Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis.

Deregulated glucose metabolism fulfills the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF-mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF-mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including hypoxia-inducible factor-1α, MYC, and MONDOA (MLXIP), drives glycolysis downstream of BRAF(V600), is critical for responses to BRAF inhibition, and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor (BRAFi)-resistant melanoma cells. Thus, we provide a proof-of-principle for treatment of melanoma with combinations of BRAFis and glycolysis inhibitors.

Creatine transporter (SLC6A8) knockout mice display an increased capacity for in vitro creatine biosynthesis in skeletal muscle.

The present study aimed to investigate whether skeletal muscle from whole body creatine transporter (CrT; SLC6A8) knockout mice (CrT(-/y)) actually contained creatine (Cr) and if so, whether this Cr could result from an up regulation of muscle Cr biosynthesis. Gastrocnemius muscle from CrT(-/y) and wild type (CrT(+/y)) mice were analyzed for ATP, Cr, Cr phosphate (CrP), and total Cr (TCr) content. Muscle protein and gene expression of the enzymes responsible for Cr biosynthesis L-arginine:glycine amidotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) were also determined as were the rates of in vitro Cr biosynthesis. CrT(-/y) mice muscle contained measurable (22.3 ± 4.3 mmol.kg(-1) dry mass), but markedly reduced (P < 0.05) TCr levels compared with CrT(+/y) mice (125.0 ± 3.3 mmol.kg(-1) dry mass). AGAT gene and protein expression were higher (~3 fold; P < 0.05) in CrT(-/y) mice muscle, however GAMT gene and protein expression remained unchanged. The in vitro rate of Cr biosynthesis was elevated 1.5 fold (P < 0.05) in CrT(-/y) mice muscle. These data clearly demonstrate that in the absence of CrT protein, skeletal muscle has reduced, but not absent, levels of Cr. This presence of Cr may be at least partly due to an up regulation of muscle Cr biosynthesis as evidenced by an increased AGAT protein expression and in vitro Cr biosynthesis rates in CrT(-/y) mice. Of note, the up regulation of Cr biosynthesis in CrT(-/y) mice muscle was unable to fully restore Cr levels to that found in wild type muscle.

Undercarboxylated osteocalcin, muscle strength and indices of bone health in older women

We investigated the association between undercarboxylated osteocalcin (ucOC) and lower-limb muscle strength in women over the age of 70years. The study also aims to confirm the association between bone turnover markers and heel ultrasound measures. A post-hoc analysis using data collected as part of a randomized placebo-controlled trial of vitamin D supplementation. An immunoassay was used to quantify total OC (tOC), with hydroxyapatite pre-treatment for ucOC. We determined associations of absolute and relative (ucOC/tOC; ucOC%) measures of ucOC with lower-limb muscle strength, heel ultrasound measures of speed of sound (SOS) and broadband ultrasound attenuation (BUA), bone turnover markers (BTMs; P1NP and CTx) and the acute phase protein alpha-1-antichymotrypsin (α-ACT). ucOC%, but not absolute ucOC concentration, was positively associated with hip flexor, hip abductor and quadriceps muscle strength (all p<0.05). ucOC% was negatively associated with α-ACT (β-coefficient=-0.24, p=0.02). tOC was positively associated with both P1NP and CTx (p<0.001). For each per unit increase in tOC (μg/L) there was a corresponding lower BUA, SOS and SI (β-coefficient = -0.28; -0.23 and -0.23, respectively; all p<0.04). In conclusion, ucOC% is positively associated with muscle strength and negatively associated with α-ACT. These data support a role for ucOC in musculoskeletal interactions in humans. Whilst tOC is associated with bone health, ucOC% and ucOC may also be linked to falls and fracture risk by influencing muscle function.

