Does Weight Loss Cause the Exercise-induced Increase in Plasma High Density Lipoproteins?

Studies showing an increase in plasma concentration of high density lipoprotein cholesterol (HDL-C) with moderate exercise have usually rejected the role of body weight change in the HDL-C raising process, ostensibly because the amount of weight lost has been negligible. To investigate HDL-C changes more thoroughly, we followed initially sedentary middle-aged men randomly assigned to either a moderate running (N=36) or a sedentary control (N=28) group for one year. Among runners, one-year changes in plasma HDL-C concentrations correlated strongly with their body weight changes (r = -0.53, P \u3c 0.001). Curve-fitting procedures and regression analysis suggested that processes associated with weight change produce much of the plasma HDL-C changes induced by moderate exercise and that changes in HDL-C concentration predominantly reflect changes in the reputedly anti-atherogenic HDL2 sub-component. Further, the interaction between weight change and plasma HDL-C concentration was significantly different (

Time- and exercise-dependent gene regulation in human skeletal muscle

BACKGROUND: Skeletal muscle remodeling is a critical component of an organism's response to environmental changes. Exercise causes structural changes in muscle and can induce phase shifts in circadian rhythms, fluctuations in physiology and behavior with a period of around 24 hours that are maintained by a core clock mechanism. Both exercise-induced remodeling and circadian rhythms rely on the transcriptional regulation of key genes. RESULTS: We used DNA microarrays to determine the effects of resistance exercise (RE) on gene regulation in biopsy samples of human quadriceps muscle obtained 6 and 18 hours after an acute bout of isotonic exercise with one leg. We also profiled diurnal gene regulation at the same time points (2000 and 0800 hours) in the non-exercised leg. Comparison of our results with published circadian gene profiles in mice identified 44 putative genes that were regulated in a circadian fashion. We then used quantitative PCR to validate the circadian expression of selected gene orthologs in mouse skeletal muscle. CONCLUSIONS: The coordinated regulation of the circadian clock genes Cry1, Per2, and Bmal1 6 hours after RE and diurnal genes 18 hours after RE in the exercised leg suggest that RE may directly modulate circadian rhythms in human skeletal muscle

Associations of resting heart rate with concentrations of lipoprotein subfractions in sedentary men

In major prospective studies it has been reported that high heart rate at rest predicts the development of coronary heart disease (CHD) or cardiovascular disease (CVD) in men, but the mechanisms producing these relationships are unknown. Since lipoprotein levels contribute strongly to the risk of CHD and CVD, we examined the relationship of resting heart rate to plasma concentrations of high-density (HDL), low-density (LDL), and very low-density (VLDL) lipoproteins, apolipoprotein (apo) A-I and A-II, and serum concentrations of lipoprotein subfractions in 81 men to determine if atherogenic lipoproteins could potentially induce the reported association of heart rate with development of CHD or CVD. The significant (p less than or equal to .05) Spearman\u27s correlations for resting heart rate vs HDL2 mass (rs = - .24), HDL3 mass (rs = - .40), HDL cholesterol (rs = - .36), apo A-I (rs = - .29), triglycerides (rs = .31), VLDL cholesterol (rs = .24), VLDL mass (rs = .27), and LDL mass of Sof 0-7 subfraction (rs = .30) lend support to our hypothesis of lipoprotein-induced relationships of CHD with heart rate. The correlations of resting heart rate vs triglycerides, HDL cholesterol, HDL3 mass, VLDL mass, and LDL mass of Sof 0-7 subfraction remain significant when adjusted for adiposity, age, smoking habits, diet, and physical fitness as measured by maximum aerobic power (VO2 max) or submaximal heart rate during a graded exercise test

An Evolutionary Conserved Role for Anaplastic Lymphoma Kinase in Behavioral Responses to Ethanol

Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention

Alternative Splicing in the Differentiation of Human Embryonic Stem Cells into Cardiac Precursors

The role of alternative splicing in self-renewal, pluripotency and tissue lineage specification of human embryonic stem cells (hESCs) is largely unknown. To better define these regulatory cues, we modified the H9 hESC line to allow selection of pluripotent hESCs by neomycin resistance and cardiac progenitors by puromycin resistance. Exon-level microarray expression data from undifferentiated hESCs and cardiac and neural precursors were used to identify splice isoforms with cardiac-restricted or common cardiac/neural differentiation expression patterns. Splice events for these groups corresponded to the pathways of cytoskeletal remodeling, RNA splicing, muscle specification, and cell cycle checkpoint control as well as genes with serine/threonine kinase and helicase activity. Using a new program named AltAnalyze (http://www.AltAnalyze.org), we identified novel changes in protein domain and microRNA binding site architecture that were predicted to affect protein function and expression. These included an enrichment of splice isoforms that oppose cell-cycle arrest in hESCs and that promote calcium signaling and cardiac development in cardiac precursors. By combining genome-wide predictions of alternative splicing with new functional annotations, our data suggest potential mechanisms that may influence lineage commitment and hESC maintenance at the level of specific splice isoforms and microRNA regulation

Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer