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The study was a two-arm randomized, placebo-controlled, investigator-blinded parallel trial in 55 subjects at risk of type 2 diabetes. The Medical Ethical Review Committee Wageningen University (METC-WU nr. 17/25) approved this study, it was carried out in according to the Declaration of Helsinki and was registered at the ISRCTN registry (ISRCTN39985847). The treatment product was an intrinsic multifibre product consisting of dried chicory roots, which are rich in native inulin enclosed within plant cell-walls made of pectin, cellulose and hemi-cellulose. Participants were eligible if they were between 40 and 75 year old and had either a fasting blood glucose level between 5.0 and 5.6 mmol/L with a high risk to develop type 2 diabetes (T2D) later in life as assessed by a diabetes risk score ≥ 9, or a fasting blood glucose level of 5.6 and 6.9 mmol/L (classified as prediabetes by the American Diabetes Association). The study consisted of three weeks intervention where subjects consumed 30 g of the multifibre product (n=28) per day or an iso-caloric placebo (maltodextrin, n=27). This study period was preceded by a two-week run-in period at half-dose and followed by a two week washout. At baseline, after the two-week run-in, after the three-weeks study and after the two-week washout faecal samples were collected to determine changes in gut microbiota composition. Samples were directly frozen at home and stored in the freezer (-20°C) until transport in frozen form to the laboratory and subsequent storage at -80°C. Besides gut microbiota composition, we also assessed faecal short-chain fatty acids a well as bowel function by monitoring stool softness and stool frequency, type 2 diabetes biomarkers by measuring circulating short-chain fatty acids, fasting insulin, fasting glucose and HOMA-ir in plasma (taken at baseline and after three weeks of 30g product intake) as well as changes in the coefficient of variation by continuous glucose measurement during baseline, run-in

Background: Handheld dynamometry (HHD) is a practical alternative to traditional testing of lower extremity strength. However, its reliability and validity across different populations and settings are not clear. Hypothesis: We hypothesize that HHD is a valid and reliable device to assess lower extremity strength in a population of older adults. Study Design: Cross-sectional/cohort. Level of Evidence: Level 3. Methods: This study included 258 older adults (≥65 years). Isometric knee extension and flexion force were measured by 1 examiner, using an HHD (n = 222), including 3 repetitions to calculate within-day intrarater reliability. These measurements were repeated by the examiner in a subgroup (n = 23) to analyze intrarater reliability over a test-retest period of on average 8 weeks. In addition, HHD force measures were performed by a second examiner (n = 29) to analyze interrater reliability. In another subgroup (n = 77), isometric knee extension and flexion torque were measured by 1 examiner using both the HHD and Biodex System 4 to assess relative validity. Results: HHD and Biodex measurements were highly correlated and showed excellent concurrent validity. HHD systematically overestimated torque as compared with Biodex by 8 N·m on average. Same-day intrarater intraclass correlation coefficients (ICCs) ranged from 0.97 to 0.98. Interrater reliability ICCs ranged from 0.83 to 0.95. Conclusion: HHD represents a reliable and valid alternative to Biodex to rank individuals on leg strength, or to assess within-person changes in leg strength over time, because of the high validity and reliability. The HHD is less suited for absolute strength assessment because of significant systematic overestimations. Clinical Relevance: Clinicians are encouraged to use HHD to rank older adults on leg strength, or to assess within-person changes in leg strength over time, but not to compare readings with cut-offs or normative values.

The response to lifestyle intervention studies is often heterogeneous, especially in older adults. Subtle responses that may represent a health gain for individuals are not always detected by classical health variables, stressing the need for novel biomarkers that detect intermediate changes in metabolic, inflammatory, and immunity-related health. Here, our aim was to develop and validate a molecular multivariate biomarker maximally sensitive to the individual effect of a lifestyle intervention; the Personalized Lifestyle Intervention Status (PLIS). We used 1 H-NMR fasting blood metabolite measurements from before and after the 13-week combined physical and nutritional Growing Old TOgether (GOTO) lifestyle intervention study in combination with a fivefold cross-validation and a bootstrapping method to train a separate PLIS score for men and women. The PLIS scores consisted of 14 and four metabolites for females and males, respectively. Performance of the PLIS score in tracking health gain was illustrated by association of the sex-specific PLIS scores with several classical metabolic health markers, such as BMI, trunk fat%, fasting HDL cholesterol, and fasting insulin, the primary outcome of the GOTO study. We also showed that the baseline PLIS score indicated which participants respond positively to the intervention. Finally, we explored PLIS in an independent physical activity lifestyle intervention study, showing similar, albeit remarkably weaker, associations of PLIS with classical metabolic health markers. To conclude, we found that the sex-specific PLIS score was able to track the individual short-term metabolic health gain of the GOTO lifestyle intervention study. The methodology used to train the PLIS score potentially provides a useful instrument to track personal responses and predict the participant's health benefit in lifestyle interventions similar to the GOTO study., Pattern Recognition and Bioinformatics

