AMP-Activated Protein Kinase-Regulated Activation of the PGC-1α Promoter in Skeletal Muscle Cells

The mechanisms by which PGC-1α gene expression is controlled in skeletal muscle remains largely undefined. Thus, we sought to investigate the transcriptional regulation of PGC-1α using AICAR, an activator of AMPK, that is known to increase PGC-1α expression. A 2.2 kb fragment of the human PGC-1α promoter was cloned and sequence analysis revealed that this TATA-less sequence houses putative consensus sites including a GC-box, a CRE, several IRSs, a SRE, binding sites for GATA, MEF2, p 53, NF-κB, and EBox binding proteins. AMPK activation for 24 hours increased PGC-1α promoter activity with concomitant increases in mRNA expression. The effect of AICAR on transcriptional activation was mediated by an overlapping GATA/EBox binding site at −495 within the PGC-1α promoter based on gel shift analyses that revealed increases in GATA/EBox DNA binding. Mutation of the EBox within the GATA/EBox binding site in the promoter reduced basal promoter activity and completely abolished the AICAR effect. Supershift analyses identified USF-1 as a DNA binding transcription factor potentially involved in regulating PGC-1α promoter activity, which was confirmed in vivo by ChIP. Overexpression of either GATA-4 or USF-1 alone increased the p851 PGC-1α promoter activity by 1.7- and 2.0-fold respectively, while co-expression of GATA-4 and USF-1 led to an additive increase in PGC-1α promoter activity. The USF-1-mediated increase in PGC-1α promoter activation led to similar increases at the mRNA level. Our data identify a novel AMPK-mediated regulatory pathway that regulates PGC-1α gene expression. This could represent a potential therapeutic target to control PGC-1α expression in skeletal muscle

Exercise Biology of Neuromuscular Disorders

Neuromuscular disorders (NMDs) are chronic conditions that affect the neuromuscular system. Many NMDs currently have no cure, however as more effective therapies become available for NMD patients, these individuals will exhibit prolonged health- and/or lifespans. As a result, persons with NMDs will likely desire to engage in a more diverse variety of activities of daily living, including increased physical activity or exercise. Therefore, there is a need to increase our knowledge of the effects of acute exercise and chronic training on the neuromuscular system in NMD contexts. Here, we discuss the disease mechanisms and exercise biology of Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and myotonic dystrophy type 1 (DM1), which are among the most prevalent NMDs in children and adults. Evidence from clinical and pre-clinical studies are reviewed, with emphasis on the functional outcomes of exercise, as well as on the putative cellular mechanisms that drive exercise-induced remodeling of the neuromuscular system. Continued investigation of the molecular mechanisms of exercise adaptation in DMD, SMA, and DM1 will assist in enhancing our understanding of the biology of these most prevalent NMDs. This information may also be useful for guiding the development of novel therapeutic targets for future pursuit.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Drivers of intentions to use healthcare information systems among health and care professionals

Although investment in healthcare technology is rapidly increasing, the readiness to use emerging technologies among healthcare professionals is still low. The present study relies on an integrated model derived from the unified theory of acceptance and use of technology and the diffusion of innovation model to assess the factors that predicted healthcare professionals’ intentions to use healthcare information systems. Using a cross-sectional correlational design, 105 healthcare professionals (M age = 41.06, standard deviation = 9.18; 49% consultants and General Practitioners (GPs); 56.2% females) from hospitals in England completed online structured questionnaires. One-way analysis of variance showed that there were no differences in healthcare information systems usage intentions, unified theory of acceptance and use of technology and diffusion of innovation variables between consultants/GPs and non-medical staff (i.e. nurses and administration staff). Linear regression analysis demonstrated that the integrative model predicted 78.1 per cent (adjusted R2) in intentions to use healthcare information systems, and variables from both unified theory of acceptance and use of technology and the diffusion of innovation had significant effects. Moderated regression analysis further revealed that the interaction between voluntariness and effort expectancy, and voluntariness and social influence significantly predicted usage intentions on top of the main effects of the individual predictors. This poses direct implications for both practice and theory in this field. Future research should consider the predictive validity of integrative theoretical models of technology acceptance and utilization in healthcare settings

Effect of chronic contractile activity on mRNA stability in skeletal muscle

Repeated bouts of exercise promote the biogenesis of mitochondria by multiple steps in the gene expression patterning. The role of mRNA stability in controlling the expression of mitochondrial proteins is relatively unexplored. To induce mitochondrial biogenesis, we chronically stimulated (10 Hz; 3 or 6 h/day) rat muscle for 7 days. Chronic contractile activity (CCA) increased the protein expression of PGC-1α, c-myc, and mitochondrial transcription factor A (Tfam) by 1.6-, 1.7- and 2.0-fold, respectively. To determine mRNA stability, we incubated total RNA with cytosolic extracts using an in vitro cell-free system. We found that the intrinsic mRNA half-lives (t1/2) were variable within control muscle. Peroxisome proliferator-activated receptor-γ, coactivator-1α (PGC-1α) and Tfam mRNAs decayed more rapidly (t1/2 = 22.7 and 31.4 min) than c-myc mRNA (t1/2 = 99.7 min). Furthermore, CCA resulted in a differential response in degradation kinetics. After CCA, PGC-1α and Tfam mRNA half-lives decreased by 48% and 44%, respectively, whereas c-myc mRNA half-life was unchanged. CCA induced an elevation of both the cytosolic RNA-stabilizing human antigen R (HuR) and destabilizing AUF1 (total) by 2.4- and 1.8-fold, respectively. Increases in the p37AUF1, p40AUF1, and p45AUF1 isoforms were most evident. Thus these data indicate that CCA results in accelerated turnover rates of mRNAs encoding important mitochondrial biogenesis regulators in skeletal muscle. This adaptation is likely beneficial in permitting more rapid phenotypic plasticity in response to subsequent contractile activity