Regulation of Skeletal Muscle Mitochondrial, Quality Control by the Transcription Factors P53 and ATF4

Well-appreciated for its role in locomotion and posture, the metabolic profile of muscle has extended implications for mobility, along with the onset of disease. It is well-documented that endurance exercise promotes enhanced aerobic capacity, while prolonged disuse results in a diminished respiratory function, accompanied by fiber atrophy and weakness. A unique, and natural, feature of aging is the progressive loss of muscle mass, which develops from molecular changes within muscle that include diminished aerobic capacity and muscle strength. Thus, understanding the molecular mechanisms that promote muscle health or contribute to muscle decline are of considerable importance to identify therapeutic strategies that can preserve muscle function. Mitochondria are the culpable organelles in the maintenance of skeletal muscle metabolic health, and are therefore important regulators of a variety of factors contributing to muscle dysfunction, such as oxidative stress and antioxidants, apoptosis, inflammation, and Ca2+ handling, in addition to their role as the energy hubs of the cell. Mitochondrial quality control (MQC) involves multiple processes that coordinately regulate organellar biogenesis, turnover, and proteostasis (mitochondrial unfolded protein response) to maintain an optimal mitochondrial pool. While recent research has elucidated the importance of this synchronized control, science has yet characterized a single regulator of broad MQC pathways. The transcription factors p53 and ATF4 are two candidates that, in muscle, respond to various stressors, and are positioned at the nexus of these processes. Therefore, we explored the necessity of p53 and ATF4 in mediating mitochondrial adaptations. p53 muscle-specific knockout mice (mKO) had dysregulated signaling for MQC following 1-day of denervation- induced disuse, with further decrements in organelle function and MQC regulation after 7 days, especially with respect to the autophagy-lysosome system. Additionally, through ATF4 overexpression (OE) and knockdown (KD) in C2C12 myotubes, we found ATF4 to be an import mediator of MQC pathways, contributing to an enhanced mitochondrial network with augmented function, following C2C12 myotube differentiation, as well as acute and chronic contractile activity. Our data identify both p53 and ATF4 as two transcriptional regulators that each exhibit multifaceted control of mitochondrial health in muscle during both the pro- and mal-adaptive stimuli of exercise and disuse

Function of specialized regulatory proteins and signaling pathways in exercise-induced muscle mitochondrial biogenesis

AbstractSkeletal muscle mitochondrial content and function are regulated by a number of specialized molecular pathways that remain to be fully defined. Although a number of proteins have been identified to be important for the maintenance of mitochondria in quiescent muscle, the requirement for these appears to decrease with the activation of multiple overlapping signaling events that are triggered by exercise. This makes exercise a valuable therapeutic tool for the treatment of mitochondrially based metabolic disorders. In this review, we summarize some of the traditional and more recently appreciated pathways that are involved in mitochondrial biogenesis in muscle, particularly during exercise

Endoplasmic reticulum unfolded protein response, aging and exercise: an update

9 p.The endoplasmic reticulum (ER) is a dynamic and multifunctional organelle responsible for protein biosynthesis, folding, assembly and modifications. Loss of protein folding regulation, which leads to unfolded or misfolded proteins accumulation inside the ER lumen, drives ER stress (ERS) and unfolded protein response (UPR) activation. During aging, there is a decline in the ability of the cell to handle protein folding, accumulation and aggregation, and the function of UPR is compromised. There is a progressive failure of the chaperoning systems and a decline in many of its components, so that the UPR activation cannot rescue the ERS. Physical activity has been proposed as a powerful tool against aged-related diseases, which are linked to ERS. Interventional studies have demonstrated that regular exercise is able to decrease oxidative stress and inflammation and reverse mitochondrial and ER dysfunctions. Exercise-induced metabolic stress could activate the UPR since muscle contraction is directly involved in its activation, mediating exercise-induced adaptation responses. In fact, regular moderate-intensity exercise-induced ERS acts as a protective mechanism against current and future stressors. However, biological responses vary according to exercise intensity and therefore induce different degrees of ERS and UPR activation. This article reviews the effects of aging and exercise on ERS and UPR, also analyzing possible changes induced by different types of exercise in elderly subjects.S

The Chronology and Function of UPR Activation in Skeletal Muscle Adaptations to Chronic Contractile Activity

During exercise-induced mitochondrial biogenesis, a rapid increase in the transcription and translation of nuclear-encoded mitochondrial proteins, under the influence of PGC-1, require integration with mitochondria-derived proteins. This has the potential to perturb cellular proteostasis and thus induce an unfolded protein response from the mitochondria (UPRmt) and/or endoplasmic reticulum (UPRER). The role of the UPR in skeletal muscle, particularly with respect to exercise is not well established. We used a chronic contractile activity model over 7 days to examine the chronology of mitochondrial biogenesis, autophagy, UPRER, and UPRmt activation, and used a drug (TUDCA) to block the ER stress-induced UPR to test its role in adaptations to CCA. Our data reveal that the UPRs are involved in acute and chronic muscle adaptations, independent of CHOP signaling, to augment protein quality control. However the specific mechanism by which the UPR influences these adaptations is an important avenue of future work

