Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

BACKGROUND\nIncreased physical activity is related to reduced risk of cardiovascular disease, possibly because it leads to improvement in the lipoprotein profile. However, the amount of exercise training required for optimal benefit is unknown. In a prospective, randomized study, we investigated the effects of the amount and intensity of exercise on lipoproteins.\n\n\nMETHODS\nA total of 111 sedentary, overweight men and women with mild-to-moderate dyslipidemia were randomly assigned to participate for six months in a control group or for approximately eight months in one of three exercise groups: high-amount-high-intensity exercise, the caloric equivalent of jogging 20 mi (32.0 km) per week at 65 to 80 percent of peak oxygen consumption; low-amount-high-intensity exercise, the equivalent of jogging 12 mi (19.2 km) per week at 65 to 80 percent of peak oxygen consumption; or low-amount-moderate-intensity exercise, the equivalent of walking 12 mi per week at 40 to 55 percent of peak oxygen consumption. Subjects were encouraged to maintain their base-line body weight. The 84 subjects who complied with these guidelines served as the basis for the main analysis. Detailed lipoprotein profiling was performed by nuclear magnetic resonance spectroscopy with verification by measurement of cholesterol in lipoprotein subfractions.\n\n\nRESULTS\nThere was a beneficial effect of exercise on a variety of lipid and lipoprotein variables, seen most clearly with the high amount of high-intensity exercise. The high amount of exercise resulted in greater improvements than did the lower amounts of exercise (in 10 of 11 lipoprotein variables) and was always superior to the control condition (11 of 11 variables). Both lower-amount exercise groups always had better responses than the control group (22 of 22 comparisons).\n\n\nCONCLUSIONS\nThe highest amount of weekly exercise, with minimal weight change, had widespread beneficial effects on the lipoprotein profile. The improvements were related to the amount of activity and not to the intensity of exercise or improvement in fitness.

Effects of the amount and intensity of exercise on plasma lipoproteins: Editor's comments

Interleukin (IL)-6 is a cytokine with pleiotropic functions in different tissues and organs. Skeletal muscle produces and releases significant levels of IL-6 after prolonged exercise and is therefore considered as a myokine. Muscle is also an important target of the cytokine. IL-6 signaling has been associated with stimulation of hypertrophic muscle growth and myogenesis through regulation of the proliferative capacity of muscle stem cells. Additional beneficial effects of IL-6 include regulation of energy metabolism, which is related to the capacity of actively contracting muscle to synthesize and release IL-6. Paradoxically, deleterious actions for IL-6 have also been proposed, such as promotion of atrophy and muscle wasting. We review the current evidence for these apparently contradictory effects, the mechanisms involved and discuss their possible biological implications.

/pdf/interleukin-6-myokine-signaling-in-skeletal-muscle-a-double-3triv5yp23.pdf

Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword?

Molecular oxygen (O2) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased oxygen concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. On a cellular level, ATP-consuming reactions are suppressed, and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense oxygen levels to coordinate diverse biological outputs during hypoxia. The best-studied mechanism of response to hypoxia involves hypoxia inducible factors (HIFs), which are stabilized by low oxygen availability and control the expression of a multitude of genes, including those involved in cell survival, angiogenesis, glycolysis and invasion/metastasis. Importantly, changes in oxygen can also be sensed via other stress pathways as well as changes in metabolite levels and the generation of reactive oxygen species by mitochondria. Collectively, this leads to cellular adaptations of protein synthesis, energy metabolism, mitochondrial respiration, lipid and carbon metabolism as well as nutrient acquisition. These mechanisms are integral inputs into fine-tuning the responses to hypoxic stress.

Cellular adaptation to hypoxia through hypoxia inducible factors and beyond.

This review proposes that physical inactivity could be considered a behavior selected by evolution for resting, and also selected to be reinforcing in life-threatening situations in which exercise would be dangerous. Underlying the notion are human twin studies and animal selective breeding studies, both of which provide indirect evidence for the existence of genes for physical inactivity. Approximately 86% of the 325 million in the United States (U.S.) population achieve less than the U.S. Government and World Health Organization guidelines for daily physical activity for health. Although underappreciated, physical inactivity is an actual contributing cause to at least 35 unhealthy conditions, including the majority of the 10 leading causes of death in the U.S. First, we introduce nine physical inactivity-related themes. Next, characteristics and models of physical inactivity are presented. Following next are individual examples of phenotypes, organ systems, and diseases that are impacted by physical inactivity, including behavior, central nervous system, cardiorespiratory fitness, metabolism, adipose tissue, skeletal muscle, bone, immunity, digestion, and cancer. Importantly, physical inactivity, itself, often plays an independent role as a direct cause of speeding the losses of cardiovascular and strength fitness, shortening of healthspan, and lowering of the age for the onset of the first chronic disease, which in turn decreases quality of life, increases health care costs, and accelerates mortality risk.

