Cerca con Google

Bjørkøy, G., Lamark, T. & Johansen, T., 2006. p62/SQSTM1: A missing link between protein aggregates and the autophagy machinery. Autophagy, 2(2), pp.138–139. Cerca con Google

Bonaldo, P. et al., 1998. Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy. Human Molecular Genetics, 7(13), pp.2135–40. Cerca con Google

Bonaldo, P. et al., 1990. Structural and functional features of the alpha 3 chain indicate a bridging role for chicken collagen VI in connective tissues. Biochemistry, 29(5), pp.1245–54. Cerca con Google

Bonaldo, P. & Sandri, M., 2013. Cellular and molecular mechanisms of muscle atrophy. Disease Models & Mechanisms, 6(1), pp.25–39. Cerca con Google

Bönnemann, C.G., 2011. The collagen VI-related myopathies: muscle meets its matrix. Nature reviews. Neurology, 7(7), pp.379–90. Cerca con Google

Booth, L. a. et al., 2014. The role of cell signaling in the crosstalk between autophagy and apoptosis. Cellular Signaling, 26(3), pp.549–555. Cerca con Google

Boya, P., Reggiori, F. & Codogno, P., 2013. Emerging regulation and functions of autophagy. Nature Cell Biology, 15(7), pp.713–20. Cerca con Google

Braghetta, P. et al., 2008. An enhancer required for transcription of the Col6a1 gene in muscle connective tissue is induced by signals released from muscle cells. Experimental Cell Research, 314(19), pp.3508–18. Cerca con Google

Braghetta, P. et al., 1996. Distinct regions control transcriptional activation of the alpha1(VI) collagen promoter in different tissues of transgenic mice. The Journal of cell biology, 135(4), pp.1163–77. Cerca con Google

Briñas, L. et al., 2010. Early onset collagen VI myopathies: Genetic and clinical correlations. Annals of neurology, 68(4), pp.511–20. Cerca con Google

Brodsky, B. & Persikov, A. V, 2005. Molecular structure of the collagen triple helix. Advances in protein chemistry, 70, pp.301–39. Cerca con Google

Brown, S. et al., 1999. The cardiac expression of striated muscle LIM protein 1 (SLIM1) is restricted to the outflow tract of the developing heart. Journal of molecular and cellular cardiology, 31(4), pp.837–43. Cerca con Google

Buraschi, S. et al., 2013. Decorin causes autophagy in endothelial cells via Peg3. Proceedings of the National Academy of Sciences of the United States of America, 110(28), pp.E2582–91. Cerca con Google

Burg, M. a et al., 1996. Binding of the NG2 proteoglycan to type VI collagen and other extracellular matrix molecules. The Journal of biological chemistry, 271(42), pp.26110–6. Cerca con Google

Carmignac, V. et al., 2011. Autophagy is increased in laminin α2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A. Human Molecular Genetics, 20(24), pp.4891–902. Cerca con Google

Castello-Cros, R. et al., 2011. Matrix remodeling stimulates stromal autophagy, “fueling” cancer cell mitochondrial metabolism and metastasis. Cell Cycle, 10(12), pp.2021–2034. Cerca con Google

Chen, P., Cescon, M., Megighian, A., et al., 2014. Collagen VI regulates peripheral nerve myelination and function. FASEB journal, 28(3), pp.1145–56. Cerca con Google

Chen, P., Cescon, M., Zuccolotto, G., et al., 2014. Collagen VI regulates peripheral nerve regeneration by modulating macrophage recruitment and polarization. Acta neuropathologica, 129, pp.97–113. Cerca con Google

Chen, P.M., Gombart, Z.J. & Chen, J.W., 2011. Chloroquine treatment of ARPE-19 cells leads to lysosome dilation and intracellular lipid accumulation: possible implications of lysosomal dysfunction in macular degeneration. Cell & bioscience, 1(1), p.10. Cerca con Google

Cheng, I.H. et al., 2011. Collagen VI protects against neuronal apoptosis elicited by ultraviolet irradiation via an Akt/phosphatidylinositol 3-kinase signaling pathway. Neuroscience, 183, pp.178–88. Cerca con Google

Cheng, J.S. et al., 2009. Collagen VI protects neurons against Abeta toxicity. Nature Neuroscience, 12(2), pp.119–21. Cerca con Google

Colombatti, A. et al., 1987. Biosynthesis of chick type VI collagen. I. Intracellular assembly and molecular structure. The Journal of biological chemistry, 262(30), pp.14454–60. Cerca con Google

Colombatti, A. & Bonaldo, P., 1987. Biosynthesis of chick type VI collagen. II. Processing and secretion in fibroblasts and smooth muscle cells. The Journal of biological chemistry, 262(30), pp.14461–6. Cerca con Google

Colombatti, A., Mucignat, M.T. & Bonaldo, P., 1995. Secretion and matrix assembly of recombinant type VI collagen. Journal of Biological Chemistry, 270, pp.13105–13111. Cerca con Google

Corcelle, E. et al., 2007. Control of the Autophagy Maturation Step by the MAPK ERK and p38: Lessons from Environmental Carcinogens. Autophagy, 3(1), pp.57–59. Cerca con Google

Cowling, B.S. et al., 2008. Identification of FHL1 as a regulator of skeletal muscle mass: implications for human myopathy. The Journal of cell biology, 183(6), pp.1033–48. Cerca con Google

Cullup, T. et al., 2013. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nature Genetics, 45(1), pp.83–7. Cerca con Google

Doliana, R. et al., 1998. Alternative splicing of VWFA modules generates variants of type VI collagen alpha 3 chain with a distinctive expression pattern in embryonic chicken tissues and potentially different adhesive function. Matrix biology, 16(7), pp.427–42. Cerca con Google

Duan, L. et al., 2014. Critical roles for nitric oxide and ERK in the completion of prosurvival autophagy in 4OHTAM-treated estrogen receptor-positive breast cancer cells. Cancer letters, 353(2), pp.290–300. Cerca con Google

Egan, D.F. et al., 2010. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science, 331(6016), pp.456–461. Cerca con Google

Eskelinen, E.-L. et al., 2002. Role of LAMP-2 in lysosome biogenesis and autophagy. Molecular biology of the cell, 13(9), pp.3355–3368. Cerca con Google

Feng, Y. et al., 2014. The machinery of macroautophagy. Cell research, 24(1), pp.24–41. Cerca con Google

Ferraro, E. & Cecconi, F., 2007. Autophagic and apoptotic response to stress signals in mammalian cells. Archives of biochemistry and biophysics, 462(2), pp.210–9. Cerca con Google

Fimia, G.M. et al., 2007. Ambra1 regulates autophagy and development of the nervous system. Nature, 447(7148), pp.1121–5. Cerca con Google

Fimia, G.M. & Piacentini, M., 2010. Regulation of autophagy in mammals and its interplay with apoptosis. Cellular and molecular life sciences, 67(10), pp.1581–8. Cerca con Google

Fortunato, F. et al., 2009. Impaired autolysosome formation correlates with Lamp-2 depletion: role of apoptosis, autophagy, and necrosis in pancreatitis. Gastroenterology, 137(1), pp.350–60, 360.e1–5. Cerca con Google

Fujita, N. et al., 2008. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Molecular biology of the cell, 19(5), pp.2092–100. Cerca con Google

Fung, C. et al., 2008. Induction of autophagy during extracellular matrix detachment promotes cell survival. Molecular biology of the cell, 19(3), pp.797–806. Cerca con Google

Galluzzi, L. et al., 2015. Essential versus accessory aspects of cell death : recommendations of the NCCD 2015. Cell Death and Differentiation, 22, pp.58–73. Cerca con Google

Gattazzo, F., Urciuolo, A. & Bonaldo, P., 2014. Extracellular matrix: a dynamic microenvironment for stem cell niche. Biochimica et biophysica acta, 1840(8), pp.2506–19. Cerca con Google

