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Gene transcripts associated with muscle strength: A CHARGE meta-analysis of 7,781 persons
Abstract
Background:
Lower muscle strength in midlife predicts disability and mortality in later life. Bloodborne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults.
Methods:
Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n=7,781, ages: 20-104 years, weighted mean=56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, male/female).
Results:
Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation and the stress response. Ten genes were only associated in younger individuals, four in males only and one in females only. For example PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 years) individuals but not older (>=60 years). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts Conclusions: This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age and sex specific gene expression signatures in blood for muscle strength.
... A gene expression analysis of blood messenger RNA from 698 people found the expression of the CEBPB gene to be significantly associated with hand grip strength as well as with physical performance (Harries et al. 2012). In a larger transcriptome-wide association study (TWAS), Pilling et al. (2016) investigated the association between hand grip strength and gene expression levels in a total of 7781 individuals aged 20-104 years from 4 independent cohorts. They identified 208 differentially expressed genes, half of which were novel in muscle-related literature, thus warranting future work on mechanisms underlying these associations (Pilling et al. 2016). ...
... In a larger transcriptome-wide association study (TWAS), Pilling et al. (2016) investigated the association between hand grip strength and gene expression levels in a total of 7781 individuals aged 20-104 years from 4 independent cohorts. They identified 208 differentially expressed genes, half of which were novel in muscle-related literature, thus warranting future work on mechanisms underlying these associations (Pilling et al. 2016). Recently, Murabito et al. (2017) examined the association of 229 whole-blood microRNAs (miRNAs) with hand grip strength in a population of 5668 individuals aged 24-90 years. ...
... Furthermore, no significant pathways were identified in the ORA of the present study; 4 pathways did relate to muscle contraction, yet to cardiac and vascular smooth (blood vessel) muscle contraction, not skeletal muscle function (Online Resource 1, Supplementary Table 7). Of the previous studies, a TWAS (Pilling et al. 2016), a genome-wide miRNA study ) and a GWAS (Willems et al. 2017) reported pathway analyses. Due to differences in methodology a complete comparison was not possible, nevertheless, if grouping pathways by the overall hierarchical level of functional events as defined by the databases, some overlap between the present ORA and the previous studies was seen: pathways related to gene expression (Pilling et al. 2016), signal transduction, the neuronal system and cell cycle/death ), the immune system (Pilling et al. 2016 andMurabito et al. 2017), DNA repair (Willems et al. 2017), RNA metabolism ) and protein metabolism (Pilling et al. 2016and Willems et al. 2017. ...
Hand grip strength is a measure of muscular strength and is used to study age-related loss of physical capacity. In order to explore the biological mechanisms that influence hand grip strength variation, an epigenome-wide association study (EWAS) of hand grip strength in 672 middle-aged and elderly monozygotic twins (age 55–90 years) was performed, using both individual and twin pair level analyses, the latter controlling the influence of genetic variation. Moreover, as measurements of hand grip strength performed over 8 years were available in the elderly twins (age 73–90 at intake), a longitudinal EWAS was conducted for this subsample. No genome-wide significant CpG sites or pathways were found, however two of the suggestive top CpG sites were mapped to the COL6A1 and CACNA1B genes, known to be related to muscular dysfunction. By investigating genomic regions using the comb-p algorithm, several differentially methylated regions in regulatory domains were identified as significantly associated to hand grip strength, and pathway analyses of these regions revealed significant pathways related to the immune system, autoimmune disorders, including diabetes type 1 and viral myocarditis, as well as negative regulation of cell differentiation. The genes contributing to the immunological pathways were HLA-B, HLA-C, HLA-DMA, HLA-DPB1, MYH10, ERAP1 and IRF8, while the genes implicated in the negative regulation of cell differentiation were IRF8, CEBPD, ID2 and BRCA1. In conclusion, this exploratory study suggests hand grip strength to associate with differentially methylated regions enriched in immunological and cell differentiation pathways, and hence merits further investigations.
... Therefore, gene expression levels capture the net influences on transcription and are more likely to be associated with age-related and other traits than are individual genetic variants. A meta-analysis of 7,781 individuals aged 20-104 years, from four cohorts, identified 221 differentially expressed genes associated with muscle strength [34]. Differential gene expression has also been identified in smokers versus never smokers in a meta-analysis of 10,233 individuals from six cohorts [35], which may in turn influence aging. ...
... No transcripts were significantly associated with gf, IQ change, six metre walk time, FEV1, grip strength, CRP, fibrinogen, HbA1c, or methylation age acceleration (Hannum or Horvath) (Supplementary Tables 6-13, [17][18]. Eight out of the top 10 genes for muscle strength in the Pilling et al. 2016 study of 7,781 participants, [34] were represented by transcripts in this study, of which one (PNP, p=0.03) was nominally significantly associated with grip strength at p<0.05, but in the opposite direction (Supplementary Table 10). ...
... This may be due to the previous study investigating gene expression in whole blood, whereas our study investigated gene expression in LCLs. Our failure to replicate previously published associations for both smoking [35] and muscle strength [34] may also be due to the smaller size of our study. ...
Gene expression is influenced by both genetic variants and the environment. As individuals age, changes in gene expression may be associated with decline in physical and cognitive abilities. We measured transcriptome-wide expression levels in lymphoblastoid cell lines derived from members of the Lothian Birth Cohort 1936 at mean ages 70 and 76 years. Changes in gene expression levels were identified for 1,741 transcripts in 434 individuals. Gene Ontology enrichment analysis indicated an enrichment of biological processes involved in the immune system. Transcriptome-wide association analysis was performed for eleven cognitive, fitness, and biomedical aging-related traits at age 70 years (N=665 to 781) and with mortality. Transcripts for genes (F2RL3, EMILIN1 and CDC42BPA) previously identified as being differentially methylated or expressed in smoking or smoking-related cancers were overexpressed in smokers compared to non-smokers and the expression of transcripts for genes (HERPUD1, GAB2, FAM167A and GLS) previously associated with stress response, autoimmune disease and cancer were associated with telomere length. No associations between expression levels and other traits, or mortality were identified.
... The combination of dihydrotestosterone and stimulation of IGF-1 affects cells adhesion, migration, and cytokines production, as well as modification expression of focal adhesion kinases [16]. Meta-analysis of the whole blood genes expression has shown that IGF1R gene is related to muscle strength [17]. Another study reported that IGF1R was overexpressed in the whole blood after high-intensity exercise in old champion athletes [18]. ...
... The wide range of expression in major subpopulations of white blood cells allows to use this molecule as a peripheral marker of training. An additional advantage is that IGF1R expression in blood can be associated with intensive exercise [18,19] and muscle strength [17]. It is also proven that suppression of IGF1R by natural autoantibodies impairs physical strength [79]. ...
A deeper insight into the mechanisms responsible for athlete performance that may serve
as specific and detailed training indicators is still desired, because conventionally used biomarkers provide limited information about the adaptive processes that occur during exercise. The objective of our study was to assess insulin-like growth factor 1 receptors (IGF1R) gene expression and evaluate plasma concentration of selected microRNAs (miRNAs) during a 10-week training period (sampling times: week 1, 4, 7, and 10) in a group of 12 professional female volleyball players. Circulating miRNAs (miR-223, miR-320a, and miR-486) with established concentration in plasma and documented association with the IGF1 signaling pathway, which is involved in muscle development
and recovery, were tested. The levels of analyzed miRNAs, tested by one-way ANOVA, were significantly different between four training periods during a 10-week training cycle (miR-223 p < 0.0001, miR-320a p = 0.00021, miR-486 p = 0.0037, respectively). The levels of IGF1R also appeared to be different (p = 0.00092), and their expression showed a trend to increase between the first and third periods. In the fourth period, the expression decreased, although it was higher compared with the baseline. Correlations between concentration levels of miR-223 and miR-320a (rs = 0.54, p < 0.001), as well as between miR-320a and miR-486 (rs = 0.73, p < 0.001) were also found. In the fourth period, a negative correlation between miR-223 plasma level and leucocyte IGF1R expression
was found (rs = −0.63, p = 0.028). Multiple linear regression analysis showed that miR-320a (p = 0.024) and creatine kinase (p = 0.028) had the greatest impact on the expression levels of the IGF1R gene. Future studies are required to define whether these miRNAs, especially miR-320a, as well as IGF1R expression could be useful biomarkers of physiological changes during exercise and to discover their detailed biological roles in mode-specific exercise training adaptations of professional athletes.