Role of Inactivity in Chronic Diseases: Evolutionary Insight and Pathophysiological Mechanisms

Skeletal muscle represents the largest organ of the body in non-obese individuals and is now considered to be an active endocrine organ releasing a host of so-called myokines. These myokines are part of a complex network that mediates communication between muscle, the liver, adipose tissue, the brain and other organs. Recent data suggest that myokines regulated by muscle contraction may play a key role in mediating the health-promoting effects of regular physical activity. Although hundreds of myokines have recently been described in proteomic studies, we currently have a rather limited knowledge of the specific role these myokines play in the prevention of insulin resistance, inflammation and associated metabolic dysfunction. Several myokines are known to have both local and endocrine functions, but in many cases the contribution of physical activity to the systemic level of these molecules remains as yet unexplored. Very recently, novel myokines such as irisin, which is thought to induce a white to brown shift in adipocytes, have gained considerable interest as potential therapeutic targets. In this review, we summarise the most recent findings on the role of myokines in the regulation of substrate metabolism and insulin sensitivity. We further explore the role of myokines in the regulation of inflammation and provide a critical assessment of irisin and other myokines regarding their potential as therapeutic targets.

/pdf/myokines-in-insulin-resistance-and-type-2-diabetes-2hv0qudu89.pdf

Myokines in insulin resistance and type 2 diabetes.

Obesity is closely associated with muscle insulin resistance and is a major risk factor for the pathogenesis of type 2 diabetes. Regular physical activity not only prevents obesity, but also considerably improves insulin sensitivity and skeletal muscle metabolism. We sought to establish and characterise an in vitro model of human skeletal muscle contraction, with a view to directly studying the signalling pathways and mechanisms that are involved in the beneficial effects of muscle activity. Contracting human skeletal muscle cell cultures were established by applying electrical pulse stimulation. To induce insulin resistance, skeletal muscle cells were incubated with human adipocyte-derived conditioned medium, monocyte chemotactic protein (MCP)-1 and chemerin. Similarly to in exercising skeletal muscle in vivo, electrical pulse stimulation induced contractile activity in human skeletal muscle cells, combined with the formation of sarcomeres, activation of AMP-activated protein kinase (AMPK) and increased IL-6 secretion. Insulin-stimulated glucose uptake was substantially elevated in contracting cells compared with control. The incubation of skeletal muscle cells with adipocyte-conditioned media, chemerin and MCP-1 significantly reduced the insulin-stimulated phosphorylation of Akt. This effect was abrogated by concomitant pulse stimulation of the cells. Additionally, pro-inflammatory signalling by adipocyte-derived factors was completely prevented by electrical pulse stimulation of the myotubes. We showed that the effects of electrical pulse stimulation on skeletal muscle cells were similar to the effect of exercise on skeletal muscle in vivo in terms of enhanced AMPK activation and IL-6 secretion. In our model, muscle contractile activity eliminates insulin resistance by blocking pro-inflammatory signalling pathways. This novel model therefore provides a unique tool for investigating the molecular mechanisms that mediate the beneficial effects of muscle contraction.

/pdf/contractile-activity-of-human-skeletal-muscle-cells-prevents-2ucawmbloe.pdf

Contractile activity of human skeletal muscle cells prevents insulin resistance by inhibiting pro-inflammatory signalling pathways

The myokine decorin is regulated by contraction and involved in muscle hypertrophy.

Soluble DPP4 induces inflammation and proliferation of human smooth muscle cells via protease-activated receptor 2

Skeletal muscle and white adipose tissue are the largest organs in the human body and both tissues act as endocrine organs capable of secreting many bioactive molecules. There has been some confusion about nomenclature and we suggest that the name myokine should be restricted to a protein or molecule secreted from myocytes, whereas the term adipokine should be used to describe proteins and molecules secreted from adipocytes. In fact, many myokines are also produced by adipocytes and we propose to name them adipo-myokines. Many adipo-myokines produced by skeletal muscle or adipose tissue are influenced by exercise. Therefore, it is likely that adipo-myokines may contribute in the mediation of the health benefits of exercise and physical inactivity probably leads to an altered adipo-myokine profile, which could provide a potential mechanism for the association between sedentary behavior and many chronic diseases. Within this review, we evaluate the effects of acute and chronic exercise on myokine, adipokine, and adipo-myokine production. By using the adipo-myokine concept and including both skeletal muscle and adipose tissue, an attempt is made to gain a global view on the beneficial effects of different exercise programs and the underlying pathways.

Sven W. Görgens

Papers

Myokines in insulin resistance and type 2 diabetes.

Contractile activity of human skeletal muscle cells prevents insulin resistance by inhibiting pro-inflammatory signalling pathways

The myokine decorin is regulated by contraction and involved in muscle hypertrophy.

Soluble DPP4 induces inflammation and proliferation of human smooth muscle cells via protease-activated receptor 2

Exercise and Regulation of Adipokine and Myokine Production