Gomes, L.C. & Scorrano, L., 2008. High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy. Biochimica et Biophysica Acta - Bioenergetics, 1777(7-8), pp.860–866. Cerca con Google

Gomes, L.C. & Scorrano, L., 2011. Mitochondrial elongation during autophagy: a stereotypical response to survive in difficult times. Autophagy, 7(10), pp.1251–3. Cerca con Google

González-Polo, R.-A. et al., 2005. The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death. Journal of cell science, 118(Pt 14), pp.3091–102. Cerca con Google

Goyal, A. et al., 2014. Decorin activates AMPK, an energy sensor kinase, to induce autophagy in endothelial cells. Matrix Biology, 35, pp.42–50. Cerca con Google

Grumati, P. et al., 2010. Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nature Medicine, 16(11), pp.1313–20. Cerca con Google

Grumati, P. et al., 2011. Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI-deficient muscles. Autophagy, 7(12), pp.1415–1423. Cerca con Google

Guo, X. et al., 2007. Morphologic characterization of organized extracellular matrix deposition by ascorbic acid-stimulated human corneal fibroblasts. Investigative ophthalmology & visual science, 48(9), pp.4050–60. Cerca con Google

Hatamochi, A. et al., 1989. Regulation of collagen VI expression in fibroblasts. Effects of cell density, cell-matrix interactions, and chemical transformation. Journal of Biological Chemistry, 264(6), pp.3494–3499. Cerca con Google

He, C. & Levine, B., 2010. The Beclin 1 interactome. Current opinion in cell biology, 22(2), pp.140–9. Cerca con Google

Howell, S.J. & Doane, K.J., 1998. Type VI collagen increases cell survival and prevents anti-beta 1 integrin-mediated apoptosis. Experimental Cell Research, 241(1), pp.230–41. Cerca con Google

Hubmacher, D. & Apte, S.S., 2013. The biology of the extracellular matrix: novel insights. Current opinion in rheumatology, 25(1), pp.65–70. Cerca con Google

Huynh, K.K. et al., 2007. LAMP proteins are required for fusion of lysosomes with phagosomes. The EMBO journal, 26(2), pp.313–24. Cerca con Google

Hynes, R.O., 2009. The extracellular matrix: not just pretty fibrils. Science, 326(5957), pp.1216–9. Cerca con Google

Ichimura, Y. et al., 2000. A ubiquitin-like system mediates protein lipidation. Nature, 408(6811), pp.488–92. Cerca con Google

Ichimura, Y. et al., 2008. Selective turnover of p62/A170/SQSTM1 by autophagy. Autophagy, 4(8), pp.1063–6. Cerca con Google

Irwin, W. a et al., 2003. Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nature Genetics, 35(4), pp.367–71. Cerca con Google

Iyengar, P. et al., 2005. Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. Journal of Clinical Investigation, 115(5), pp.1163–1176. Cerca con Google

Jiang, P. & Mizushima, N., 2014. LC3- and p62-based biochemical methods for the analysis of autophagy progression in mammalian cells. Methods, pp.18–22. Cerca con Google

Jimenez-Mallebrera, C. et al., 2006. A comparative analysis of collagen VI production in muscle, skin and fibroblasts from 14 Ullrich congenital muscular dystrophy patients with dominant and recessive COL6A mutations. Neuromuscular Disorders, 16(9-10), pp.571–82. Cerca con Google

Kabeya, Y. et al., 2004. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. Journal of cell science, 117(Pt 13), pp.2805–12. Cerca con Google

Kasahara, A. & Scorrano, L., 2014. Mitochondria: from cell death executioners to regulators of cell differentiation. Trends in cell biology, 24(12), pp.761–770. Cerca con Google

Keene, D.R., Engvall, E. & Glanville, R.W., 1988. Ultrastructure of type VI collagen in human skin and cartilage suggests an anchoring function for this filamentous network. The Journal of cell biology, 107(5), pp.1995–2006. Cerca con Google