Various forms of fasting and ketogenic diet have shown promise in (pre-)clinical studies to normalize body weight, improve metabolic health, and protect against disease. Recent studies suggest that β-hydroxybutyrate (βOHB), a fasting-characteristic ketone body, potentially acts as a signaling molecule mediating its beneficial effects via histone deacetylase inhibition. Here, we have investigated whether βOHB, in comparison to the well-established histone deacetylase inhibitor butyrate, influences cellular differentiation and gene expression. In various cell lines and primary cell types, millimolar concentrations of βOHB did not alter differentiation in vitro, as determined by gene expression and histological assessment, whereas equimolar concentrations of butyrate consistently impaired differentiation. RNA sequencing revealed that unlike butyrate, βOHB minimally impacted gene expression in primary adipocytes, macrophages, and hepatocytes. However, in myocytes, βOHB up-regulated genes involved in the TCA cycle and oxidative phosphorylation, while down-regulating genes belonging to cytokine and chemokine signal transduction. Overall, our data do not support the notion that βOHB serves as a powerful signaling molecule regulating gene expression but suggest that βOHB may act as a niche signaling molecule in myocytes.

This SuperSeries is composed of the SubSeries listed below. Overall design: Refer to individual Series, This SuperSeries is composed of the SubSeries listed below. Overall design: Refer to individual Series

Background: Cold acclimation and exercise training were previously shown to increase peripheral insulin sensitivity in human volunteers with type 2 diabetes. Although cold is a potent activator of brown adipose tissue, the increase in peripheral insulin sensitivity by cold is largely mediated by events occurring in skeletal muscle and at least partly involves GLUT4 translocation, as is also observed for exercise training. Results: To investigate if cold acclimation and exercise training overlap in the molecular adaptive response in skeletal muscle, we performed transcriptomics analysis on vastus lateralis muscle collected from human subjects before and after 10 days of cold acclimation, as well as before and after a 12-week exercise training intervention. Methods: Cold acclimation altered the expression of 756 genes (422 up, 334 down, P<0.01), while exercise training altered the expression of 665 genes (444 up, 221 down, P<0.01). Principal Component Analysis, Venn diagram, similarity analysis and Rank–rank Hypergeometric Overlap all indicated significant overlap between cold acclimation and exercise training in upregulated genes, but not in downregulated genes. Overlapping gene regulation was especially evident for genes and pathways associated with extracellular matrix remodeling. Interestingly, the genes most highly induced by cold acclimation were involved in contraction and in signal transduction between nerve and muscle cells, while no significant changes were observed in genes and pathways related to insulin signaling or glucose metabolism. Conclusions: Overall, our results indicate that cold acclimation and exercise training have overlapping effects on gene expression in human skeletal muscle, but strikingly these overlapping genes are designated to pathways related to cell remodeling rather than metabolic pathways. Overall design: Microarray analysis was performed on a muscle biopsies taken from overweight middle-aged male subjects before and after a 12 week, Background: Cold acclimation and exercise training were previously shown to increase peripheral insulin sensitivity in human volunteers with type 2 diabetes. Although cold is a potent activator of brown adipose tissue, the increase in peripheral insulin sensitivity by cold is largely mediated by events occurring in skeletal muscle and at least partly involves GLUT4 translocation, as is also observed for exercise training. Results: To investigate if cold acclimation and exercise training overlap in the molecular adaptive response in skeletal muscle, we performed transcriptomics analysis on vastus lateralis muscle collected from human subjects before and after 10 days of cold acclimation, as well as before and after a 12-week exercise training intervention. Methods: Cold acclimation altered the expression of 756 genes (422 up, 334 down, P<0.01), while exercise training altered the expression of 665 genes (444 up, 221 down, P<0.01). Principal Component Analysis, Venn diagram, similarity analysis and Rank–rank Hypergeometric Overlap all indicated significant overlap between cold acclimation and exercise training in upregulated genes, but not in downregulated genes. Overlapping gene regulation was especially evident for genes and pathways associated with extracellular matrix remodeling. Interestingly, the genes most highly induced by cold acclimation were involved in contraction and in signal transduction between nerve and muscle cells, while no significant changes were observed in genes and pathways related to insulin signaling or glucose metabolism. Conclusions: Overall, our results indicate that cold acclimation and exercise training have overlapping effects on gene expression in human skeletal muscle, but strikingly these overlapping genes are designated to pathways related to cell remodeling rather than metabolic pathways. Overall design: Microarray analysis was performed on a muscle biopsies taken from overweight middle-aged male subjects before and after a 12 week