Individual (co)variation in thermal reaction norms of standard and maximal metabolic rates in wild-caught slimy salamanders

Standard metabolic rate (SMR) and maximal metabolic rate (MMR) are fundamental measures in ecology and evolution because they set the scope within which animals can perform activities that directly affect fitness. In ectotherms, both SMR and MMR are repeatable over time when measured at a single ambient temperature (Ta). Many ectotherms encounter variable Ta from day to day and over their lifetime, yet it is currently unknown whether individual differences hold across an ecologically relevant range of Ta (i.e. thermal repeatability; RT). Moreover, it is possible that thermal sensitivity of SMR and MMR are important individual attributes, and correlated with one another, but virtually nothing is known about this at present. We measured SMR and MMR across an ecologically relevant Ta gradient (i.e. from 10 to 25 °C) in wild-caught salamanders (Plethodon albagula) and found that RT was significant in both traits. SMR and MMR were also positively correlated, resulting in a lower RT in absolute and factorial aerobic scopes (AAS and FAS). We found significant individual differences in thermal sensitivity for both SMR and MMR, but not for AAS and FAS. The intercept (at Ta = 0 °C) and the slope of the thermal reaction norms were negatively correlated; individuals with low MR at low Ta had a higher thermal sensitivity. Finally, individuals with a high thermal sensitivity for SMR also had high thermal sensitivity for MMR. Our results suggest that natural selection occurring over variable Ta may efficiently target the overall level of - and thermal sensitivity in - SMR and MMR. However, this may not be the case for metabolic scopes, as the positive correlation between SMR and MMR, in addition to their combined changes in response to Ta, yielded little individual variation in AAS and FAS. Our results support the idea that organisms with low metabolism at low Ta have a high metabolic thermal sensitivity as a compensatory mechanism to benefit in periods of warmer environmental conditions. Hence, our study reveals the importance of considering within-individual variation in metabolism, as it may represent additional sources of adaptive (co)variation.

Individual (co)variation in standard metabolic rate, feeding rate, and exploratory behavior in wild-caught semiaquatic salamanders

Repeatability is an important concept in evolutionary analyses because it provides information regarding the benefit of repeated measurements and, in most cases, a putative upper limit to heritability estimates. Repeatability (R) of different aspects of energy metabolism and behavior has been demonstrated in a variety of organisms over short and long time intervals. Recent research suggests that consistent individual differences in behavior and energy metabolism might covary. Here we present new data on the repeatability of body mass, standard metabolic rate (SMR), voluntary exploratory behavior, and feeding rate in a semiaquatic salamander and ask whether individual variation in behavioral traits is correlated with individual variation in metabolism on a whole-animal basis and after conditioning on body mass. All measured traits were repeatable, but the repeatability estimates ranged from very high for body mass (R = 0.98), to intermediate for SMR (R = 0.39) and food intake (R = 0.58), to low for exploratory behavior (R = 0.25). Moreover, repeatability estimates for all traits except body mass declined over time (i.e., from 3 to 9 wk), although this pattern could be a consequence of the relatively low sample size used in this study. Despite significant repeatability in all traits, we find little evidence that behaviors are correlated with SMR at the phenotypic and among-individual levels when conditioned on body mass. Specifically, the phenotypic correlations between SMR and exploratory behavior were negative in all trials but significantly so in one trial only. Salamanders in this study showed individual variation in how their exploratory behavior changed across trials (but not body mass, SMR, and feed intake), which might have contributed to observed changing correlations across trials.

Changes in mitochondrial function and mitochondria associated protein expression in response to 2-weeks of high intensity interval training

PURPOSE: High-intensity short-duration interval training (HIT) stimulates functional and metabolic adaptation in skeletal muscle, but the influence of HIT on mitochondrial function remains poorly studied in humans. Mitochondrial metabolism as well as mitochondrial-associated protein expression were tested in untrained participants performing HIT over a 2-week period. METHODS: Eight males performed a single-leg cycling protocol (12 × 1 min intervals at 120% peak power output, 90 s recovery, 4 days/week). Muscle biopsies (vastus lateralis) were taken pre- and post-HIT. Mitochondrial respiration in permeabilized fibers, citrate synthase (CS) activity and protein expression of peroxisome proliferator-activated receptor gamma coactivator (PGC-1α) and respiratory complex components were measured. RESULTS: HIT training improved peak power and time to fatigue. Increases in absolute oxidative phosphorylation (OXPHOS) capacities and CS activity were observed, but not in the ratio of CCO to the electron transport system (CCO/ETS), the respiratory control ratios (RCR-1 and RCR-2) or mitochondrial-associated protein expression. Specific increases in OXPHOS flux were not apparent after normalization to CS, indicating that gross changes mainly resulted from increased mitochondrial mass. CONCLUSION: Over only 2 weeks HIT significantly increased mitochondrial function in skeletal muscle independently of detectable changes in mitochondrial-associated and mitogenic protein expression.