Khan, T. et al., 2009. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Molecular and Cellular Biology, 29(6), pp.1575–91. Cerca con Google

Kim, J. et al., 2011. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biology, 13(2), pp.132–41. Cerca con Google

Kim, J.H. et al., 2014. Raf/MEK/ERK can regulate cellular levels of LC3B and SQSTM1/p62 at expression levels. Experimental Cell Research, 327(2), pp.340–52. Cerca con Google

Klionsky, D.J. et al., 2012. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 8(4), pp.445–544. Cerca con Google

Komatsu, M. et al., 2007. Homeostatic Levels of p62 Control Cytoplasmic Inclusion Body Formation in Autophagy-Deficient Mice. Cell, 131(6), pp.1149–1163. Cerca con Google

Kroemer, G., Mariño, G. & Levine, B., 2010. Autophagy and the integrated stress response. Molecular cell, 40(2), pp.280–93. Cerca con Google

Kuo, H.-J.J. et al., 1997. Type VI collagen anchors endothelial basement membranes by interacting with type IV collagen. Journal of Biological Chemistry, 272(42), pp.26522–26529. Cerca con Google

Kuo, J.-C., 2013. Mechanotransduction at focal adhesions: integrating cytoskeletal mechanics in migrating cells. Journal of cellular and molecular medicine, 17(6), pp.704–12. Cerca con Google

Lampe, A.K. & Bushby, K.M.D., 2005. Collagen VI related muscle disorders. Journal of medical genetics, 42(9), pp.673–685. Cerca con Google

Lee, J.Y. et al., 2012. Fhl1 as a downstream target of Wnt signaling to promote myogenesis of C2C12 cells. Molecular and Cellular Biochemistry, 365(1-2), pp.251–262. Cerca con Google

Lee, S.J. et al., 2010. A functional role for the p62-ERK1 axis in the control of energy homeostasis and adipogenesis. EMBO reports, 11(3), pp.226–32. Cerca con Google

Levine, B. & Kroemer, G., 2008. Autophagy in the pathogenesis of disease. Cell, 132(1), pp.27–42. Cerca con Google

Liesa, M. & Shirihai, O.S., 2013. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metabolism, 17(4), pp.491–506. Cerca con Google

Lock, R. & Debnath, J., 2008. Extracellular matrix regulation of autophagy. Current opinion in cell biology, 20(5), pp.583–8. Cerca con Google

Malicdan, M.C. V & Nishino, I., 2012. Autophagy in lysosomal myopathies. Brain pathology, 22(1), pp.82–8. Cerca con Google

Mammucari, C. et al., 2007. FoxO3 controls autophagy in skeletal muscle in vivo. Cell metabolism, 6(6), pp.458–71. Cerca con Google

Manning, B.D. & Cantley, L.C., 2007. AKT/PKB Signaling: Navigating Downstream. Cell, 129, pp.1261–1274. Cerca con Google

Mariño, G. et al., 2014. Self-consumption: the interplay of autophagy and apoptosis. Molecular Cell Biology, 15(2), pp.81–94. Cerca con Google

Martina, J.A. et al., 2012. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy, 8(6), pp.903–14. Cerca con Google

Masiero, E. et al., 2009. Autophagy is required to maintain muscle mass. Cell metabolism, 10(6), pp.507–15. Cerca con Google

Menazza, S. et al., 2010. Oxidative stress by monoamine oxidases is causally involved in myofiber damage in muscular dystrophy. Human Molecular Genetics, 19(21), pp.4207–15. Cerca con Google

Mercuri, E. & Longman, C., 2005. Congenital muscular dystrophy. Pediatric annals, 34(7), pp.560–2, 564–8. Cerca con Google

Merlini, L. et al., 2008. Autosomal recessive myosclerosis myopathy is a collagen VI disorder. Neurology, 71(16), pp.1245–53. Cerca con Google