... p value = 1.3EÀ6) and PIK3R2 (r = À0.82, p value = 3.3EÀ6), two genes that were recently associated with muscle strength, 39 and NRK (r = À0.82, p value = 3.8EÀ6), known to be specifically expressed during myotome formation and early muscle development in mice, but not in the adult. ...
... Finally, this analytical approach proved very effective to identify RNA biomarkers of XLMTM correction. Interestingly, several of the top 12 candidate genes not only align with XLMTM phenotypes but could also help deepen our understanding of disease development: ALAS2 and PIK3R2 have recently been negatively associated with muscle strength in a meta-analysis of more than 7,500 human subjects 39 and were also found overexpressed in XLMTM dogs; Nik-related kinase (NRK) is a protein kinase involved in actin polymerization through phosphorylation and inhibition of cofilin, is only expressed during embryonic myogenesis, 40 and is overexpressed in XLMTM dogs, which adds to the list of dysregulated developmental genes; APEX2 encodes an endonuclease physically associated with proliferating cell nuclear antigen (PCNA) and driving cell-cycle progression through base-excision repair on the replicative nuclear and mitochondrial DNA. 47,48 APEX2 is also overexpressed in untreated XLMTM muscles and corrected in the Therapeutic group, suggesting that de-regulation/re-regulation of the cell cycle is a key component of disease development and rescue. ...
Multiple clinical trials employing recombinant adeno-associated viral (rAAV) vectors have been initiated for neuromuscular disorders, including Duchenne and limb-girdle muscular dystrophies, spinal muscular atrophy, and recently X-linked myotubular myopathy (XLMTM). Our previous work on a canine model of XLMTM showed that a single rAAV8-cMTM1 systemic infusion corrected structural abnormalities within the muscle and restored contractile function, with affected dogs surviving more than 4 years post injection. This remarkable therapeutic efficacy presents a unique opportunity to identify the downstream molecular drivers of XLMTM pathology and to what extent the whole muscle transcriptome is restored to normal after gene transfer. Herein, RNA-sequencing was used to examine the transcriptomes of the Biceps femoris and Vastus lateralis in a previously described canine cohort that showed dose-dependent clinical improvements after rAAV8-cMTM1 gene transfer. Our analysis confirmed several dysregulated genes previously observed in XLMTM mice but also identified transcripts linked to XLMTM pathology. We demonstrated XLMTM transcriptome remodeling and dose-dependent normalization of gene expression after gene transfer and created metrics to pinpoint potential biomarkers of disease progression and correction.
... A large-scale transcriptome-wide study of muscle strength in human adults identified a total of 221 genes, of which circulating expression levels were associated with muscle strength. This study confirmed associations with known pathways involved in muscle and provides new evidence for over half of the genes identified [210]. ...
... Similarly, transcriptomic profiles were identified for smoking [386], fasting glucose and insulin levels [387] and muscle strength [210]. The first epigenome-wide study was also attempted in relation to bone mineral density variation [388]. ...
The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1500 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.
... Muscle strength and performance are also modulated by the ubiquitin proteasome pathway and its upstream mediators AKT, FoxO-1, and insulin-like growth factor-1 (IGF-1) Pilling et al., 2016). Circulating IGF-1 levels were lower in KO compared to WT animals and were not affected significantly by age. ...
During aging, decreases in energy expenditure and locomotor activity lead to body weight and fat gain. Aging is also associated with decreases in muscle strength and endurance leading to functional decline. Here, we show that lifelong deletion of ghrelin prevents development of obesity associated with aging by modulating food intake and energy expenditure. Ghrelin deletion also attenuated the decrease in phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) and downstream mediators in muscle, and increased the number of type IIa (fatigue resistant, oxidative) muscle fibers, preventing the decline in muscle strength and endurance seen with aging. Longevity was not affected by ghrelin deletion. Treatment of old mice with pharmacologic doses of ghrelin increased food intake, body weight, and muscle strength in both ghrelin wild-type and knockout mice. These findings highlight the relevance of ghrelin during aging and identify a novel AMPK-dependent mechanism for ghrelin action in muscle.
... It can be questioned whether surrogate biomarkers such as transcriptomic age can predict age-associated decline in specific tissues, like skeletal muscle. Nonetheless, a recent meta-analysis of whole blood gene expression (overall 17 534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7781, ages: 20-104 y) identified robust associations between the expression of 221 genes and muscle strength in adults [50 ]. Although blood is generally easily accessible, plasma levels of biomarkers reflect an overall status and the contribution of individual body tissues is not known [45,49]. ...
Aging is associated with a decline in muscle mass and strength (sarcopenia), impacting not only mobility but also metabolic health. Phenotypic flexibility, as a proxy for health, impairs during aging and varies considerably between subjects, as identified from challenge studies with multiple biomarkers. Recent studies have linked transcriptomics and metabolomics in serum and muscle tissue to functional outcomes, such as muscle strength. Age-related changes in skeletal muscle gene expression were partially reversed by resistance exercise, indicating the plasticity of muscle. Supplementation of high-quality dietary proteins enhances the beneficial effects of exercise on sarcopenia. Signaling pathways and molecules associated with atrophy in aged skeletal muscle are increasingly revealed, providing novel opportunities for optimizing and personalizing nutritional concepts for the elderly population.
Electric pulse-stimulated C2C12 myotubes are gaining interest in the field of muscle physiology and biotechnology because electric pulse stimulation (EPS) enhances sarcomere structure development and active tension generation capability. Recently, we found that termination of EPS results in the rapid loss of active tension generation accompanied by disassembly of the sarcomere structure, which may represent an in vitro muscle atrophy model. To elucidate the molecular mechanism underlying this rapid loss of active tension generation and sarcomere structure disassembly after termination of EPS, we performed transcriptomic analysis using microarray. After termination of EPS, 74 genes were upregulated and 120 genes were downregulated after 30 min; however, atrophy-related genes were not found among these genes. To further assess the effect of EPS on gene expression, we re-applied EPS after its termination for 8 h and searched for genes whose expression was reversed. Four genes were upregulated by termination of EPS and downregulated by the re-application of EPS, whereas two genes were downregulated by termination of EPS and upregulated by the re-application of EPS. Although none of these genes were atrophy- or hypertrophy-related, the results presented in this study will contribute to the understanding of gene expression changes that mediate rapid loss of active tension generation and sarcomere structure disassembly following termination of EPS in C2C12 myotubes.
Synovial fibroblasts (SFs) of rheumatoid arthritis (RA) are phenotypically aggressive, typically progressing into arthritic cartilage degradation. Throughout our study, we made explorations into the effects of microRNA‐135a (miR‐135a) on the SFs involved in RA by mediating the phosphatidylinositol 3‐kinase (PI3K)/AKT signaling pathway via regulation of phosphatidylinositol 3‐kinase regulatory subunit 2 (PIK3R2). The expression of PI3K was higher, the expression of PIK3R2 was lower, and AKT was phosphorylated in the RA synovial tissues, relative to the levels found in the normal synovial tissues. We predicted miR‐135a to be a candidate miR targeting PIK3R2 using an online website, microRNA.org, which was verified with a dual‐luciferase reporter gene assay. Subsequently, high miR‐135a expression was observed in RA synovial tissues. To study the effect of the interaction between miR‐135a and PIK3R2 in RA, the SFs isolated from RA samples were cultured and transfected with mimic, inhibitor, and small interfering RNA. The proliferation, invasion, and apoptosis of the SFs were detected after the transfection. The cells transfected with miR‐135a inhibitor showed inhibited cell proliferation, migration, and invasion, while also displaying promoted cell apoptosis, G0/G1 cell ratio, and decreased S cell ratio, through upregulation of PIK3R2 and inactivation of the PI3K/AKT signaling pathway. These findings provided evidence that downregulation of miR‐135a inhibits proliferation, migration, and invasion and promotes apoptosis of SFs in RA by upregulating the PIK3R2 coupled with inactivating the PI3K/AKT signaling pathway. The downregulation of miR‐135a might be a potential target in the treatment of RA.
