Differences in chromatin organization are key to the multiplicity of cell states that arise from a single genetic background, yet the landscapes of in vivo tissues remain largely uncharted. Here, we ...mapped chromatin genome-wide in a large and diverse collection of human tissues and stem cells. The maps yield unprecedented annotations of functional genomic elements and their regulation across developmental stages, lineages, and cellular environments. They also reveal global features of the epigenome, related to nuclear architecture, that also vary across cellular phenotypes. Specifically, developmental specification is accompanied by progressive chromatin restriction as the default state transitions from dynamic remodeling to generalized compaction. Exposure to serum in vitro triggers a distinct transition that involves de novo establishment of domains with features of constitutive heterochromatin. We describe how these global chromatin state transitions relate to chromosome and nuclear architecture, and discuss their implications for lineage fidelity, cellular senescence, and reprogramming.
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► A resource of chromatin state maps for phenotypically diverse human tissues ► Annotation of regulatory elements across developmental stages and environments ► Developmental specification is accompanied by progressive chromatin restriction ► Chromatin architecture changes in cultured cells have implications for reprogramming
A large collection of chromatin state maps, representing human cells and tissues in vivo, reveals tissue-specific enhancer-like elements as well as repressive chromatin domains that arise during development or in response to nonphysiologic cellular environments and may present a hindrance to cellular reprogramming.
Recent guidelines on exercise for weight loss and weight maintenance include resistance training as part of the exercise prescription. Yet few studies have compared the effects of similar amounts of ...aerobic and resistance training on body mass and fat mass in overweight adults. STRRIDE AT/RT, a randomized trial, compared aerobic training, resistance training, and a combination of the two to determine the optimal mode of exercise for obesity reduction. Participants were 119 sedentary, overweight or obese adults who were randomized to one of three 8-mo exercise protocols: 1) RT: resistance training, 2) AT: aerobic training, and 3) AT/RT: aerobic and resistance training (combination of AT and RT). Primary outcomes included total body mass, fat mass, and lean body mass. The AT and AT/RT groups reduced total body mass and fat mass more than RT (P < 0.05), but they were not different from each other. RT and AT/RT increased lean body mass more than AT (P < 0.05). While requiring double the time commitment, a program of combined AT and RT did not result in significantly more fat mass or body mass reductions over AT alone. Balancing time commitments against health benefits, it appears that AT is the optimal mode of exercise for reducing fat mass and body mass, while a program including RT is needed for increasing lean mass in middle-aged, overweight/obese individuals.
The purpose of this study is to evaluate the effect of exercise training with modest or greater weight loss (≥3%) or not (<3%) on insulin sensitivity, lipoprotein concentrations, and lipoprotein ...particle size in overweight and obese participants.
Adults (N = 163, body mass index: 25-37 kg/m2) participated in 8 months of exercise training. Insulin sensitivity, lipid concentrations, lipid particle size and other cardiometabolic variables were measured at baseline and follow-up. Participants were categorized by whether they achieved at least modest weight loss (≥ 3%) or not (<3%) following the intervention.
A greater improvement in insulin sensitivity was observed in adults performing exercise training with at least modest weight loss (2.2 mU·l-1 ·min -1, CI: 1.5 to 2.8) compared to those who did not (0.8 mU·l-1 ·min -1, CI: 0.5 to 1.2). Similar results were observed for acute insulin response, triglycerides, non-HDL cholesterol concentration, low density lipoprotein (LDL) particle size and high density lipoprotein (HDL) particle size (p<0.05), when all exercise groups were combined. No significant results across weight loss categories were observed for LDL, HDL, glucose, or insulin levels.
The present study suggests that aerobic exercise combined with at least modest weight loss leads to greater improvements in insulin sensitivity, triglycerides as well as other non-traditional lipid risk factors (non-HDL cholesterol, HDL/LDL particle size). Clinicians should advocate patients who are overweight/obese to exercise and obtain modest weight loss for improved cardiovascular benefits.