Merlini, L. & Nishino, I., 2014. 201st ENMC International Workshop: Autophagy in muscular dystrophies--translational approach, 1-3 November 2013, Bussum, The Netherlands. Neuromuscular Disorders, 24(6), pp.546–61. Cerca con Google

Mizushima, N. et al., 2008. Autophagy fights disease through cellular self-digestion. Nature, 451(7182), pp.1069–75. Cerca con Google

Mizushima, N. et al., 2004. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Molecular biology of the cell, 15(3), pp.1101–11. Cerca con Google

Mizushima, N. et al., 2003. Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. Journal of cell science, 116(Pt 9), pp.1679–88. Cerca con Google

Mizushima, N., 2010. The role of the Atg1/ULK1 complex in autophagy regulation. Current opinion in cell biology, 22(2), pp.132–9. Cerca con Google

Mizushima, N. & Komatsu, M., 2011. Autophagy: renovation of cells and tissues. Cell, 147(4), pp.728–41. Cerca con Google

Mizushima, N. & Kuma, A., 2008. Autophagosomes in GFP-LC3 Transgenic Mice. Methods in molecular biology, 445, pp.119–24. Cerca con Google

Mizushima, N. & Levine, B., 2010. Autophagy in mammalian development and differentiation. Nature Cell Biology, 12(9), pp.823–30. Cerca con Google

Mizushima, N. & Yoshimori, T., 2007. How to Interpret LC3 Immunoblotting. Autophagy, 3(12), pp.542–545. Cerca con Google

Morgan, M.J. & Madgwick, A.J., 1999. The LIM proteins FHL1 and FHL3 are expressed differently in skeletal muscle. Biochemical and biophysical research communications, 255(2), pp.245–250. Cerca con Google

Murphy, M.M. et al., 2011. Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development, 138(17), pp.3625–37. Cerca con Google

Nair, U. & Klionsky, D.J., 2011. Activation of autophagy is required for muscle homeostasis during physical exercise. Autophagy, 7(12), pp.1405–6. Cerca con Google

Narendra, D. et al., 2008. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. The Journal of cell biology, 183(5), pp.795–803. Cerca con Google

Nazio, F. et al., 2013. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nature Cell Biology, 15(4), pp.406–16. Cerca con Google

Neill, T., Schaefer, L. & Iozzo, R. V, 2012. Decorin: a guardian from the matrix. The American journal of pathology, 181(2), pp.380–7. Cerca con Google

Neill, T., Schaefer, L. & Iozzo, R. V, 2014. Instructive Roles of Extracellular Matrix on Autophagy. The American journal of pathology, 184(6), pp.2146–53. Cerca con Google

Nemoto, T. et al., 2003. The Mouse APG10 Homologue, an E2-like Enzyme for Apg12p Conjugation, Facilitates MAP-LC3 Modification. Journal of Biological Chemistry, 278(41), pp.39517–39526. Cerca con Google

Nguyen, T.M.B. et al., 2009. Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and beta-catenin levels. Journal of cellular and molecular medicine, 13(9B), pp.3687–98. Cerca con Google

Nguyen, T.M.B. et al., 2007. Kringle 5 of human plasminogen, an angiogenesis inhibitor, induces both autophagy and apoptotic death in endothelial cells. Blood, 109(11), pp.4793–802. Cerca con Google

Ohsumi, Y., 2001. Molecular dissection of autophagy: two ubiquitin-like systems. Nature reviews. Molecular Cell Biology, 2(3), pp.211–6. Cerca con Google

Olsen, D.R. et al., 1989. Collagen gene expression by cultured human skin fibroblasts. Abundant steady-state levels of type VI procollagen messenger RNAs. The Journal of clinical investigation, 83(3), pp.791–5. Cerca con Google

De Palma, C. et al., 2012. Autophagy as a new therapeutic target in Duchenne muscular dystrophy. Cell Death & Disease, 3(11), p.e418. Cerca con Google