Multiple clinical trials employing recombinant adeno-associated viral (rAAV) vectors have been initiated for neuromuscular disorders, including Duchenne and limb-girdle muscular dystrophies, spinal muscular atrophy, and recently X-linked myotubular myopathy (XLMTM). Previous work from our laboratory on a canine model of XLMTM showed that a single rAAV8-cMTM1 systemic infusion corrects structural abnormalities within the muscle and restores contractile function, with affected dogs surviving more than four years post injection. This exceptional therapeutic efficacy presents a unique opportunity to identify the downstream molecular drivers of XLMTM pathology, and to what extent the whole muscle transcriptome is restored to normal after gene transfer. Herein, RNA-sequencing was used to examine the transcriptomes of the Biceps femoris and Vastus lateralis in a previously-described canine cohort showing dose-dependent clinical improvements after rAAV8-cMTM1 gene transfer. Our analysis confirmed several dysregulated genes previously observed in XLMTM mice, but also identified new transcripts linked to XLMTM pathology. We demonstrated XLMTM transcriptome remodeling and dose-dependent normalization of gene expression after gene transfer and created new metrics to pinpoint potential biomarkers of disease progression and correction.
Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%-9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension.
Sarcopenia is associated with adverse health outcomes. This study investigated whether skeletal muscle gene expression was associated with lean mass and grip strength in community-dwelling older men. Utilising a cross-sectional study design, lean muscle mass and grip strength were measured in 88 men aged 68-76 years. Expression profiles of 44 genes implicated in the cellular regulation of skeletal muscle were determined. Serum was analysed for circulating cytokines TNF (tumour necrosis factor), IL-6 (interleukin 6, IFNG (interferon gamma), IL1R1 (interleukin-1 receptor-1). Relationships between skeletal muscle gene expression, circulating cytokines, lean mass and grip strength were examined. Participant groups with higher and lower values of lean muscle mass (n = 18) and strength (n = 20) were used in the analysis of gene expression fold change. Expression of VDR (vitamin D receptor) [fold change (FC) 0.52, standard error for fold change (SE) ± 0.08, p = 0.01] and IFNG mRNA (FC 0.31; SE ± 0.19, p = 0.01) were lower in those with higher lean mass. Expression of IL-6 (FC 0.43; SE ± 0.13, p = 0.02), TNF (FC 0.52; SE ± 0.10, p = 0.02), IL1R1 (FC 0.63; SE ± 0.09, p = 0.04) and MSTN (myostatin) (FC 0.64; SE ± 0.11, p = 0.04) were lower in those with higher grip strength. No other significant changes were observed. Significant negative correlations between serum IL-6 (R = -0.29, p = 0.005), TNF (R = -0.24, p = 0.017) and grip strength were demonstrated. This novel skeletal muscle gene expression study carried out within a well-characterized epidemiological birth cohort has demonstrated that lower expression of VDR and IFNG is associated with higher lean mass, and lower expression of IL-6, TNF, IL1R1 and myostatin is associated with higher grip strength. These findings are consistent with a role of proinflammatory factors in mediating lower muscle strength in community-dwelling older men.
Hand grip strength is a useful measurement for individuals with rheumatoid arthritis, since this disease is often associated with functional anomalies of the hands and a con- sequent reduction in muscular strength. Thus, the standardization of the test protocol is important in relation to make reproducible and reliable studies. The aim of this systematic review was to verify the parameters associated with the measurement of the hand grip strength in individuals with rheumatoid arthritis. The review was carried out according to the recommendations of PRISMA, based on the databases of the Web of Science and the Journals Website of the Brazilian governmental agency CAPES. The following inclusion criteria were established: articles whose themes involved dynamometry to measure the hand grip in adult patients with rheumatoid arthritis, published in English between 1990 and 2012. The articles were selected by two independent reviewers. Initially, 628 articles were identified, and in the final review only 40 were included in the qualitative synthesis, that is, those in which the main tool used to evaluate the hand grip strength was the Jamar®. In relation to the hand grip strength parameters feedback type, hand dominance, repeti- tions, contraction intensity, acquisition time and rest period many data are imprecise and were not detailed in the method description. It is clear that there is a need for the stan- dardization of a protocol which establishes the type of dynamometer and the parameters to be evaluated and also takes into consideration the clinical conditions of patients with rheumatoid arthritis.
Our understanding of genes that cause skeletal muscle disease has increased tremendously over the past three decades. Advances in approaches to genetics and genomics have aided in the identification of new pathogenic mechanisms in rare genetic disorders and have opened up new avenues for therapeutic interventions by identification of new molecular pathways in muscle disease. Recent studies have identified mutations of several Kelch proteins in skeletal muscle disorders. The Kelch superfamily is one of the largest evolutionary conserved gene families. The 66 known family members all possess a Kelch-repeat containing domain and are implicated in diverse biological functions. In skeletal muscle development, several Kelch family members regulate the processes of proliferation and/or differentiation resulting in normal functioning of mature muscles. Importantly, many Kelch proteins function as substrate-specific adaptors for Cullin E3 ubiquitin ligase (Cul3), a core component of the ubiquitin-proteasome system to regulate the protein turnover. This review discusses the emerging roles of Kelch proteins in skeletal muscle function and disease.
Maximum likelihood or restricted maximum likelihood (REML) estimates of the
parameters in linear mixed-effects models can be determined using the lmer
function in the lme4 package for R. As for most model-fitting functions in R,
the model is described in an lmer call by a formula, in this case including
both fixed- and random-effects terms. The formula and data together determine a
numerical representation of the model from which the profiled deviance or the
profiled REML criterion can be evaluated as a function of some of the model
parameters. The appropriate criterion is optimized, using one of the
constrained optimization functions in R, to provide the parameter estimates. We
describe the structure of the model, the steps in evaluating the profiled
deviance or REML criterion, and the structure of classes or types that
represents such a model. Sufficient detail is included to allow specialization
of these structures by users who wish to write functions to fit specialized
linear mixed models, such as models incorporating pedigrees or smoothing
splines, that are not easily expressible in the formula language used by lmer.
Telomere attrition has been associated with age-related diseases, although causality is unclear and controversial; low-grade systemic inflammation (inflammaging) has also been implicated in age-related pathogenesis. Unpicking the relationship between aging, telomere length (TL), and inflammaging is hence essential to the understanding of aging and management of age-related diseases. This longitudinal study explored whether telomere attrition is a cause or consequence of aging and whether inflammaging explains some of the associations between TL and one marker of aging, grip strength. We studied 253 Hertfordshire Ageing Study participants at baseline and 10-year follow-up (mean age at baseline 67.1 years). Participants completed a health questionnaire and had blood samples collected for immune–endocrine and telomere analysis at both time points. Physical aging was characterized at follow-up using grip strength. Faster telomere attrition was associated with lower grip strength at follow-up (β = 0.98, p = 0.035). This association was completely attenuated when adjusted for inflammaging burden (p = 0.86) over the same period. Similarly, greater inflammaging burden was associated with lower grip strength at follow-up (e.g., interleukin [IL]-1β: β = −2.18, p = 0.001). However, these associations were maintained when adjusted for telomere attrition (IL-1β, p = 0.006). We present evidence that inflammaging may be driving telomere attrition and in part explains the associations that have previously been reported between TL and grip strength. Thus, biomarkers of physical aging, such as inflammaging, may require greater exploration. Further work is now indicated.
