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Peña Paz, Marcia Ivonne (2013) The role of the clock gene Bmal1 in skeletal muscle. [Tesi di dottorato]

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Abstract (inglese)

Circadian rhythms are responsible for various rhythmic 24-hour changes in physiological and behavioral parameters. A core oscillator located in the suprachiasmatic nucleus (SCN) of the hypothalamus is responsible for the coordination of these rhythms. The SCN controls the endogenous timing system by coordinating the tissue-specific clocks present in all cells of the body. The regulation is mainly based on a core transcriptional-translational feedback loop that keeps internal gene expression entrained by the external light-dark cycle. The transcription factor Bmal1 is a major component of both central and peripheral clocks, and its absence leads to disruption of circadian rhythms.

In order to understand the function of the intrinsic muscle clock we compared two muscle specific knockouts of the Bmal1 gene (a conditional model Bmal1 mKO and an inducible model Bmal1 imKO) and their normal wild type littermates. Changes in muscle phenotype were analyzed at morphological and physiological level, and muscle gene expression was determined.

We have observed that in contrast with the whole body Bmal1 knockout, Bmal1 mKO mice have a normal lifespan and growth. Contrary to the extreme muscle atrophy found in Bmal1 null mice, muscle-specific Bmal1 mKO causes a small but significant increase in muscle mass. However, this hypertrophic phenotype is not accompanied by an increase in muscle force, and indeed there is a marked reduction in both absolute muscle force and muscle force normalized to muscle weight. Myofibrillar architecture is conserved in Bmal1 mKO muscles, and there are no major histological abnormalities in the muscles. Myosin heavy chain composition is slightly shifted to fast myosin heavy chain isoforms. We have compared the muscle circadian gene expression profile of these mice and their control littermates. Our analyses indicate that the transcription of many circadian muscle genes is greatly altered. By Gene Set Enrichment Analysis (GSEA) we found that the p38 pathway, including upstream activators and downstream targets, is down−regulated, suggesting that this pathway, which is known to be linked to contractile activity, is controlled by BMAL1.

Abstract (italiano)

I ritmi circadiani sono responsabili della variazione giornaliera di molteplici parametri fisiologici e di comportamento. L’orologio centrale preposto alla coordinazione di questi ritmi è localizzato nel nucleo soprachiasmatico dell’ipotalamo. Il nucleo soprachiasmatico scandisce il ritmo globale dell’organismo sincronizzando il ritmo dei cosiddetti orologi periferici dei tessuti, presenti in tutte le cellule del corpo. La regolazione avviene principalmente tramite un circuito accoppiato di trascrizione-traduzione, che mantiene l’espressione genica interna vincolata al ciclo esterno di luce e buio. Il fattore di trascrizione Bmal1 è uno dei principali componenti sia dell’orologio centrale che di quelli periferici, e la sua assenza porta alla scomparsa dei ritmi circadiani nell’organismo.

Al fine di comprendere la funzione dell’orologio intrinseco del muscolo, abbiamo confrontato due diverse linee di topi in cui il gene Bmal1 è assente esclusivamente nel muscolo scheletrico (un modello condizionale, nominato Bmal1 mKO, e un modello inducibile, chiamato Bmal1 imKO), con dei topi di controllo appartenenti allo stesso ceppo selvatico. Cambiamenti fenotipici a livello muscolare sono stati analizzati sia a livello morfologico che fisiologico, ed è stata inoltre valutata l’espressione genica globale del muscolo.