Pan, T.-C. et al., 2003. New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype. American journal of human genetics, 73(2), pp.355–69. Cerca con Google

Pepe, G. et al., 2002. Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th ENMC international workshop, 23-24 November 2001, Naarden, The Netherlands. Neuromuscular Disorders, 12(10), pp.984–93. Cerca con Google

Poluzzi, C. et al., 2014. Endorepellin evokes autophagy in endothelial cells. The Journal of biological chemistry, 289(23), pp.16114–28. Cerca con Google

Raben, N. et al., 2008. Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease. Human Molecular Genetics, 17(24), pp.3897–908. Cerca con Google

Ricard-Blum, S., 2011. The Collagen Family. Cold Spring Harbor Perspectives in Biology, 3, pp.1–19. Cerca con Google

Rühl, M. et al., 1999. Soluble collagen VI drives serum-starved fibroblasts through S phase and prevents apoptosis via down-regulation of Bax. The Journal of biological chemistry, 274(48), pp.34361–8. Cerca con Google

Russell, R.C., Yuan, H.-X. & Guan, K.-L., 2014. Autophagy regulation by nutrient signaling. Cell research, 24(1), pp.42–57. Cerca con Google

Sabatelli, P. et al., 2001. Collagen VI deficiency affects the organization of fibronectin in the extracellular matrix of cultured fibroblasts. Matrix Biology, 20(7), pp.475–86. Cerca con Google

Sabatelli, P. et al., 2012. Critical evaluation of the use of cell cultures for inclusion in clinical trials of patients affected by collagen VI myopathies. Journal of cellular physiology, 227(7), pp.2927–35. Cerca con Google

Saitta, B. et al., 1990. Alternative splicing of the human alpha 2(VI) collagen gene generates multiple mRNA transcripts which predict three protein variants with distinct carboxyl termini. The Journal of biological chemistry, 265(11), pp.6473–80. Cerca con Google

Sandri, M. et al., 2013. Misregulation of autophagy and protein degradation systems in myopathies and muscular dystrophies. Journal of cell science, 126(Pt 23), pp.5325–33. Cerca con Google

Sardiello, M. et al., 2009. A gene network regulating lysosomal biogenesis and function. Science, 325(5939), pp.473–7. Cerca con Google

Schiaffino, S. et al., 2013. Mechanisms regulating skeletal muscle growth and atrophy. The FEBS journal, 280(17), pp.4294–314. Cerca con Google

Schneider, J.L. & Cuervo, A.M., 2014. Autophagy and human disease: emerging themes. Current opinion in genetics & development, 26C, pp.16–23. Cerca con Google

Scorrano, L., 2005. Proteins that fuse and fragment mitochondria in apoptosis: Con-fissing a deadly con-fusion? Journal of Bioenergetics and Biomembranes, 37(3), pp.165–170. Cerca con Google

Settembre, C. et al., 2012. A lysosome-to-nucleus signaling mechanism senses and regulates the lysosome via mTOR and TFEB. The EMBO Journal, 31(5), pp.1095–1108. Cerca con Google

Settembre, C. et al., 2011. TFEB links autophagy to lysosomal biogenesis. Science, 332(6036), pp.1429–33. Cerca con Google

Settembre, C. & Ballabio, A., 2011. TFEB regulates autophagy. An integrated coordination of cellular degradation and recycling processes. Autophagy, 7(11), pp.1379–1381. Cerca con Google

Shalini, S. et al., 2014. Old , new and emerging functions of caspases. Cell Death and Differentiation, pp.1–14. Cerca con Google

Shang, L. & Wang, X., 2011. AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation. Autophagy, 7(8), pp.924–926. Cerca con Google

Shen, H. & Codogno, P., 2011. Autophagic cell death: Loch Ness monster or endangered species? Autophagy, 7(5), pp.457–465. Cerca con Google

Shen, H. & Mizushima, N., 2014. At the end of the autophagic road: an emerging understanding of lysosomal functions in autophagy. Trends in biochemical sciences, 39(2), pp.61–71. Cerca con Google