Hand grip strength is a useful measurement for individuals with rheumatoid arthritis, since this disease is often associated with functional anomalies of the hands and a consequent reduction in muscular strength. Thus, the standardization of the test protocol is important in relation to make reproducible and reliable studies. The aim of this systematic review was to verify the parameters associated with the measurement of the hand grip strength in individuals with rheumatoid arthritis. The review was carried out according to the recommendations of PRISMA, based on the databases of the Web of Science and the Journals Website of the Brazilian governmental agency CAPES. The following inclusion criteria were established: articles whose themes involved dynamometry to measure the hand grip in adult patients with rheumatoid arthritis, published in English between 1990 and 2012. The articles were selected by two independent reviewers. Initially, 628 articles were identified, and in the final review only 40 were included in the qualitative synthesis, that is, those in which the main tool used to evaluate the hand grip strength was the Jamar®. In relation to the hand grip strength parameters feedback type, hand dominance, repetitions, contraction intensity, acquisition time and rest period many data are imprecise and were not detailed in the method description. It is clear that there is a need for the standardization of a protocol which establishes the type of dynamometer and the parameters to be evaluated and also takes into consideration the clinical conditions of patients with rheumatoid arthritis.
Parabiosis experiments indicate that impaired regeneration in aged mice is reversible by exposure to a young circulation,
suggesting that young blood contains humoral “rejuvenating” factors that can restore regenerative function. Here, we demonstrate
that the circulating protein growth differentiation factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation
of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant
protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased
GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise
capacity. These data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing
age-related skeletal muscle and stem cell dysfunction.
The National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) database is a collection of annotated
genomic, transcript and protein sequence records derived from data in public sequence archives and from computation, curation
and collaboration (http://www.ncbi.nlm.nih.gov/refseq/). We report here on growth of the mammalian and human subsets, changes to NCBI’s eukaryotic annotation pipeline and modifications
affecting transcript and protein records. Recent changes to NCBI’s eukaryotic genome annotation pipeline provide higher throughput,
and the addition of RNAseq data to the pipeline results in a significant expansion of the number of transcripts and novel
exons annotated on mammalian RefSeq genomes. Recent annotation changes include reporting supporting evidence for transcript
records, modification of exon feature annotation and the addition of a structured report of gene and sequence attributes of
biological interest. We also describe a revised protein annotation policy for alternatively spliced transcripts with more
divergent predicted proteins and we summarize the current status of the RefSeqGene project.
A systemic inflammatory response is observed in patients undergoing hemorrhagic shock and sepsis. Here we report increased levels of cold-inducible RNA-binding protein (CIRP) in the blood of individuals admitted to the surgical intensive care unit with hemorrhagic shock. In animal models of hemorrhage and sepsis, CIRP is upregulated in the heart and liver and released into the circulation. In macrophages under hypoxic stress, CIRP translocates from the nucleus to the cytosol and is released. Recombinant CIRP stimulates the release of tumor necrosis factor-α (TNF-α) and HMGB1 from macrophages and induces inflammatory responses and causes tissue injury when injected in vivo. Hemorrhage-induced TNF-α and HMGB1 release and lethality were reduced in CIRP-deficient mice. Blockade of CIRP using antisera to CIRP attenuated inflammatory cytokine release and mortality after hemorrhage and sepsis. The activity of extracellular CIRP is mediated through the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex. Surface plasmon resonance analysis indicated that CIRP binds to the TLR4-MD2 complex, as well as to TLR4 and MD2 individually. In particular, human CIRP amino acid residues 106-125 bind to MD2 with high affinity. Thus, CIRP is a damage-associated molecular pattern molecule that promotes inflammatory responses in shock and sepsis.
Functional enrichment analysis is an essential task for the interpretation of gene lists derived from large-scale genetic,
transcriptomic and proteomic studies. WebGestalt (WEB-based GEne SeT AnaLysis Toolkit) has become one of the popular software
tools in this field since its publication in 2005. For the last 7 years, WebGestalt data holdings have grown substantially
to satisfy the requirements of users from different research areas. The current version of WebGestalt supports 8 organisms
and 201 gene identifiers from various databases and different technology platforms, making it directly available to the fast
growing omics community. Meanwhile, by integrating functional categories derived from centrally and publicly curated databases
as well as computational analyses, WebGestalt has significantly increased the coverage of functional categories in various
biological contexts including Gene Ontology, pathway, network module, gene–phenotype association, gene–disease association,
gene–drug association and chromosomal location, leading to a total of 78 612 functional categories. Finally, new interactive
features, such as pathway map, hierarchical network visualization and phenotype ontology visualization have been added to
WebGestalt to help users better understand the enrichment results. WebGestalt can be freely accessed through http://www.webgestalt.org or http://bioinfo.vanderbilt.edu/webgestalt/.
The complex actions of the insulin-like-growth factor binding proteins (IGFBPs) in skeletal muscle are becoming apparent, with IGFBP2 being implicated in skeletal muscle cell proliferation and differentiation (Ernst et al., 1992; Sharples et al., 2010). Furthermore, PTEN signalling has been linked to IGFBP2 action in other cell types by co-ordinating downstream Akt signalling, a known modulator of myoblast differentiation. The present study therefore aimed to determine the interaction between IGFBP2 and PTEN on myoblast differentiation. It has previously been established that C2C12 cells have high IGFBP2 gene expression upon transfer to low serum media, and that expression reduces rapidly as cells differentiate over 72h [1]. Wishing to establish a potential role for IGFBP2 in this model, a neutralising IGFBP2 antibody was administered to C2C12 myoblasts upon initiation of differentiation. Myoblasts subsequently displayed reduced morphological differentiation (myotube number), biochemical differentiation (creatine kinase) and myotube hypertrophy (myotube area) with an early reduction in Akt phosphorylation. Knock-down of phosphatase and tensin homologue (PTEN) using siRNA in the absence of the neutralising antibody did not improve differentiation or hypertrophy vs. control conditions, however, in the presence of the neutralising IGFBP2 antibody, differentiation was restored and importantly hypertrophy exceeded that of control levels. Overall, these data suggest that; 1) reduced early availability of IGFBP2 can inhibit myoblast differentiation at later time points, 2) knock-down of PTEN levels can restore myoblast differentiation in the presence of neutralising IGFBP2 antibody, and 3) PTEN inhibition acts as a potent inducer of myotube hypertrophy when the availability of IGFBP2 is reduced in C2C12 myoblasts.
Microarray profiling of gene expression is widely applied in molecular biology and functional genomics. Experimental and technical variations make meta-analysis of different studies challenging. In a total of 3358 samples, all from German population-based cohorts, we investigated the effect of data preprocessing and the variability due to sample processing in whole blood cell and blood monocyte gene expression data, measured on the Illumina HumanHT-12 v3 BeadChip array.Gene expression signal intensities were similar after applying the log(2) or the variance-stabilizing transformation. In all cohorts, the first principal component (PC) explained more than 95% of the total variation. Technical factors substantially influenced signal intensity values, especially the Illumina chip assignment (33-48% of the variance), the RNA amplification batch (12-24%), the RNA isolation batch (16%), and the sample storage time, in particular the time between blood donation and RNA isolation for the whole blood cell samples (2-3%), and the time between RNA isolation and amplification for the monocyte samples (2%). White blood cell composition parameters were the strongest biological factors influencing the expression signal intensities in the whole blood cell samples (3%), followed by sex (1-2%) in both sample types. Known single nucleotide polymorphisms (SNPs) were located in 38% of the analyzed probe sequences and 4% of them included common SNPs (minor allele frequency >5%). Out of the tested SNPs, 1.4% significantly modified the probe-specific expression signals (Bonferroni corrected p-value
Changing demographics make it ever more important to understand the modifiable risk factors for disability and loss of independence with advancing age. For more than two decades there has been increasing interest in the role of sarcopenia, the age-related loss of muscle or lean mass, in curtailing active and healthy aging. There is now evidence to suggest that lack of strength, or dynapenia, is a more constant factor in compromised wellbeing in old age and it is apparent that the decline in muscle mass and the decline in strength can take quite different trajectories. This demands recognition of the concept of muscle quality; that is the force generating per capacity per unit cross-sectional area (CSA). An understanding of the impact of aging on skeletal muscle will require attention to both the changes in muscle size and the changes in muscle quality. The aim of this review is to present current knowledge of the decline in human muscle mass and strength with advancing age and the associated risk to health and survival and to review the underlying changes in muscle characteristics and the etiology of sarcopenia. Cross-sectional studies comparing young (18-45 years) and old (>65 years) samples show dramatic variation based on the technique used and population studied. The median of values of rate of loss reported across studies is 0.47% per year in men and 0.37% per year in women. Longitudinal studies show that in people aged 75 years, muscle mass is lost at a rate of 0.64-0.70% per year in women and 0.80-00.98% per year in men. Strength is lost more rapidly. Longitudinal studies show that at age 75 years, strength is lost at a rate of 3-4% per year in men and 2.5-3% per year in women. Studies that assessed changes in mass and strength in the same sample report a loss of strength 2-5 times faster than loss of mass. Loss of strength is a more consistent risk for disability and death than is loss of muscle mass.
The common approach to the multiplicity problem calls for controlling the familywise error rate (FWER). This approach, though, has faults, and we point out a few. A different approach to problems of multiple significance testing is presented. It calls for controlling the expected proportion of falsely rejected hypotheses – the false discovery rate. This error rate is equivalent to the FWER when all hypotheses are true but is smaller otherwise. Therefore, in problems where the control of the false discovery rate rather than that of the FWER is desired, there is potential for a gain in power. A simple sequential Bonferroni-type procedure is proved to control the false discovery rate for independent test statistics, and a simulation study shows that the gain in power is substantial. The use of the new procedure and the appropriateness of the criterion are illustrated with examples.
The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy ). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.
How the pore-forming protein perforin delivers apoptosis-inducing granzymes to the cytosol of target cells is uncertain. Perforin induces a transient Ca2+ flux in the target cell, which triggers a process to repair the damaged cell membrane. As a consequence, both perforin and granzymes are endocytosed into enlarged endosomes called 'gigantosomes'. Here we show that perforin formed pores in the gigantosome membrane, allowing endosomal cargo, including granzymes, to be gradually released. After about 15 min, gigantosomes ruptured, releasing their remaining content. Thus, perforin delivers granzymes by a two-step process that involves first transient pores in the cell membrane that trigger the endocytosis of granzyme and perforin and then pore formation in endosomes to trigger cytosolic release.
METAL provides a computationally efficient tool for meta-analysis of genome-wide association scans, which is a commonly used approach for improving power complex traits gene mapping studies. METAL provides a rich scripting interface and implements efficient memory management to allow analyses of very large data sets and to support a variety of input file formats.
Availability and implementation: METAL, including source code, documentation, examples, and executables, is available at http://www.sph.umich.edu/csg/abecasis/metal/
Contact: goncalo@umich.edu
Macrophages play an essential role in the resolution of tissue damage through removal of necrotic cells, thus paving the way for tissue regeneration. Macrophages also directly support the formation of new tissue to replace the injury, through their acquisition of an anti-inflammatory, or M2, phenotype, characterized by a gene expression program that includes IL-10, the IL-13 receptor, and arginase 1. We report that deletion of two CREB-binding sites from the Cebpb promoter abrogates Cebpb induction upon macrophage activation. This blocks the downstream induction of M2-specific Msr1, Il10, II13ra, and Arg-1 genes, whereas the inflammatory (M1) genes Il1, Il6, Tnfa, and Il12 are not affected. Mice carrying the mutated Cebpb promoter (betaDeltaCre) remove necrotic tissue from injured muscle, but exhibit severe defects in muscle fiber regeneration. Conditional deletion of the Cebpb gene in muscle cells does not affect regeneration, showing that the C/EBPbeta cascade leading to muscle repair is muscle-extrinsic. While betaDeltaCre macrophages efficiently infiltrate injured muscle they fail to upregulate Cebpb, leading to decreased Arg-1 expression. CREB-mediated induction of Cebpb expression is therefore required in infiltrating macrophages for upregulation of M2-specific genes and muscle regeneration, providing a direct genetic link between these two processes.
The aging process is associated with loss of muscle mass and strength and decline in physical functioning. The term sarcopenia is primarily defined as low level of muscle mass resulting from age-related muscle loss, but its definition is often broadened to include the underlying cellular processes involved in skeletal muscle loss as well as their clinical manifestations. The underlying cellular changes involve weakening of factors promoting muscle anabolism and increased expression of inflammatory factors and other agents which contribute to skeletal muscle catabolism. At the cellular level, these molecular processes are manifested in a loss of muscle fiber cross-sectional area, loss of innervation, and adaptive changes in the proportions of slow and fast motor units in muscle tissue. Ultimately, these alterations translate to bulk changes in muscle mass, strength, and function which lead to reduced physical performance, disability, increased risk of fall-related injury, and, often, frailty. In this review, we summarize current understanding of the mechanisms underlying sarcopenia and age-related changes in muscle tissue morphology and function. We also discuss the resulting long-term outcomes in terms of loss of function, which causes increased risk of musculoskeletal injuries and other morbidities, leading to frailty and loss of independence.
Sarcopenia, the age-related loss of muscle mass, may not be an isolated process but is associated with an increase in fat mass. The aim of this study was to estimate the mortality risk of sarcopenia in the presence or absence of obesity.
Data are from 934 participants aged 65 years or older, enrolled in the "Invecchiare in Chianti" study, and followed for 6 years. At baseline, a peripheral quantitative computerized tomography (pQCT) scan was performed on all participants to evaluate the muscle density, and the muscular and fat cross-sectional areas of the calf. Walking speed was measured on a 7-m track. Cox proportional hazard models were performed to estimate the association of pQCT measures (per 1 standard deviation increase) with mortality.
Unadjusted analyses showed significant associations of muscle density (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.69-0.88), muscle area (HR 0.75, 95% CI 0.66-0.86), and fat area (HR 0.82, 95% CI 0.73-0.92) with mortality. After adjustment for potential confounders, no body composition parameter was significantly associated with mortality. Walking speed (used as a reference measure to verify whether the negative results were due to peculiarities of the study sample) confirmed its well-established association with mortality risk (HR 0.73, 95% CI 0.60-0.88). These results did not change after the analyses were stratified according to sarcopenia and body mass index groups, and restricted to participants with frailty or a high inflammatory profile.
Calf skeletal muscle and fat mass are not significant risk factors for mortality in community-dwelling older adults. Walking speed confirmed to be a powerful predictor of health-related events.
Functional assessment is an important part of the evaluation of elderly persons. We conducted this study to determine whether objective measures of physical function can predict subsequent disability in older persons.
This prospective cohort study included men and women 71 years of age or older who were living in the community, who reported no disability in the activities of daily living, and who reported that they were able to walk one-half mile (0.8 km) and climb stairs without assistance. The subjects completed a short battery of physical-performance tests and participated in a follow-up interview four years later. The tests included an assessment of standing balance, a timed 8-ft (2.4-m) walk at a normal pace, and a timed test of five repetitions of rising from a chair and sitting down.
Among the 1122 subjects who were not disabled at base line and who participated in the four-year follow-up, lower scores on the base-line performance tests were associated with a statistically significant, graduated increase in the frequency of disability in the activities of daily living and mobility-related disability at follow-up. After adjustment for age, sex, and the presence of chronic disease, those with the lowest scores on the performance tests were 4.2 to 4.9 times as likely to have disability at four years as those with the highest performance scores, and those with intermediate performance scores were 1.6 to 1.8 times as likely to have disability.
Among nondisabled older persons living in the community, objective measures of lower-extremity function were highly predictive of subsequent disability. Measures of physical performance may identify older persons with a preclinical stage of disability who may benefit from interventions to prevent the development of frank disability.
Low muscle strength is associated with poorer physical function, but limited empirical evidence is available to prove the relationship between muscle mass and physical function. We tested the hypothesis that persons with lower muscle mass or muscle strength have poorer lower-extremity performance (LEP).
A cross-sectional, population-based study.
A cohort of 449 men and women aged 65 years and older living in Amsterdam and its surroundings participating in the second examination (1995-1996) of the Longitudinal Aging Study Amsterdam.
Leg skeletal muscle mass was measured using dual-energy X-ray absorptiometry (DXA). Grip strength was used as an indicator of muscle strength. Timed functional performance tests, including walking and repeated chair stands, were used to assess LEP.