Abbiamo così osservato che a differenza dei topi in cui il gene Bmal1 è assente in tutte le cellule del corpo (Bmal1-/-), i topi Bmal1 mKO hanno una durata della vita ed una crescita normale. Al contrario della forte atrofia riscontrata nel topo Bmal1-/-, nel nostro modello muscolo-specifico Bmal1 mKO abbiamo rilevato un significativo, benché piccolo, incremento di massa muscolare. Ad ogni modo, ciò non è accompagnato da un aumento della forza muscolare ne’ assoluta, ne’ normalizzata rispetto al peso del muscolo. L’architettura del muscolo è preservata nei topi Bmal1 mKO, e questi non presentano anomalie vistose a livello istologico. Nei topi Bmal1 mKO si nota un leggero incremento nel numero delle fibre che esprimono catene pesanti delle miosine di tipo rapido. Abbiamo inoltre confrontato l’espressione genica circadiana di questi topi rispetto ai loro controlli. Le nostre analisi indicano che la trascrizione di molti geni circadiani muscolari è fortemente alterata. Tramite analisi di arricchimento di gruppi genici (Gene Set Enrichment Analysis, o GSEA), abbiamo trovato che la via di segnalazione della proteina p38, inclusi attivatori a monte e bersagli a valle, è ridotta, suggerendo così che questa via, nota per essere legata all’attività contrattile, sia controllata da BMAL1.

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Tipo di EPrint:Tesi di dottorato
Relatore:Lanfranchi, Gerolamo
Correlatore:Schiaffino, Stefano
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > BIOSCIENZE E BIOTECNOLOGIE > GENETICA E BIOLOGIA MOLECOLARE DELLO SVILUPPO
Data di deposito della tesi:29 Gennaio 2013
Anno di Pubblicazione:29 Gennaio 2013
Parole chiave (italiano / inglese):Bmal1, Bmal1 knockout, skeletal muscle, p38, circadian rhythms.
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Area 05 - Scienze biologiche > BIO/09 Fisiologia
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:5683
Depositato il:22 Ott 2013 10:31
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Akashi M, Takumi T. The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1. Nature structural & molecular biology 12: 441–8, 2005. Cerca con Google

Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs C, Rosenberg PB, Williams RS, Yan Z. Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. The Journal of biological chemistry 280: 19587–93, 2005. Cerca con Google

Albrecht U, Sun ZS, Eichele G, Lee CC. A differential response of two putative mammalian circadian regulators, mper1 and mPer2, to light. Cell 91: 1055–64, 1997. Cerca con Google

Albrecht U. Orchestration of gene expression and physiology by the circadian clock. Journal of physiology, Paris 100: 243–51, 2007. Cerca con Google

Amthor H, Macharia R, Navarrete R, Schuelke M, Brown SC, Otto A, Voit T, Muntoni F, Vrbóva G, Partridge T, Zammit P, Bunger L, Patel K. Lack of myostatin results in excessive muscle growth but impaired force generation. Proceedings of the National Academy of Sciences of the United States of America 104: 1835–40, 2007. Cerca con Google

Andrews JL, Zhang X, McCarthy JJ, McDearmon EL, Hornberger T A, Russell B, Campbell KS, Arbogast S, Reid MB, Walker JR, Hogenesch JB, Takahashi JS, Esser K A. CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function. Proceedings of the National Academy of Sciences of the United States of America 107: 19090–5, 2010. Cerca con Google

Asher G, Schibler U. Crosstalk between components of circadian and metabolic cycles in mammals. Cell metabolism 13: 125–37, 2011. Cerca con Google

Baker J, Riley G, Romero MR, Haynes AR, Hilton H, Simon M, Hancock J, Tateossian H, Ripoll VM, Blanco G. Identification of a Z-band associated protein complex involving KY, FLNC and IGFN1. Experimental cell research 316: 1856–70, 2010. Cerca con Google

Balsalobre A, Brown SA, Marcacci L, Tronche F, Kellendonk C, Reichardt HM, Schütz G, Schibler U. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289: 2344–7, 2000. Cerca con Google

Berson DM, Dunn F A, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295: 1070–3, 2002. Cerca con Google

Blaauw B, Canato M, Agatea L, Toniolo L, Mammucari C, Masiero E, Abraham R, Sandri M, Schiaffino S, Reggiani C. Inducible activation of Akt increases skeletal muscle mass and force without satellite cell activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23: 3896–905, 2009. Cerca con Google