Spitali, P. et al., 2013. Autophagy is Impaired in the Tibialis Anterior of Dystrophin Null Mice. PLoS currents, 5, pp.1–12. Cerca con Google

Stallcup, W.B., 2002. The NG2 proteoglycan: past insights and future prospects. Journal of neurocytology, 31(6-7), pp.423–35. Cerca con Google

Stolz, A., Ernst, A. & Dikic, I., 2014. Cargo recognition and trafficking in selective autophagy. Nature Cell Biology, 16(6), pp.495–501. Cerca con Google

Tanaka, Y. et al., 2000. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature, 406(8), pp.902–906. Cerca con Google

Tillet, E. et al., 1994. Recombinant expression and structural and binding properties of alpha 1(VI) and alpha 2(VI) chains of human collagen type VI. European journal of biochemistry / FEBS, 221(1), pp.177–85. Cerca con Google

Tsang, K.Y. et al., 2010. The developmental roles of the extracellular matrix: beyond structure to regulation. Cell and tissue research, 339(1), pp.93–110. Cerca con Google

Tuloup-Minguez, V. et al., 2013. Autophagy modulates cell migration and β1 integrin membrane recycling. Cell Cycle, 12(20), pp.3317–28. Cerca con Google

Tuloup-Minguez, V. et al., 2011. Regulation of autophagy by extracellular matrix glycoproteins in HeLa cells. Autophagy, 7(1), pp.27–39. Cerca con Google

Turrina, A., Martínez-González, M.A. & Stecco, C., 2013. The muscular force transmission system: Role of the intramuscular connective tissue. Journal of Bodywork and Movement Therapies, 17(1), pp.95–102. Cerca con Google

Twig, G. et al., 2008. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. The EMBO journal, 27(2), pp.433–46. Cerca con Google

Urciuolo, A. et al., 2013. Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nature Communications, 4(5), p.1964. Cerca con Google

Vainshtein, A. et al., 2014. Skeletal muscle, autophagy, and physical activity: the ménage à trois of metabolic regulation in health and disease. Journal of molecular medicine, 92(2), pp.127–37. Cerca con Google

Wirawan, E. et al., 2012. Autophagy: for better or for worse. Cell research, 22(1), pp.43–61. Cerca con Google

Wooten, M.W. et al., 2008. Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins. The Journal of biological chemistry, 283(11), pp.6783–9. Cerca con Google

Yoon, Y.H. et al., 2010. Induction of lysosomal dilatation, arrested autophagy, and cell death by chloroquine in cultured ARPE-19 cells. Investigative ophthalmology & visual science, 51(11), pp.6030–7. Cerca con Google

Youle, R.J. & Narendra, D.P., 2011. Mechanisms of mitophagy. Molecular Cell Biology, 12(1), pp.9–14. Cerca con Google

Yu, L. et al., 2004. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science, 304(5676), pp.1500–2. Cerca con Google

Zanotti, S. et al., 2011. Fibroblasts from the muscles of Duchenne muscular dystrophy patients are resistant to cell detachment apoptosis. Experimental Cell Research, 317(17), pp.2536–47. Cerca con Google

Zhang, Y. et al., 2010. Myofibroblasts protect myoblasts from intrinsic apoptosis associated with differentiation via β1 integrin-PI3K/Akt pathway. Development, growth & differentiation, 52(8), pp.725–33. Cerca con Google

Zhou, L. et al., 2013. Bcl-2-dependent upregulation of autophagy by sequestosome 1/p62 in vitro. Acta pharmacologica Sinica, 34(5), pp.651–6. Cerca con Google

Zou, Y. et al., 2008. Muscle interstitial fibroblasts are the main source of collagen VI synthesis in skeletal muscle: implications for congenital muscular dystrophy types Ullrich and Bethlem. Journal of neuropathology and experimental neurology, 67(2), pp.144–54. Cerca con Google

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