After adjustment for body height and age, leg muscle mass was positively associated with LEP in men (regression coefficient 0.178 [95% confidence interval 0.013-0.343], P = .035). In women an inverse association was observed, which became positive after additional adjustment for body mass index (BMI) (0.202 [-0.001-0.405], P = .052). Grip strength was positively associated with LEP in men and women. After additional adjustment for behavioral, physiological, and psychological variables, the associations between leg muscle mass and LEP disappeared, whereas grip strength remained to be independently associated with LEP in men (0.079 [0.042-0.116], P = .0001), with a tendency in women (0.046 [-0.009-0.101], P = .11). Results were similar when quartiles of leg muscle mass or grip strength were used.
These results suggest that low muscle strength, but not low muscle mass, is associated with poor physical function in older men and women. However, prospective studies are needed to investigate the association between loss of muscle mass and physical function.
DNA microarrays were used to measure the time course of gene expression during skeletal muscle damage and regeneration in mice following femoral artery ligation (FAL). We found 1,289 known sequences were differentially expressed between the FAL and control groups. Gene expression peaked on day 3, and the functional cluster "inflammation" contained the greatest number of genes. Muscle function was depressed for 3 days postligation, but returned to normal by day 7. Decreased muscle function was accompanied by reduced expression of genes involved in mitochondrial energy production, muscle contraction, and calcium handling. The induction of MyoD on day 1 denoted the beginning of muscle regeneration and was followed by the reemergence of the embryonic forms of muscle contractile proteins, which peaked at day 7. Transcriptional analysis indicated that the ischemic skeletal muscle may transition through a functional adaptation stage with recovery of contractile force prior to full regeneration. Several members of the insulin-like growth factor axis were coordinately induced in a time frame consistent with their playing a role in the regenerative process.
Deregulation of the inflammatory response plays a major role in the age-related decline of physical performance. The causal pathway leading from inflammation to disability has not been fully clarified, but several researches suggest that interleukin-6 (IL-6) causes a reduction of physical performance in elderly through its effect on muscle function. In vitro studies demonstrated that IL-6 inhibits the secretion of insulin-like growth factor I (IGF-I) and its biological activity, suggesting that the negative effect of IL-6 on muscle function might be mediated through IGF-I. We evaluated the joint effect of IGF-I and IL-6 on muscle function in a population-based sample of 526 persons with a wide age range (20-102 yr). After adjusting for potential confounders, such as age, sex, body mass index, IL-6 receptor, and IL-6 promoter polymorphism, IL-6, IGF-I, and their interaction were significant predictors of handgrip and muscle power. In analyses stratified by IL-6 tertiles, IGF-I was an independent predictor of muscle function only in subjects in the lowest IL-6 tertile, suggesting that the effect of IGF-I on muscle function depends on IL-6 levels. This mechanism may explain why IL-6 is a strong risk factor for disability.
Anemia is associated with reduced physical performance and muscle strength. The aim of the study was to explore whether anemia and hemoglobin levels are associated with differences in quantitative and qualitative measures of muscle and fat.
The study sample consisted of 909 participants 65 years and older enrolled in the "Invecchiare in Chianti" (InCHIANTI) study, a prospective population-based study of older people aimed at identifying risk factors for late-life disability. All the analyses were performed considering continuous hemoglobin levels as well as the dichotomous anemia variable (defined according to World Health Organization criteria as hemoglobin <12 g/dL in women and <13 g/dL in men). A peripheral quantitative computed tomography (pQCT) scan was performed in all participants to evaluate total, muscular, and fat cross-sectional areas of the calf and relative muscle density. Ankle extension strength was measured using a hand-held dynamometer. Linear regression analyses were used to assess the multivariate relationship of pQCT and skeletal muscle strength measures with hemoglobin levels and anemia after adjustment for demographics, chronic conditions, medication use, and other biological variables.
Participants were aged 74.8 +/- 6.8 years. In our sample, 94 participants (10.3%) were anemic. Hemoglobin levels were significantly associated with muscle density (beta = 0.225 [SE, standard error 0.098], p=.02), muscle area/total area ratio (beta=0.778 [SE 0.262], p=.003), fat area/total area ratio (beta=-0.869 [SE 0.225]; p<.001). Skeletal muscle strength and muscle density were highly associated with anemia (beta=-3.266 [SE 1.173], p=.005 and beta=-0.816 [SE 0.374], p=.03, respectively). Results did not change when analyses were rerun in a restricted sample of participants not affected by major medical conditions.
The present study shows that hemoglobin levels are associated with the parameters of body composition obtained by pQCT, and that decreases in muscular strength measures occur in the presence of anemia.
The Framingham Heart Study (FHS) was started in 1948 as a prospective investigation of cardiovascular disease in a cohort of adult men and women. Continuous surveillance of this sample of 5209 subjects has been maintained through biennial physical examinations. In 1971 examinations were begun on the children of the FHS cohort. This study, called the Framingham Offspring Study (FOS), was undertaken to expand upon knowledge of cardiovascular disease, particularly in the area of familial clustering of the disease and its risk factors. This report reviews the sampling design of the FHS and describes the nature of the FOS sample. The FOS families appear to be of typical size and age structure for families with parents born in the late 19th or early 20th century. In addition, there is little evidence that coronary heart disease (CHD) experience and CHO risk factors differ in parents of those who volunteered for this study and the parents ot those who did not volunteer.
The Framingham Heart Study (FHS) was started in 1948 as a prospective investigation of cardiovascular disease in a cohort of adult men and women. Continuous surveillance of this sample of 5209 subjects has been maintained through biennial physical examinations. In 1971 examinations were begun on the children of the FHS cohort. This study, called the Framingham Offspring Study (FOS), was undertaken to expand upon knowledge of cardiovascular disease, particularly in the area of familial clustering of the disease and its risk factors. This report reviews the sampling design of the FHS and describes the nature of the FOS sample. The FOS families appear to be of typical size and age structure for families with parents born in the late 19th or early 20th century. In addition, there is little evidence that coronary heart disease (CHD) experience and CHD risk factors differ in parents of those who volunteered for this study and the parents of those who did not volunteer.
Background:
Reduced muscular strength, as measured by grip strength, has been associated with an increased risk of all-cause and cardiovascular mortality. Grip strength is appealing as a simple, quick, and inexpensive means of stratifying an individual's risk of cardiovascular death. However, the prognostic value of grip strength with respect to the number and range of populations and confounders is unknown. The aim of this study was to assess the independent prognostic importance of grip strength measurement in socioculturally and economically diverse countries.
Methods:
The Prospective Urban-Rural Epidemiology (PURE) study is a large, longitudinal population study done in 17 countries of varying incomes and sociocultural settings. We enrolled an unbiased sample of households, which were eligible if at least one household member was aged 35-70 years and if household members intended to stay at that address for another 4 years. Participants were assessed for grip strength, measured using a Jamar dynamometer. During a median follow-up of 4.0 years (IQR 2.9-5.1), we assessed all-cause mortality, cardiovascular mortality, non-cardiovascular mortality, myocardial infarction, stroke, diabetes, cancer, pneumonia, hospital admission for pneumonia or chronic obstructive pulmonary disease (COPD), hospital admission for any respiratory disease (including COPD, asthma, tuberculosis, and pneumonia), injury due to fall, and fracture. Study outcomes were adjudicated using source documents by a local investigator, and a subset were adjudicated centrally.
Findings:
Between January, 2003, and December, 2009, a total of 142,861 participants were enrolled in the PURE study, of whom 139,691 with known vital status were included in the analysis. During a median follow-up of 4.0 years (IQR 2.9-5.1), 3379 (2%) of 139,691 participants died. After adjustment, the association between grip strength and each outcome, with the exceptions of cancer and hospital admission due to respiratory illness, was similar across country-income strata. Grip strength was inversely associated with all-cause mortality (hazard ratio per 5 kg reduction in grip strength 1.16, 95% CI 1.13-1.20; p<0.0001), cardiovascular mortality (1.17, 1.11-1.24; p<0.0001), non-cardiovascular mortality (1.17, 1.12-1.21; p<0.0001), myocardial infarction (1.07, 1.02-1.11; p=0.002), and stroke (1.09, 1.05-1.15; p<0.0001). Grip strength was a stronger predictor of all-cause and cardiovascular mortality than systolic blood pressure. We found no significant association between grip strength and incident diabetes, risk of hospital admission for pneumonia or COPD, injury from fall, or fracture. In high-income countries, the risk of cancer and grip strength were positively associated (0.916, 0.880-0.953; p<0.0001), but this association was not found in middle-income and low-income countries.