Blaauw B, Mammucari C, Toniolo L, Agatea L, Abraham R, Sandri M, Reggiani C, Schiaffino S. Akt activation prevents the force drop induced by eccentric contractions in dystrophin-deficient skeletal muscle. Human molecular genetics 17: 3686–96, 2008. Cerca con Google

Boden MJ, Varcoe TJ, Voultsios A, Kennaway DJ. Reproductive biology of female Bmal1 null mice. Reproduction 139: 1077–90, 2010. Cerca con Google

Boppart MD, Hirshman MF, Sakamoto K, Fielding RA, Goodyear LJ. Static stretch increases c-Jun NH2-terminal kinase activity and p38 phosphorylation in rat skeletal muscle. American journal of physiology. Cell physiology 280: C352–8, 2001. Cerca con Google

Bothe GW, Haspel J a, Smith CL, Wiener HH, Burden SJ. Selective expression of Cre recombinase in skeletal muscle fibers. Genesis 26: 165−6, 2000. Cerca con Google

Buhr ED, Yoo S-H, Takahashi JS. Temperature as a universal resetting cue for mammalian circadian oscillators. Science 330: 379–85, 2010. Cerca con Google

Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe L a, Hogenesch JB, Simon MC, Takahashi JS, Bradfield C a. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103: 1009–17, 2000. Cerca con Google

Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM, Godinho SIH, Draetta GF, Pagano M. SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science 316: 900–4, 2007. Cerca con Google

Cardone L, Hirayama J, Giordano F, Tamaru T, Palvimo JJ, Sassone-Corsi P. Circadian clock control by SUMOylation of BMAL1. Science 309: 1390–4, 2005. Cerca con Google

Conesa A, Nueda MJ, Ferrer A, Talón M. maSigPro: a method to identify significantly differential expression profiles in time-course microarray experiments. Bioinformatics 22: 1096–102, 2006. Cerca con Google

Dai M, Wang P, Boyd AD, Kostov G, Athey B, Jones EG, Bunney WE, Myers RM, Speed TP, Akil H, Watson SJ, Meng F. Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic acids research 33: e175, 2005. Cerca con Google

Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes & development 14: 2950–61, 2000. Cerca con Google

Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annual review of physiology 72: 517–49, 2010. Cerca con Google

Eide EJ, Vielhaber EL, Hinz W a, Virshup DM. The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon. The Journal of biological chemistry 277: 17248–54, 2002. Cerca con Google

Gallego M, Virshup DM. Post-translational modifications regulate the ticking of the circadian clock. Nature reviews. Molecular cell biology 8: 139–48, 2007. Cerca con Google

Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, Takahashi JS, Weitz CJ. Role of the CLOCK Protein in the Mammalian Circadian Mechanism. Science 280: 1564–1569, 1998. Cerca con Google

Girgenrath S, Song K, Whittemore L-A. Loss of myostatin expression alters fiber-type distribution and expression of myosin heavy chain isoforms in slow- and fast-type skeletal muscle. Muscle & nerve 31: 34–40, 2005. Cerca con Google

Godinho SIH, Maywood ES, Shaw L, Tucci V, Barnard AR, Busino L, Pagano M, Kendall R, Quwailid MM, Romero MR, O’neill J, Chesham JE, Brooker D, Lalanne Z, Hastings MH, Nolan PM. The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316: 897–900, 2007. Cerca con Google

Griffin EA, Staknis D, Weitz CJ. Light-independent role of CRY1 and CRY2 in the mammalian circadian clock. Science 286: 768–71, 1999. Cerca con Google

Hirota T, Okano T, Kokame K, Shirotani-Ikejima H, Miyata T, Fukada Y. Glucose down-regulates Per1 and Per2 mRNA levels and induces circadian gene expression in cultured Rat-1 fibroblasts. The Journal of biological chemistry 277: 44244–51, 2002. Cerca con Google