Metabolic rate and thermal conductance of lemmings from high-arctic Canada and Siberia

The arctic climate places high demands on the energy metabolism of its inhabitants. We measured resting (RMR) and basal metabolic rates (BMR), body temperatures, and dry and wet thermal conductances in summer morphs of the lemmings Dicrostonyx groenlandicus and Lemmus trimucronatus in arctic Canada, and the BMR of D. torquatus, D. groenlandicus, L. sibiricus, L. bungei and L. trimucronatus in Siberia. In contrast to previous studies the data were collected on animals that had spent only a limited time in captivity. All parameters were analysed in relation to the variations in body mass (20-90 g). Body temperature and BMR were lower in D. groenlandicus than L. trimucronatus, which coincides with greater longevity in the former species. Wet and dry thermal conductances of both species were similar and comparable with those of other Myomorpha (mouse-type rodents), indicating no evidence for a previously claimed lower thermal conductance in lemmings. BMR in lemmings appeared to be higher than in other Arvicolidae (voles, lemmings and muskrats), which could relate to their typically high-latitude distribution. However, the more southerly living Lemmus species had higher BMR than the more northerly living Dicrostonyx species, which may be explained by the former having a relatively low-quality diet.

Child and adolescent obesity: part of a bigger picture

The prevalence of childhood overweight and obesity has risen substantially worldwide in less than one generation. In the USA, the average weight of a child has risen by more than 5 kg within three decades, to a point where a third of the country's children are overweight or obese. Some low-income and middle-income countries have reported similar or more rapid rises in child obesity, despite continuing high levels of undernutrition. Nutrition policies to tackle child obesity need to promote healthy growth and household nutrition security and protect children from inducements to be inactive or to overconsume foods of poor nutritional quality. The promotion of energy-rich and nutrient-poor products will encourage rapid weight gain in early childhood and exacerbate risk factors for chronic disease in all children, especially those showing poor linear growth. Whereas much public health effort has been expended to restrict the adverse marketing of breastmilk substitutes, similar effort now needs to be expanded and strengthened to protect older children from increasingly sophisticated marketing of sedentary activities and energy-dense, nutrient-poor foods and beverages. To meet this challenge, the governance of food supply and food markets should be improved and commercial activities subordinated to protect and promote children's health.

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.

Classroom standing desks and sedentary behavior: a systematic review

CONTEXT: Reducing sedentary behaviors, or time spent sitting, is an important target for health promotion in children. Standing desks in schools may be a feasible, modifiable, and acceptable environmental strategy to this end. OBJECTIVE: To examine the impact of school-based standing desk interventions on sedentary behavior and physical activity, health-related outcomes, and academic and behavioral outcomes in school-aged children. DATA SOURCES: Ovid Embase, Medline, PsycINFO, Web of Science, Global Health, and CINAHL. STUDY SELECTION: Full-text peer-reviewed journal publications written in English; samples of school-aged youth (5-18 years of age); study designs including the same participants at baseline and follow-up; and use of a standing desk as a component of the intervention. DATA EXTRACTION: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Eight studies satisfied selection criteria and used quasi-experimental (n = 4), randomized controlled trial (n = 3), and pre-post, no control (n = 1) designs. When examined, time spent standing increased in all studies (effect sizes: 0.38-0.71), while sitting time decreased from a range of 59 to 64 minutes (effect sizes: 0.27-0.49). Some studies reported increased physical activity and energy expenditure and improved classroom behavior. LIMITATIONS: One-half of the studies had nonrandomized designs, and most were pilot or feasibility studies. CONCLUSIONS: This initial evidence supports integrating standing desks into the classroom environment; this strategy has the potential to reduce sitting time and increase standing time among elementary schoolchildren. Additional research is needed to determine the impact of standing desks on academic performance and precursors of chronic disease risk.