Interpretation:
This study suggests that measurement of grip strength is a simple, inexpensive risk-stratifying method for all-cause death, cardiovascular death, and cardiovascular disease. Further research is needed to identify determinants of muscular strength and to test whether improvement in strength reduces mortality and cardiovascular disease.
Funding:
Full funding sources listed at end of paper (see Acknowledgments).
Objective: we measured muscle strength and functional mobility in healthy men and women over the adult age range to investigate the changes with age and sex, and to establish the effects of the anthropometric indices height and weight. Design: cross-sectional study. Subjects and methods: we recruited 74 healthy women (mean age 49.0, range 20‐90) and 81 healthy men (mean age 51.6, range 20‐90). We measured maximum isometric knee extension strength, handgrip strength and explosive leg extensor power. We assessed functional mobility quantitatively with the timed ‘get up and go’ test and the modified Cooper test. Results: older subjects had lower values for muscle strength and muscle power than young subjects. Times for the timed ‘get up and go’ test were longer and distances in the modified Cooper test shorter. At about the age of 55, women showed an acceleration in the decline of isometric knee extension strength and handgrip strength (between 20 and 55 years, knee strength decreased by 10.3% and handgrip strength decreased by 8.2%, between 55 and 80 years the decreases were 40.2% and 28% respectively). Men showed a more gradual declines over the adult age range, with decreases in knee and handgrip strength of 24% and 19.6% between 20 and 55 years, and 23% and 17.4% between 55 and 80 years. The age-related decline is partly associated with differences in height and body weight. Women had higher correlations between muscle strength and functional mobility tests than men. Conclusions: muscle strength and functional mobility decline with age in healthy people; in women we observed an accelerated decrement in muscle strength above the age of 55. Lower values in healthy old subjects are partly associated with differences in height and body weight.
In mouse models, CCAAT enhancer-binding protein beta (CEBPB) is necessary for M2 macrophage-mediated regeneration after muscle injury. In humans, CEBPB expression in blood was strongly associated with muscle strength. In this study we aimed to test whether CEBPB expression in blood in people is increased 2 days after exercise designed to induce muscle damage and subsequent repair. Sixteen healthy male volunteers undertook elbow flexor exercises designed to induce acute muscle micro-damage. Peripheral blood samples were collected at baseline and days 1, 2, 4 and 7 following exercise. Expression of CEBPB and related genes were analysed by qRT-PCR. Extent of muscle damage was determined by decline in maximal voluntary isometric torque and by plasma creatine kinase activity. Nine subjects had peak (day 4) creatine kinase activity exceeding 10,000 U/l. In this subgroup, CEBPB expression was elevated from baseline to 2 days post exercise (paired-samples t(1,8) = 3.72, p = 0.006). Related expression and selected cytokine changes after exercise did not reach significance. Muscle-damaging exercise in humans can be followed by induction of CEBPB transcript expression in peripheral blood. Associations between CEBPB expression in blood and muscle strength may be consistent with the CEBPB-dependent muscle repair process.
Electronic supplementary material
The online version of this article (doi:10.1007/s12576-014-0350-7) contains supplementary material, which is available to authorized users.
Introduction:
Both grip and knee extension strength are often used to characterize overall limb muscle strength. We sought to determine if the measures actually reflect a common construct.
Methods:
The isometric grip and knee extension strength of 164 healthy men and women (range, 18-85 years) were measured bilaterally using standard procedures. Pearson correlations (r), Cronbach alpha, principal components analysis, and multiple regression/correlation were used to investigate the dimensionality of the measures.
Results:
Left and right grip forces and knee extension torques were highly correlated, internally consistent, and loaded on a single component. Gender and age explained the variance in both measures, but height added to the explanation of grip strength, whereas weight added to the explanation of knee extension strength.
Conclusions:
Among healthy adults, grip and knee extension strength reflect a common underlying construct. The measures, however, are affected differently by height and weight.
Although the therapeutic potential of mesenchymal stem cells (MSC) is widely accepted, loss of cell function due to donor aging or culture senescence are major limiting factors hampering their clinical application. Our laboratory recently showed that MSC originating from older donors suffer from limited proliferative capacity and significantly reduced myogenic differentiation potential. This is a major concern, as the patients most likely to suffer from cardiovascular disease are elderly. Here we tested the hypothesis that a single pluripotency associated transcription factor, namely Nanog, may reverse the proliferation and differentiation potential of BM-MSC from adult donors. Microarray analysis showed that adult (a)BM-MSC expressing Nanog clustered close to Nanog-expressing neonatal cells. Nanog markedly upregulated genes involved in cell cycle, DNA replication and DNA damage repair and enhanced the proliferation rate and clonogenic capacity of aBM-MSC. Notably, Nanog reversed the myogenic differentiation potential and restored the contractile function of aBM-MSC to a similar level as that of neonatal (n)BM-MSC. The effect of Nanog on contractility was mediated -- at least in part - through activation of the TGF-β pathway by diffusible factors secreted in the conditioned medium of Nanog-expressing BM-MSC. Overall, our results suggest that Nanog may be used to overcome the effects of organismal aging on aBM-MSC, thereby increasing the potential of MSC from aged donors for cellular therapy and tissue regeneration.
The formation of skeletal muscle is a tightly regulated process that is critically modulated by Wnt signaling. Myogenesis is dependent on the precise and dynamic integration of multiple Wnt signals allowing self-renewal and progression of muscle precursors in the myogenic lineage. Dysregulation of Wnt signaling can lead to severe developmental defects and perturbation of muscle homeostasis. Recent work has revealed novel roles for the non-canonical planar cell polarity (PCP) and AKT/mTOR pathways in mediating the effects of Wnt on skeletal muscle. In this review, we discuss the role of Wnt signaling in myogenesis and in regulating the homeostasis of adult muscle.
Declining muscle strength is a core feature of aging. Several mechanisms have been postulated, including CCAAT/enhancer-binding protein-beta (C/EBP-β)-triggered macrophage-mediated muscle fiber regeneration after micro-injury, evidenced in a mouse model. We aimed to identify in vivo circulating leukocyte gene expression changes associated with muscle strength in the human adult population. We undertook a genome-wide expression microarray screen, using peripheral blood RNA samples from InCHIANTI study participants (aged 30 and 104). Logged expression intensities were regressed with muscle strength using models adjusted for multiple confounders. Key results were validated by real-time PCR. The Short Physical Performance Battery (SPPB) score tested walk speed, chair stand, and balance. CEBPB expression levels were associated with muscle strength (β coefficient = 0.20560, P = 1.03*10(-6), false discovery rate q = 0.014). The estimated handgrip strength in 70-year-old men in the lowest CEBPB expression tertile was 35.2 kg compared with 41.2 kg in the top tertile. CEBPB expression was also associated with hip, knee, ankle, and shoulder strength and the SPPB score (P = 0.018). Near-study-wide associations were also noted for TGF-β3 (P = 3.4*10(-5) , q = 0.12) and CEBPD expression (P = 9.7*10(-5) , q = 0.18) but not for CEBPA expression. We report here a novel finding that raised CEBPB expression in circulating leukocyte-derived RNA samples in vivo is associated with greater muscle strength and better physical performance in humans. This association may be consistent with mouse model evidence of CEBPB-triggered muscle repair: if this mechanism is confirmed, it may provide a target for intervention to protect and enhance aging muscle.
Aging is a major risk factor for chronic disease in the human population, but there are little human data on gene expression alterations that accompany the process. We examined human peripheral blood leukocyte in-vivo RNA in a large-scale transcriptomic microarray study (subjects aged 30-104 years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n= 58), following-up findings in a replication set (n=240). We confirmed expression of key results by real-time PCR. Of 16,571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (area under the curve in replication set; 95%). The focused nature of age-related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways were age-associated, in gene set enrichment analysis, notably including the processing of messenger RNAs (mRNAs); [P<0.002, false discovery rate (FDR) q<0.05]. This is supported by our observation of age-associated disruption to the balance of alternatively expressed isoforms for selected genes, suggesting that modification of mRNA processing may be a feature of human aging.