Hogenesch JB, Gu YZ, Jain S, Bradfield CA. The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proceedings of the National Academy of Sciences of the United States of America 95: 5474–9, 1998. Cerca con Google

Hughes ME, Hogenesch JB, Kornacker K. JTK_CYCLE: an efficient nonparametric algorithm for detecting rhythmic components in genome-scale data sets. Journal of biological rhythms 25: 372–80, 2010. Cerca con Google

Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A, Murphy PJ, Jones B, Czajkowski L, Ptácek LJ. Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans. Nature medicine 5: 1062–5, 1999. Cerca con Google

Jouffe C, Cretenet G, Symul L, Martin E, Atger F, Naef F, Gachon F. The circadian clock coordinates ribosome biogenesis. PLoS biology 11: e1001455, 2013. Cerca con Google

Ko ML, Shi L, Tsai J-Y, Young ME, Neuendorff N, Earnest DJ, Ko GY-P. Cardiac-specific mutation of Clock alters the quantitative measurements of physical activities without changing behavioral circadian rhythms. Journal of biological rhythms 26: 412–22, 2011. Cerca con Google

Kondratov R V, Kondratova AA, Gorbacheva VY, Vykhovanets O V, Antoch MP. Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. Genes & development 20: 1868–73, 2006. Cerca con Google

Kondratov R V, Shamanna RK, Kondratova A a, Gorbacheva VY, Antoch MP. Dual role of the CLOCK/BMAL1 circadian complex in transcriptional regulation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20: 530–2, 2006. Cerca con Google

Kornmann B, Schaad O, Bujard H, Takahashi JS, Schibler U. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS biology 5: e34, 2007. Cerca con Google

Lamia K a, Storch K-F, Weitz CJ. Physiological significance of a peripheral tissue circadian clock. Proceedings of the National Academy of Sciences of the United States of America 105: 15172–7, 2008. Cerca con Google

4Lehman MN, Silver R, Gladstone WR, Kahn RM, Gibson M, Bittman EL. Circadian rhythmicity restored by neural transplant. Immunocytochemical characterization of the graft and its integration with the host brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 7: 1626–38, 1987. Cerca con Google

Liu AC, Tran HG, Zhang EE, Priest A a, Welsh DK, Kay S a. Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms. PLoS genetics 4: e1000023, 2008. Cerca con Google

Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, Ralph MR, Menaker M, Takahashi JS. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288: 483–92, 2000. Cerca con Google

McCarthy JJ, Andrews JL, McDearmon EL, Campbell KS, Barber BK, Miller BH, Walker JR, Hogenesch JB, Takahashi JS, Esser KA. Identification of the circadian transcriptome in adult mouse skeletal muscle. Physiological genomics 31: 86–95, 2007. Cerca con Google

McDearmon EL, Patel KN, Ko CH, Walisser J a, Schook AC, Chong JL, Wilsbacher LD, Song EJ, Hong H-K, Bradfield C a, Takahashi JS. Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice. Science (New York, N.Y.) 314: 1304–8, 2006. Cerca con Google

McPherron AC, Huynh T V, Lee S-J. Redundancy of myostatin and growth/differentiation factor 11 function. BMC developmental biology 9: 24, 2009. Cerca con Google

Mitsui S, Yamaguchi S, Matsuo T, Ishida Y, Okamura H. Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism. Genes & development 15: 995–1006, 2001. Cerca con Google

Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U. The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110: 251–60, 2002. Cerca con Google

Sanada K, Okano T, Fukada Y. Mitogen-activated protein kinase phosphorylates and negatively regulates basic helix-loop-helix-PAS transcription factor BMAL1. The Journal of biological chemistry 277: 267–71, 2002. Cerca con Google

Sandonà D, Desaphy J-F, Camerino GM, Bianchini E, Ciciliot S, Danieli-Betto D, Dobrowolny G, Furlan S, Germinario E, Goto K, Gutsmann M, Kawano F, Nakai N, Ohira T, Ohno Y, Picard A, Salanova M, Schiffl G, Blottner D, Musarò A, Ohira Y, Betto R, Conte D, Schiaffino S. Adaptation of mouse skeletal muscle to long-term microgravity in the MDS mission. PloS one 7: e33232, 2012. Cerca con Google

Sartori R, Milan G, Patron M, Mammucari C, Blaauw B, Abraham R, Sandri M. Smad2 and 3 transcription factors control muscle mass in adulthood. American journal of physiology. Cell physiology 296: C1248–57, 2009. Cerca con Google

Sato TK, Panda S, Miraglia LJ, Reyes TM, Rudic RD, McNamara P, Naik K a, FitzGerald G a, Kay S a, Hogenesch JB. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43: 527–37, 2004. Cerca con Google

Schiaffino S, Gorza L, Sartore S, Saggin L, Ausoni S, Vianello M, Gundersen K, Lømo T. Three myosin heavy chain isoforms in type 2 skeletal muscle fibres. Journal of muscle research and cell motility 10: 197–205, 1989. Cerca con Google

Schiaffino S. Fibre types in skeletal muscle: a personal account. Acta physiologica 199: 451–63, 2010. Cerca con Google

Schuler M, Ali F, Metzger E, Chambon P, Metzger D. Temporally controlled targeted somatic mutagenesis in skeletal muscles of the mouse. Genesis 41: 165–70, 2005. Cerca con Google

Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, Zheng B, Kume K, Lee CC, Van der Horst GT, Hastings MH, Reppert SM. Interacting molecular loops in the mammalian circadian clock. Science 288: 1013–9, 2000. Cerca con Google

Siepka SM, Yoo S-H, Park J, Song W, Kumar V, Hu Y, Lee C, Takahashi JS. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell 129: 1011–23, 2007. Cerca con Google

Stephan FK, Zucker I. Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proceedings of the National Academy of Sciences of the United States of America 69: 1583–6, 1972. Cerca con Google

Stokkan K a, Yamazaki S, Tei H, Sakaki Y, Menaker M. Entrainment of the circadian clock in the liver by feeding. Science 291: 490–3, 2001. Cerca con Google

Storch K-F, Paz C, Signorovitch J, Raviola E, Pawlyk B, Li T, Weitz CJ. Intrinsic circadian clock of the mammalian retina: importance for retinal processing of visual information. Cell 130: 730–41, 2007. Cerca con Google

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences of the United States of America 102: 15545–50, 2005. Cerca con Google

Sun ZS, Albrecht U, Zhuchenko O, Bailey J, Eichele G, Lee CC. RIGUI, a putative mammalian ortholog of the Drosophila period gene. Cell 90: 1003–11, 1997. Cerca con Google

Takano a, Shimizu K, Kani S, Buijs RM, Okada M, Nagai K. Cloning and characterization of rat casein kinase 1epsilon. FEBS letters 477: 106−12, 2000. Cerca con Google

Travnickova-Bendova Z, Cermakian N, Reppert SM, Sassone-Corsi P. Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proceedings of the National Academy of Sciences of the United States of America 99: 7728–33, 2002. Cerca con Google

Vanselow K, Vanselow JT, Westermark PO, Reischl S, Maier B, Korte T, Herrmann A, Herzel H, Schlosser A, Kramer A. Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS). Genes & development 20: 2660–72, 2006. Cerca con Google

Yamaguchi S, Mitsui S, Yan L, Yagita K, Miyake S, Okamura H. Role of DBP in the circadian oscillatory mechanism. Molecular and cellular biology 20: 4773–81, 2000. Cerca con Google

Yoo S-H, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, Siepka SM, Hong H-K, Oh WJ, Yoo OJ, Menaker M, Takahashi JS. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proceedings of the National Academy of Sciences of the United States of America 101: 5339–46, 2004. Cerca con Google

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