4,940 research outputs found
Activity-dependent and -independent control of circadian rhythms in mammalian skeletal muscle
No full textAutonomous 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
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
The functional significance of the skeletal muscle clock: Lessons from Bmal1 knockout models
No full textThe 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
Raw "origscale" 24-h metabolomics intensity data from 8 different murine tissues under chow or high fat diet
No full textRaw 24-h metabolomic intensity data from 8 different murine tissues: suprachiasmatic nucleus (SCN), medial prefrontal cortex (mPFC), gastrocnemius skeletal muscle, interscapular brown adipose tissue (BAT), epididymal white adipose tissue (WAT), liver, serum, and cauda epididymal sperm. Six week old male C57BL6/J mice were purchased from JAX / Jackson Labs (Stock Number: 000664). Mice were were randomly assigned to experimental groups, maintained on a 12hr light/12hr dark cycle (ZT0 corresponds to lights on and ZT12 to lights off in the animal facility), and fed ad libitum for 10 weeks with either standard chow diet (Prolab RMH 2500) or high fat diet (HFD) composed of 60% Kcal from fat (Research Diets, D12492). Animals were separated into individual cages 1 week before tissue collection. Five male mice for each time point/diet were used. Tissues were immediately collected after cervical dislocation and stored at -80°C until further processing/analysis. Serum was prepared from an abdominal/thoracic blood sample and stored at -80°C. Sperm was collected after swimming out from the caudal portion of the epididymis in non-capacitating media (MEM without BSA) for 10min at 37°C.Non-targeted metabolite profiling, peak identification, and curation was performed by Metabolon (Durham, NC, USA) and by the Genome Analysis Center (GAC), Helmholtz Zentrum München (Neuherberg, Germany). Liver, serum, and sperm were processed and run by Metabolon on an HD3 system using described methods (Abbondante et al., 2016; Eckel-Mahan et al., 2012). Briefly, this analytical system combines a Linear Ion Trap MS/MS (LTQ XL, Thermo Scientific) coupled with UPLC (Acquity, Waters), and consists of 2 reverse phase (RP)/UPLC-MS/MS methods: 1) with positive ion mode electrospray ionization (ESI) optimized for acidic species, and 2) with negative ion mode ESI optimized for basic species. An additional GC/MS platform for volatile compounds was used in parallel. WAT and BAT samples were processed and run by the GAC on the same analytical system, with the exception of the GC/MS platform, and with curation again performed by Metabolon. Skeletal muscle and brain tissues (SCN & mPFC) were processed and run by Metabolon on their HD4 platform, which runs with High Resolution Accurate Mass (HRAM) MS/MS (QExactive, Thermo Scientific) also coupled with UPLC (Acquity, Waters). Overall, we processed and analyzed a total of 70 tissues each of liver, serum, BAT, and WAT (5 replicates x 2 groups x 7 time points, including additional time point ZT24), and 60 tissues each for SCN, mPFC, gastrocnemius skeletal muscle, and sperm (5 replicates x 2 groups x 6 time points). One biological replicate each from chow-fed SCN at ZT20 and from HFD-fed mPFC at ZT4 were lost during sample processing, leaving 4 remaining replicates each for these particular time points/diets. Two biological replicates from chow-fed mPFC at ZT4 were likewise lost, leaving 3 remaining replicates
Interview with Kenneth Sprunt
No full textKenneth Sprunt was born in Wilmington in 1920, the third son of James Lawrence Sprunt. The Sprunts have a long history in and around Wilimington. His grandfather was a cotton merchant in the area and his great-great Uncle is the man for whom James Sprunt Community College is named for as well as the author of Chronicles of the Lower Cape Fear. Mr. Kenneth Sprunt relates his family history both before his birth and after. He spent three years in the Coast Guard during WWII primarily working on anti-submarine warfare in small boats
A Review by Kenneth Atkinson of Alexandria and Qumran: Back to the Beginning, by Kenneth Silver
No full textKenneth Silver (a.k.a. Kenneth A. K. Lönnqvist), is a historian and professional archaeologist, who has lived and worked for decades in the Near East. With extensive publications on Hellenistic and Roman archaeology, history, and numismatics, Silver is the director of a survey and mapping project in Northern Mesopotamia studying the border zone between the late Roman/ Byzantine Empires and Persia. Author of numerous publications on Qumran and related topics, Silver’s lengthy monograph proposes that the documents and type of library found at Qumran were based on models derived from Egypt. The main thesis of the volume is that Pythagorean philosophy is the core and basis for the beliefs reflected in the non-Biblical texts found at Qumran
NFAT isoforms control activity-dependent muscle fiber type specification
No full textThe intracellular signals that convert fast and slow motor neuron activity into muscle fiber type specific transcriptional programs have only been partially defined. The calcium/calmodulin-dependent phosphatase calcineurin (Cn) has been shown to mediate the transcriptional effects of motor neuron activity, but precisely how 4 distinct muscle fiber types are composed and maintained in response to activity is largely unknown. Here, we show that 4 nuclear factor of activated T cell (NFAT) family members act coordinately downstream of Cn in the specification of muscle fiber types. We analyzed the role of NFAT family members in vivo by transient transfection in skeletal muscle using a loss-of-function approach by RNAi. Our results show that, depending on the applied activity pattern, different combinations of NFAT family members translocate to the nucleus contributing to the transcription of fiber type specific genes. We provide evidence that the transcription of slow and fast myosin heavy chain (MyHC) genes uses different combinations of NFAT family members, ranging from MyHC-slow, which uses all 4 NFAT isoforms, to MyHC-2B, which only uses NFATc4. Our data contribute to the elucidation of the mechanisms whereby activity can modulate the phenotype and performance of skeletal muscle
Food fraud and the Partnership for a ‘Healthier’ America: a case study in state-corporate crime
No full textAt a moment of heightened public concern over food-related health issues, major corporations in the food industry have found their products and practices under scrutiny. Needing to be understood as socially responsible, these corporations have established partnerships with the state to construct a positive, proactive, and cooperative public image. One major public-private partnership that evolved from former First Lady Michelle Obama’s Let’s Move initiative—the Partnership for a Healthier America (PHA)—serves as a case study in this paper, which analyzes the opportunity costs and social harms perpetuated by a public health campaign bound by the imperative to maximize profit. By using trusted state actors to deliver accurate but deceptive claims about food companies’ commitment to public health, this public-private partnership actively misleads the public and potentially exacerbates public health challenges, warranting a skeptical revision of how we understand corporate social responsibility and neoliberal governance on issues of health and nutrition. As a form of fraud, these attempts to mislead the public go beyond the actions of public sector individuals or members of corporate boards, but are structurally incentivized by the legal rights, regulatory privileges, and profit-related incentives central to the modern corporate form. While conventional criminological research tends to underemphasize state and corporate harms, we make use of a critical criminological perspective to analyze state-corporate partnerships in the space between food industry practices and public health policy.Peer reviewe
Minority-owned cannabis businesses as a social justice imperative
No full textWhen the growth, distribution, and point of sales for cannabis were explicitly illegal enterprises, black and brown bodies bore the brunt of the state’s coercive force via the enforcement of laws that had little to do with the objective properties of cannabis, and more to do with instrumentally moving targeted groups into formal spheres of oversight and control. Today, where the supply chain and consumption of cannabis is both an attractive and highly profitable enterprise, race, class, and power remain salient. The roster of those who profit from the legal cannabis industry is overwhelmingly unrepresentative of the rosters of those who were victimized by the earlier regulatory regimes. This irony has not gone unnoticed, with journalists, bloggers, business owners, and scholars pointing out how a plant that served as a pretext for disproportionate carceral control of communities of color is—quite literally overnight via the result of a ballot initiative or legislative reform—now responsible for advancing the capital interests of majority-white agents and enterprises. To provide additional social context to this empirical trend, this chapter highlights some of the proposed and actual steps currently underway to advance economic equity among communities of color in the cannabis industry, framing the expansion and success of minority-owned cannabis businesses as a social justice imperative.Peer reviewe
Legitimized fraud and the state-corporate criminology of food - a Spectrum-based theory
No full textThe role that food corporations have in determining our health and nutrition is concomitant with the power and influence that corporations exercise across all commercial sectors. These large, powerful, and often multinational entities – collectively referred to as Big Food – employ a robust array of strategies to advance the organizational interests associated with a seemingly paradoxical business model: securing the continuous and ever-growing consumption of food products increasingly associated with negative health outcomes. As this model proliferates globally, the implications of this contradiction warrant specific attention to the activities of Big Food corporations through a critical criminological framework. The pervasive and increasingly legitimized activity of Big Food relies on a legal, regulatory, and moral framework that allows for the relegation of all non-market oriented value systems to be secondary to a pro-corporatist ideological and moral superstructure. Whereas previous scholarship has contributed to an understanding of what occurs when profit-maximization values collide with – and then co-opt – public health and nutrition interests, the present study offers a spectrum-based theory to explain how various degrees of food fraud are systematically incentivized by the legal privileges of corporations and the hegemonic moral economy of neoliberal governance.Peer reviewe
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