Objective: Vitamin D deficiency is common among older adults and has been linked to muscle weakness. Vitamin D supplementation has been proposed as a strategy to improve muscle function in older adults. The aim of this study was to investigate the effect of calcifediol (25-hydroxycholecalciferol) on whole genome gene expression in skeletal muscle of vitamin D deficient frail older adults. Methods: A double-blind placebo-controlled trial was conducted in vitamin D deficient frail older adults (aged above 65), characterized by blood 25-hydroxycholecalciferol concentrations between 20 and 50 nmol/L. Subjects were randomized across the placebo group and the calcifediol group (10 μg per day). Muscle biopsies were obtained before and after 6 months of calcifediol (n = 10) or placebo (n = 12) supplementation and subjected to whole genome gene expression profiling using Affymetrix HuGene 2.1ST arrays. Results: Expression of the vitamin D receptor gene was virtually undetectable in human skeletal muscle biopsies, with Ct values exceeding 30. Blood 25-hydroxycholecalciferol levels were significantly higher after calcifediol supplementation (87.3 ± 20.6 nmol/L) than after placebo (43.8 ± 14.1 nmol/L). No significant difference between treatment groups was observed on strength outcomes. The whole transcriptome effects of calcifediol and placebo were very weak, as indicated by the fact that correcting for multiple testing using false discovery rate did not yield any differentially expressed genes using any reasonable cut-offs (all q-values ~ 1). P-values were uniformly distributed across all genes, suggesting that low p-values are likely to be false positives. Partial least squares-discriminant analysis and principle component analysis was unable to separate treatment groups. Conclusion: Calcifediol supplementation did not significantly affect the skeletal muscle transcriptome in frail older adults. Our findings indicate that vitamin D supplementation has no effects on skelet

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Prolonged lifespan and decreased fertility will lead to an increased proportion of older adults in the world population (population aging). An important strategy to deal with population aging has been to promote healthy aging; not only to prevent mounting health care costs, but also to maintain independence and quality of life of older populations for as long as possible. Close to the opposite of the healthy aging is frailty. A major component of (physical) frailty is sarcopenia: age-related loss of muscle mass. Decreased muscle size and strength has been associated with a wide variety of negative health outcomes, including increased risk of hospitalization, physical disability and even death. Therefore, maintaining muscle size and strength is very important for healthy aging. Nutrition and physical activity are possible strategies to maintain or even improve muscle function with age. The effect of nutrition, age, frailty and physical activity on the function of skeletal muscle is complex. A better understanding of the molecular mechanisms involved can provide new insights in potential strategies to maintain muscle function over the life course. This thesis aims to investigate these mechanisms and processes that underlie the effects of age, frailty and physical activity by leveraging the sensitivity and comprehensiveness of transcriptomics and metabolomics. Chapter 2 and 3 describe the effects of age, frailty and resistance-type exercise training on the skeletal muscle transcriptome and metabolome. Both the transcriptome and metabolome show significant differences between frail and healthy older adults. These differences are similar to the differneces between healthy young men and healthy older adults, suggesting that frailty presents itself as a more pronounced form of aging, somewhat independent of chronological age. These age and frailty related differences in the transcriptome are partially reversed by resistance-type exercise training, in accordance with the ob

Background: A short period of leg immobilization leads to rapid loss of muscle mass and strength. Creatine supplementation has been shown to increase lean body mass in active individuals and can be used to augment gains in muscle mass and strength during prolonged resistance-type exercise training. Objective: Our objective was to investigate whether creatine loading can attenuate the loss of muscle mass and strength during short-term leg immobilization. Methods: Healthy young men (n = 30; aged 23 ± 1 years; body mass index [BMI] 23.3 ± 0.5 kg/m−2) were randomly assigned to either a creatine or a placebo group. Subjects received placebo or creatine supplements (20 g/d) for 5 days before one leg was immobilized by means of a full-leg cast for 7 days. Muscle biopsies were taken before creatine loading, prior to and immediately after leg immobilization, and after 7 days of subsequent recovery. Quadriceps cross-sectional area (CSA) (computed tomography [CT] scan) and leg muscle strength (one-repetition maximum [1-RM] knee extension) were assessed before and immediately after immobilization and after 1 week of recovery. Data were analyzed using repeated measures analysis of variance (ANOVA). Data are presented consistently as mean ± standard error of the mean (SEM). Results: There was a significant overall increase in muscle total creatine content following the 5-day loading phase (p = 0.049), which appeared driven by an increase in the creatine group (from 90 ± 9 to 107 ± 4 mmol/kg−1 dry muscle) with no apparent change in the placebo group (from 88 ± 4 to 90 ± 3 mmol/kg−1; p = 0.066 for time × treatment interaction). Quadriceps muscle CSA had declined by 465 ± 59 and 425 ± 69 mm2 (p <0.01) in the creatine and placebo group, respectively, with no differences between groups (p = 0.76). Leg muscle strength decreased from 56 ± 4 to 53 ± 4 kg in the creatine and from 59 ± 3 to 53 ± 3 kg in the placebo group, with no differences between groups (p = 0.20). Muscle fiber size did

Background: Exercising is know to have an effect on exercising skeletal muscle, but unkown is the effect on non-exercising skeletal muscle. Gene expression changes in the non-exercising skeletal muscle would point to a signalling role of skeletal muscle, Background: Exercising is know to have an effect on exercising skeletal muscle, but unkown is the effect on non-exercising skeletal muscle. Gene expression changes in the non-exercising skeletal muscle would point to a signalling role of skeletal muscle