2015 Nigerian Presidential Election: A New Reality

After the end of 33 years of military rule, Nigeria returned to democracy in 1998. The People’s Democratic Party (PDP) has won every election in the new republic, but many of these elections have been everything but free and fair. The 2007 presidential election was wrought with corruption and violence. There was vast improvement in 2011, an election often referred to as Nigeria’s best ever, despite 800 deaths in election violence. The 2010 appointment of Attiheru Jega as chairman of the Independent National Electoral Commission (INEC) was seen as the catalyst for 2011’s improvement. The 2015 election will bring new challenges like the terror organization Boko Haram and a newly formed opposition party capable of challenging the PDP. This paper examines INEC strategies and potential threats for the 2015 election through personal interviews with several stakeholders in Nigerian society. These unique perspectives are invaluable to better understanding an election that could destabilize the nation and possibly the region. Stakeholders interviewed include journalists and politicians who are deeply engaged in Nigerian civil society, INEC directors who clearly delineate detailed steps of commission plans, and INEC chairman Attiheru Jega.\u3c /p\u3

Best to Bend While it is a Twig – About Gender Reproduction in Libraries

This Master's Thesis studies the attitude that library employees have regarding a sex and gender-neutral treatment of their clients. The analysis is based upon replies to a questionnaire which was submitted though channels directed at library employees, like BIBLIST and BiblFeed. The respondent’s replies contained a number of welldeveloped comments making the resultant analysis both quantitative and qualitative in nature. In performing the analysis a theoretical framework combining Hirdman’s gender system with symbolic interactionism has been used together with literature about gender roles. The questionnaire showed that gender neutrality is a complex concept that can be interpreted in many different ways and is therefore easily misunderstood. It is obvious that sex is an important category when respondents are dealing with their clients, but also that sex and gender are problematic concepts which respondents find difficult to know exactly how to relate to. A lot of the respondents see a need to address gender issues, but a lot of them also state that gender is a biological concept and therefore impossible or unnecessary to have to relate to. In general, in the replies to the questionnaire availability tops the list over important questions to be addressed in the library while sex and gender have very low priority. My belief is that gender norms are possible to change and that sex and gender issues should be prioritized by virtue of being recognised as an availability issue. It is everybody’s individual fundamental values that together form society’s common fundamental values. If we all put on our gender glasses and are prepared to alter how we treat one another we can, eventually, make sex and gender less important categories and begin to see our clients as individuals

The Influence of Thermal Barrier Coating Surface Roughness on Spark Ignition Engine Performance and Emissions

The effects on heat transfer of piston crown surface finish and use of a metal based thermal barrier coating (TBC) on the piston crown were studied in an SI engine. Measured engine parameters such as power, fuel consumption, emissions and cylinder pressure were used to identify the effects of the coating and its surface finish. Two piston coatings were tested: a baseline copper coating and a metal TBC. Reducing surface roughness of both coatings increased in-cylinder temperature and pressure as a result of reduced heat transfer through the piston crown. These increases resulted in small improvements in both power and fuel consumption, while also having measurable effect on emissions. Oxides of nitrogen emissions were increased while total hydrocarbon emissions were decreased. Improvements attributed to the TBC were found to be small, but statistically significant. At an equivalent surface finish, the TBC performed better than the baseline copper finish.MAS

Induction and professional development support of newly qualified professional nurses during community service

Text in EnglishIn South Africa, retention of newly qualified professional nurses in public health institutions upon completion of their year of compulsory remunerated community service remains a challenge that exacerbates the shortage of professional nurses in these institutions. The literature indicates that many newly qualified professional nurses leave the public health institutions due to lack of professional development support and heavy workloads while they are still finding their feet. A mixed-methods design of concurrent triangulation approach was used to answer the question: How are the newly qualified professional nurses supported in terms of induction and professional development during community service in South Africa? Triangulation was achieved by using both quantitative and qualitative methods. Induction/orientation documents from public health institutions were analysed using a checklist. A survey questionnaire with mixed quantitative closed items (1–43) and qualitative open-ended questions (43–46) was sent to newly qualified professional nurses who had recently completed community service. Focus groups held with operational nurse managers and individual interviews with coordinators of community service for nurses yielded rich qualitative data. Descriptive and inferential statistics were used to describe and synthesise data. The qualitative findings confirmed the quantitative findings. Findings were lack of professional development support in some public health institutions, informal, non-comprehensive support where given, shortage of experienced professional nurses, reluctance by some professional nurses and operational nurse managers to supervise newly qualified nurses, and increased workload due to the shortage of experienced professional nurses in the public health institutions. Inadequate clinical skills, poor discipline and lack of professionalism in the newly qualified professional nurses also played a part. Respondents suggested constructive recommendations for the induction and professional development support of the newly qualified professional nurses, and these were incorporated in the recommended guidelines for the induction and professional development support of newly qualified professional nurses during community service.Health StudiesD. Litt. et Phil. (Health Studies