Wearable cameras can reduce dietary under-reporting: doubly labelled water validation of a camera-assisted 24 h recall

Preliminary research has suggested that wearable cameras may reduce under-reporting of energy intake (EI) in self-reported dietary assessment. The aim of the present study was to test the validity of a wearable camera-assisted 24 h dietary recall against the doubly labelled water (DLW) technique. Total energy expenditure (TEE) was assessed over 15 d using the DLW protocol among forty adults (n 20 males, age 35 (sd 17) years, BMI 27 (sd 4) kg/m2 and n 20 females, age 28 (sd 7) years, BMI 22 (sd 2) kg/m2). EI was assessed using three multiple-pass 24 h dietary recalls (MP24) on days 2-4, 8-10 and 13-15. On the days before each nutrition assessment, participants wore an automated wearable camera (SenseCam (SC)) in free-living conditions. The wearable camera images were viewed by the participants following the completion of the dietary recall, and their changes in self-reported intakes were recorded (MP24+SC). TEE and EI assessed by the MP24 and MP24+SC methods were compared. Among men, the MP24 and MP24+SC measures underestimated TEE by 17 and 9%, respectively (P< 0.001 and P= 0.02). Among women, these measures underestimated TEE by 13 and 7%, respectively (P< 0.001 and P= 0.004). The assistance of the wearable camera (MP24+SC) reduced the magnitude of under-reporting by 8% for men and 6% for women compared with the MP24 alone (P< 0.001 and P< 0.001). The increase in EI was predominantly from the addition of 265 unreported foods (often snacks) as revealed by the participants during the image review. Wearable cameras enhance the accuracy of self-report by providing passive and objective information regarding dietary intake. High-definition image sensors and increased imaging frequency may improve the accuracy further.

Family-based interventions for reducing sedentary time in youth: a systematic review of randomized controlled trials

Family involvement in interventions to reduce sedentary time may help foster appropriate long-term screen-based habits in children. This review systematically synthesized evidence from randomized controlled trials of interventions with a family component that targeted reduction of sedentary time, including TV viewing, video games and computer use, in children. MEDLINE, PubMed, PsycInfo, CINAHL and Embase were searched from inception through March 2012. Seventeen articles were considered eligible and included in the review. Studies were judged to be at low-to-moderate risk of bias. Despite inconsistent study results, level of parental involvement, rather than the setting itself, appeared an important determinant of intervention success. Studies including a parental component of medium-to-high intensity were consistently associated with statistically significant changes in sedentary behaviours. Participant age was also identified as a determinant of intervention outcomes; all three studies conducted in pre-school children demonstrated significant decreases in sedentary time. Finally, TV exposure appeared to be related to changes in energy intake rather than physical activity. Future studies should assess the effects of greater parental involvement and child age on success of sedentary behaviour interventions. More research is required to better understand the relationship between screen time and health behaviours, particularly energy intake.

Active video games and health indicators in children and youth: a systematic review

BACKGROUND: Active video games (AVGs) have gained interest as a way to increase physical activity in children and youth. The effect of AVGs on acute energy expenditure (EE) has previously been reported; however, the influence of AVGs on other health-related lifestyle indicators remains unclear.

OBJECTIVE: This systematic review aimed to explain the relationship between AVGs and nine health and behavioural indicators in the pediatric population (aged 0-17 years). DATA SOURCES: Online databases (MEDLINE, EMBASE, psycINFO, SPORTDiscus and Cochrane Central Database) and personal libraries were searched and content experts were consulted for additional material.

DATA SELECTION: Included articles were required to have a measure of AVG and at least one relevant health or behaviour indicator: EE (both habitual and acute), adherence and appeal (i.e., participation and enjoyment), opportunity cost (both time and financial considerations, and adverse events), adiposity, cardiometabolic health, energy intake, adaptation (effects of continued play), learning and rehabilitation, and video game evolution (i.e., sustainability of AVG technology).

RESULTS: 51 unique studies, represented in 52 articles were included in the review. Data were available from 1992 participants, aged 3-17 years, from 8 countries, and published from 2006-2012. Overall, AVGs are associated with acute increases in EE, but effects on habitual physical activity are not clear. Further, AVGs show promise when used for learning and rehabilitation within special populations. Evidence related to other indicators was limited and inconclusive.

CONCLUSIONS: Controlled studies show that AVGs acutely increase light- to moderate-intensity physical activity; however, the findings about if or how AVG lead to increases in habitual physical activity or decreases in sedentary behaviour are less clear. Although AVGs may elicit some health benefits in special populations, there is not sufficient evidence to recommend AVGs as a means of increasing daily physical activity.