Aerobic training (AT) improves the metabolic syndrome (MS) and its component risk factors; however, to our knowledge, no randomized clinical studies have addressed whether resistance training (RT) ...improves the MS when performed alone or combined with AT. Sedentary, overweight dyslipidemic men and women, aged 18 to 70 years completed a 4-month inactive run-in period and were randomized to 1 of 3 eight-month exercise programs (n = 196). The exercise programs were (1) RT (3 days/week, 3 sets/day of 8 to 12 repetitions of 8 different exercises targeting all major muscle groups); (2) AT (∼120 minutes/week at 75% of the maximum oxygen uptake), and (3) AT and RT combined (AT/RT) (exact combination of AT and RT). Of the 196 randomized patients, 144 completed 1 of the 3 exercise programs. The 86 participants with complete data for all 5 MS criteria were used in the present analysis, and a continuous MS z score was calculated. Eight months of RT did not change the MS score. AT improved the MS score (p <0.07) and showed a trend toward significance compared to RT (p <0.10). AT/RT significantly decreased the MS score and was significantly different from RT alone. In conclusion, RT was not effective at improving the MS score; however, AT was effective. Combined AT and RT was similarly effective but not different from AT alone. When weighing the time commitment versus health benefit, the data suggest that AT alone was the most efficient mode of exercise for improving cardiometabolic health.
Increased Secretion and Expression of Myostatin in Skeletal Muscle From Extremely Obese Women
Dustin S. Hittel 1 ,
Jason R. Berggren 2 ,
Jane Shearer 1 ,
Kristen Boyle 2 and
Joseph A. Houmard 2
1 ...Human Performance Laboratory, Faculty of Kinesiology, Roger Jackson Center for Health and Wellness, University of Calgary,
Calgary, Alberta, Canada
2 Human Performance Laboratory and Department of Exercise and Sport Science, East Carolina University, Greenville, North Carolina
Corresponding author: Dustin S. Hittel, dhittel{at}kin.ucalgary.ca
Abstract
OBJECTIVE— Obesity is associated with endocrine abnormalities that predict the progression of insulin resistance to type 2 diabetes.
Because skeletal muscle has been shown to secrete proteins that could be used as biomarkers, we characterized the secreted
protein profile of muscle cells derived from extremely obese (BMI 48.8 ± 14.8 kg/m 2 ; homeostasis model assessment HOMA 3.6 ± 1.0) relative to lean healthy subjects (BMI 25.7 ± 3.2 kg/m 2 ; HOMA 0.8 ± 0.2).
RESEARCH DESIGN AND METHODS— We hypothesized that skeletal muscle would secrete proteins that predict the severity of obesity. To test this hypothesis,
we used a “bottom-up” experimental design using stable isotope labeling by amino acids in culture (SILAC) and liquid chromatography/mass
spectometry/mass spectometry (LC-MS/MS) to both identify and quantify proteins secreted from cultured myotubes derived from
extremely obese compared with healthy nonobese women.
RESULTS— Using SILAC, we discovered a 2.9-fold increase in the secretion of myostatin from extremely obese human myotubes. The increased
secretion and biological activity of myostatin were validated by immunoblot (3.16 ± 0.18, P < 0.01) and a myoblast proliferation assay using conditioned growth medium. Myostatin was subsequently shown to increase
in skeletal muscle (23%, P < 0.05) and plasma (35%, P < 0.05) and to correlate ( r 2 = 0.6, P < 0.05) with the severity of insulin resistance.
CONCLUSIONS— Myostatin is a potent antianabolic regulator of muscle mass that may also play a role in energy metabolism. These findings
show that increased expression of myostatin in skeletal muscle with obesity and insulin resistance results in elevated circulating
myostatin. This may contribute to systemic metabolic deterioration of skeletal muscle with the progression of insulin resistance
to type 2 diabetes.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 3 October 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted September 19, 2008.
Received July 14, 2008.
DIABETES
High dietary fat intake leads to insulin resistance in skeletal muscle, and this represents a major risk factor for type 2 diabetes and cardiovascular disease. Mitochondrial dysfunction and oxidative ...stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the H(2)O(2)-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial H(2)O(2) emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial H(2)O(2) emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity.
Blood lactate concentrations traditionally have been used as an index of exercise intensity or clinical hyperlactatemia. However, more recent data suggest that fasting plasma lactate can also be ...indicative of the risk for subsequent metabolic disease. The hypothesis presented is that fasting blood lactate accumulation reflects impaired mitochondrial substrate use, which in turn influences metabolic disease risk.
The purpose of this study was to determine whether plasma lactate and skeletal muscle glucose regulatory pathways, specifically PDH dephosphorylation, are impaired during hyperinsulinemic conditions ...in middle- to older-aged individuals and determine whether exercise training could improve key variables responsible for skeletal muscle PDH regulation. Eighteen young (19-29 yr; n = 9 males and 9 females) and 20 middle- to older-aged (57-82 yr; n = 10 males and 10 females) individuals underwent a 2-h euglycemic hyperinsulinemic clamp. Plasma samples were obtained at baseline and at 30, 50, 90, and 120 min for analysis of lactate, and skeletal muscle biopsies were performed at 60 min for analysis of protein associated with glucose metabolism. In response to insulin, plasma lactate was elevated in aged individuals when normalized to insulin action. Insulin-stimulated phosphorylation of skeletal muscle PDH on serine sites 232, 293, and 300 decreased in young individuals only. Changes in insulin-stimulated PDH phosphorylation were positively related to changes in plasma lactate. No age-related differences were observed in skeletal muscle phosphorylation of LDH, GSK-3α, or GSK-3β in response to insulin or PDP1, PDP2, PDK2, PDK4, or MPC1 total protein. Twelve weeks of endurance- or strength-oriented exercise training improved insulin-stimulated PDH dephosphorylation, which was related to a reduced lactate response. These findings suggest that impairments in insulin-induced PDH regulation in a sedentary aging population contribute to impaired glucose metabolism and that exercise training is an effective intervention for treating metabolic inflexibility.
Although exercise improves individual risk factors for metabolic syndrome (MS), there is little research on the effect of exercise on MS as a whole. The objective of this study was to determine how ...much exercise is recommended to decrease the prevalence of MS. Of 334 subjects randomly assigned, 227 finished and 171 (80 women, 91 men) had complete data for all 5 Adult Treatment Panel III–defined MS risk factors and were included in this analysis. Subjects were randomly assigned to a 6-month control or 1 of 3 eight-month exercise training groups of (1) low amount/moderate intensity (equivalent to walking ∼19 km/week), (2) low amount/vigorous intensity (equivalent to jogging ∼19 km/week), or (3) high amount/vigorous intensity (equivalent to jogging ∼32 km/week). The low-amount/moderate-intensity exercise prescription improved MS relative to inactive controls (p <0.05). However, the same amount of exercise at vigorous intensity was not significantly better than inactive controls, suggesting that lower-intensity exercise may be more effective in improving MS. The high-amount/vigorous-intensity group improved MS relative to controls (p <0.0001), the low-amount/vigorous-intensity group (p = 0.001), and the moderate-intensity group (p = 0.07), suggesting an exercise-dose effect. In conclusion, a modest amount of moderate-intensity exercise in the absence of dietary changes significantly improved MS and thus supported the recommendation that adults get 30 minutes of moderate-intensity exercise every day. A higher amount of vigorous exercise had greater and more widespread benefits. Finally, there was an indication that moderate-intensity may be better than vigorous-intensity exercise for improving MS.
The obese are at increased risk for cardiovascular disease and type 2 diabetes. However, some who are obese have no metabolic abnormalities. So, it is not adipose tissue per se, but perhaps where it ...is located that is important for determining metabolic consequences. Regular exercise is known to reduce risk for metabolic disease through numerous mechanisms. The purpose of this report is to highlight some of the efficacy-based data on the effects of exercise (and also a sedentary lifestyle) on abdominal obesity, visceral fat, and metabolic risk. We also discuss how impaired fatty acid oxidation (FAO) in skeletal muscle may be related to both insulin resistance and a contributor to weight gain. In summary, it is evident that exercise in sufficient amounts can lead to substantial decreases in body weight, total body fat, and visceral fat. Additionally, evidence now supports the conclusion that there is a dose–response relationship between exercise amount and these changes, i.e., more exercise leads to additional benefits. Additionally, there are a number of important cardiometabolic risk factors that were most favorably effected by moderate-intensity compared to vigorous-intensity exercise. Unfortunately, it is also apparent that in sedentary middle-aged men and women, short periods of physical inactivity lead to significant weight gain, substantial increases in visceral fat, and further metabolic deterioration. Finally, favorable modulation of mitochondrial oxidative capacity in skeletal muscle by exercise training may reduce a block for complete oxidation of fatty acids in muscle and thereby relieve a block to effective insulin signaling.
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