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Activity-dependent and -independent control of circadian rhythms in mammalian skeletal muscle
Get PDFAutonomous biological rhythms allow organisms to coordinate internal processes with environmental conditions. Mammals exhibit a diverse array of both behavioral and physiological rhythms that are generated by an endogenous molecular timing system composed of a central pacemaker within the suprachiasmatic nucleus (SCN) of the hypothalamus in addition to autonomous oscillators within the cells of peripheral tissues. Previous reports have shown that clock-controlled outputs are essential for the temporally coordinated execution of many tissue-specific functions, yet specific entrainment pathways for skeletal muscle, a peripheral tissue that accounts for the majority of daily energy consumption, remain largely speculative. Studies suggest that both neural and humoral factors contribute to phase-coordinate the expression of rhythmic genes in peripheral tissues, and locomotor activity, autonomic innervation and metabolic signals resulting from food availability are all probable mediators of rhythmic gene expression in skeletal muscle. Here we investigated entrainment of the skeletal muscle core oscillator by selectively manipulating each proposed pathway in vivo while monitoring expression profiles of the core clock genes Bmal1, Per1 and Per2. Monitoring circadian nucleocytoplasmic shuttling and transcriptional activity of the nerve activity-dependent sensor NFAT, we demonstrate that while some rhythmically expressed genes are strictly activity-dependent, motor innervation is not an important factor regulating phase entrainment of the core oscillator. Similarly, a chemical sympathectomy with 6-OHDA failed to significantly alter the phase of the core clock genes. However, two weeks of a restricted feeding schedule significantly shifted the phase of Bmal1 expression in skeletal muscle as in liver, while, surprisingly, both Per1 and Per2 expression lost rhythmicity. These results clearly show that the circadian transcriptome in skeletal muscle is composed of both activity-dependent and –independent genes, and furthermore, that entrainment of the skeletal muscle circadian oscillator depends on metabolic factors rather than on neural activity.I ritmi biologici autonomi permettono agli organismi di coordinare i processi interni con le condizioni ambientali. I mammiferi mostrano diversi tipi di ritmi comportamentali e fisiologici, che sono generati da un orologio molecolare endogeno composto da un “pacemaker” centrale presente all'interno del nucleo soprachiasmatico (SCN) dell'ipotalamo e degli oscillatori autonomi all'interno delle cellule dei tessuti periferici. Studi precedenti hanno indicato che i segnali generati da questo sono essenziali per la coordinazione temporale di molte funzioni tessuto-specifiche. Tuttavia, rimane in gran parte speculativo quale sia ruolo specifico di questo sistema nel muscolo scheletrico, un tessuto periferico in cui avviene la maggior parte del consumo di energia quotidiano. Alcuni studi suggeriscono che sia i fattori neuronali che quelli umorali contribuiscono all'espressione dei geni ritmici nei tessuti periferici e dall'attività locomotoria e che l’innervazione autonoma ed i segnali metabolici regolati dalla disponibilità di cibo sono i probabili mediatori dell'espressione di geni ritmici nel muscolo scheletrico. In questo lavoro di tesi abbiamo studiato il ruolo dell’orologio biologico nel muscolo scheletrico, analizzando selettivamente ogni via di segnale proposta “in vivo” e controllando i profili di espressione dei geni dell'orologio Bmal1, Per1 e Per2. L’osservazione della traslocazione circadiana nucleo-citoplasma e l’attività trascrizionale del fattore NFAT, un sensore dell’attività nervo-dipendente, ci ha permesso di dimostrare che l’espressione dei geni dell’orologio e’ direttamente correlato con l’attività e che l’innervazione non e’ essenziale nella regolazione dell’orologio biologico. Similmente, l’uso di un composto chimico (6-hydroxydopamine) non ci ha permesso di alterare significativamente la fase dei geni dell'orologio. Tuttavia, sottoponendo gli animali a due settimane di programma d'alimentazione limitato abbiamo osservato un significativo spostamento di fase dell’espressione Bmal1 nel muscolo scheletrico e nel fegato, mentre, l’espressione sia di Per1 che di Per2 ha perso la fase di ritmo. Questi risultati indicano chiaramente che la transcritoma circadiano nel muscolo scheletrico comprende sia geni attività-dipendente che indipendente e, che l’oscillazioni dell’orologio circadiano nel muscolo scheletrico dipendono dai fattori metabolici e non dall’attività neuronale
The functional significance of the skeletal muscle clock: Lessons from Bmal1 knockout models
Get PDFThe circadian oscillations of muscle genes are controlled either directly by the intrinsic muscle clock or by extrinsic factors, such as feeding, hormonal signals, or neural influences, which are in turn regulated by the central pacemaker, the suprachiasmatic nucleus of the hypothalamus. A unique feature of circadian rhythms in skeletal muscle is motor neuron-dependent contractile activity, which can affect the oscillation of a number of muscle genes independently of the muscle clock. The role of the intrinsic muscle clock has been investigated using different Bmal1 knockout (KO) models. A comparative analysis of these models reveals that the dramatic muscle wasting and premature aging caused by global conventional KO are not present in muscle-specific Bmal1 KO or in global Bmal1 KO induced in the adult, therefore must reflect the loss of Bmal1 function during development in non-muscle tissues. On the other hand, muscle-specific Bmal1 knockout causes impaired muscle glucose uptake and metabolism, supporting a major role of the muscle clock in anticipating the sleep-to-wake transition, when glucose becomes the predominant fuel for the skeletal muscle
Skeletal muscle mass is controlled by the MRF4-MEF2 axis.
No full textPurpose of reviewThe review is focused on the unexpected role of myogenic regulatory factor 4 (MRF4) in controlling muscle mass by repressing myocyte enhancer binding factor 2 (MEF2) activity in adult skeletal muscle, and on the emerging role of MEF2 in skeletal muscle growth.Recent findingsThe MRF4s of the MyoD family (MyoD, MYF5, MRF4, myogenin) and the MEF2 factors are known to play a major role in embryonic myogenesis. However, their function in adult muscle tissue is not known. A recent study shows that MRF4 loss in adult skeletal muscle causes muscle hypertrophy and prevents denervation atrophy. This effect is mediated by MEF2 factors that promote muscle growth, with MRF4 acting as a repressor of MEF2 activity. The role of MEF2 in skeletal muscle growth is supported by the finding that muscle regeneration is impaired by muscle-specific triple knockout of Mef2a, c, and d genes.SummaryThe finding that the MRF4-MEF2 axis controls muscle growth opens a new perspective for preventing muscle wasting. A unique feature of this pathway is that MRF4 is exclusively expressed in skeletal muscle, thus reducing the risk that interventions aimed at down-regulating MRF4 or interfering with the interaction between MRF4 and MEF2 may have off-target effects in other tissues
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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