Heme serves as a co-factor in proteins involved in fundamental biological processes including oxidative metabolism, oxygen storage and transport, signal transduction and drug metabolism. In addition, heme is important for systemic iron homeostasis in mammals. Heme has important regulatory roles in cell biology, yet excessive levels of intracellular heme are toxic; thus, mechanisms have evolved to control the acquisition, synthesis, catabolism and expulsion of cellular heme. Recently, a number of transporters of heme and heme synthesis intermediates have been described. Here we review aspects of heme metabolism and discuss our current understanding of heme transporters, with emphasis on the function of the cell-surface heme exporter, FLVCR. Knockdown of Flvcr in mice leads to both defective erythropoiesis and disturbed systemic iron homeostasis, underscoring the critical role of heme transporters in mammalian physiology. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
Myostatin is a TGF-β family member that normally acts to limit skeletal muscle mass. Follistatin is a myostatin-binding protein that can inhibit myostatin activity in vitro and promote muscle growth in vivo. Mice homozygous for a mutation in the Fst gene have been shown to die immediately after birth but have a reduced amount of muscle tissue, consistent with a role for follistatin in regulating myogenesis. Here, we show that Fst mutant mice exhibit haploinsufficiency, with muscles of Fst heterozygotes having significantly reduced size, a shift toward more oxidative fiber types, an impairment of muscle remodeling in response to cardiotoxin-induced injury, and a reduction in tetanic force production yet a maintenance of specific force. We show that the effect of heterozygous loss of Fst is at least partially retained in a Mstn-null background, implying that follistatin normally acts to inhibit other TGF-β family members in addition to myostatin to regulate muscle size. Finally, we present genetic evidence suggesting that activin A may be one of the ligands that is regulated by follistatin and that functions with myostatin to limit muscle mass. These findings potentially have important implications with respect to the development of therapeutics targeting this signaling pathway to preserve muscle mass and prevent muscle atrophy in a variety of inherited and acquired forms of muscle degeneration.
Background:
The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods- The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci.
Conclusions:
The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.
The Netherlands Study of Depression and Anxiety (NESDA) is a multi-site naturalistic cohort study to: (1) describe the long-term course and consequences of depressive and anxiety disorders, and (2) to integrate biological and psychosocial research paradigms within an epidemiological approach in order to examine (interaction between) predictors of the long-term course and consequences.
Its design is an eight-year longitudinal cohort study among 2981 participants aged 18 through 65 years. The sample consists of 1701 persons with a current (six-month recency) diagnosis of depression and/or anxiety disorder, 907 persons with life-time diagnoses or at risk because of a family history or subthreshold depressive or anxiety symptoms, and 373 healthy controls. Recruitment took place in the general population, in general practices (through a three-stage screening procedure), and in mental health organizations in order to recruit persons reflecting various settings and developmental stages of psychopathology. During a four-hour baseline assessment including written questionnaires, interviews, a medical examination, a cognitive computer task and collection of blood and saliva samples, extensive information was gathered about key (mental) health outcomes and demographic, psychosocial, clinical, biological and genetic determinants. Detailed assessments will be repeated after one, two, four and eight years of follow-up.
The findings of NESDA are expected to provide more detailed insight into (predictors of) the long-term course of depressive and anxiety disorders in adults. Besides its scientific relevance, this may contribute to more effective prevention and treatment of depressive and anxiety disorders. Copyright
The Framingham Heart Study (FHS) was started in 1948 as a prospective investigation of cardiovascular disease in a cohort of adult men and women. Continuous surveillance of this sample of 5209 subjects has been maintained through biennial physical examinations. In 1971 examinations were begun on the children of the FHS cohort. This study, called the Framingham Offspring Study (FOS), was undertaken to expand upon knowledge of cardiovascular disease, particularly in the area of familial clustering of the disease and its risk factors. This report reviews the sampling design of the FHS and describes the nature of the FOS sample. The FOS families appear to be of typical size and age structure for families with parents born in the late 19th or early 20th century. In addition, there is little evidence that coronary heart disease (CHD) experience and CHD risk factors differ in parents of those who volunteered for this study and the parents of those who did not volunteer.
As compared with age-matched controls, extensor digitorum longus (EDL) muscles autografted in young rats regenerated significantly greater mass (1.8 times) and developed greater maximum contractile force (2.6 times) than EDL muscles autografted in old rats. A cross-age transplantation study showed that the mass and maximum force of old muscles grafted into young hosts were not significantly different from those of young muscles grafted into the same young hosts. Conversely, young muscle grafted into old hosts regenerated no better than old muscles grafted into the same old hosts. We conclude 1) that chronological age alone is not a factor that limits the intrinsic ability of a muscle to regenerate and 2) that the poor regeneration of muscles in old animals is a function of the environment for regeneration provided by the old host.
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we measured muscle strength and functional mobility in healthy men and women over the adult age range to investigate the changes with age and sex, and to establish the effects of the anthropometric indices height and weight.
cross-sectional study. SUBJECTS and methods: we recruited 74 healthy women (mean age 49.0, range 20-90) and 81 healthy men (mean age 51.6, range 20-90). We measured maximum isometric knee extension strength, handgrip strength and explosive leg extensor power. We assessed functional mobility quantitatively with the timed 'get up and go' test and the modified Cooper test.
older subjects had lower values for muscle strength and muscle power than young subjects. Times for the timed 'get up and go' test were longer and distances in the modified Cooper test shorter. At about the age of 55, women showed an acceleration in the decline of isometric knee extension strength and handgrip strength (between 20 and 55 years, knee strength decreased by 10.3% and handgrip strength decreased by 8.2%, between 55 and 80 years the decreases were 40.2% and 28% respectively). Men showed a more gradual declines over the adult age range, with decreases in knee and handgrip strength of 24% and 19.6% between 20 and 55 years, and 23% and 17.4% between 55 and 80 years. The age-related decline is partly associated with differences in height and body weight. Women had higher correlations between muscle strength and functional mobility tests than men.
muscle strength and functional mobility decline with age in healthy people; in women we observed an accelerated decrement in muscle strength above the age of 55. Lower values in healthy old subjects are partly associated with differences in height and body weight.
Older patients are often referred to geriatricians because of complaints of progressive difficulties in walking. The diagnostic and therapeutic approach to these patients is complex. Multiple physiologic subsystems may influence the ability to walk, and no standard criteria are currently available to establish whether these subsystems are functioning within the normal range. To address this lack of knowledge we conducted the InCHIANTI study.
To identify measures that clinicians can use to understand the causes of walking difficulties in older persons.
A population-based study of persons living in the Chianti geographic area (Tuscany, Italy).
1,453 persons (age-range 20-102 years; 91.6% of the eligible) selected from city registry of Greve in Chianti and Bagno a Ripoli (Tuscany, Italy), using a multistage sampling method.
Factors that influence walking ability were classified into six main physiologic subsystems: central nervous system, perceptual system, peripheral nervous system, muscles, bone/joints, and energy production/delivery. Measures of the integrity and functioning of each of these proposed subsystems were identified and administered to all participants.
Data collected in InCHIANTI will be used to identify the main risk factors that influence loss of the ability to walk in older persons, to define physiologic subsystems that are critical for walking, to select the best measures of their integrity, and to establish critical ranges in these measures that are compatible with "normal" walking ability. The final goal is to translate epidemiological research into a geriatric clinical tool that makes possible more precise diagnosis and more effective treatment in patients with walking dysfunction.
The aims of this review are to address (1) the role of muscle strength in the disablement process and (2) muscle strength as a predictor of length of life using data from prospective studies. Functional limitations, such as slow walking speed, predispose older people to disabilities. How much strength is needed for daily motor tasks such as walking varies according to other impairments present. For example, when postural balance is good, only minimum amount of strength is needed for walking. However, in the presence of balance impairment, having good level of strength may help to compensate for the deficit. Having strength well above the required level indicates reserve capacity. It was studied using data from the Honolulu Heart Program launched in 1965 among 8006 men initially aged 45-68 years, whether reserve of strength would be protective of development of future disability. All men with documented diseases at baseline were excluded from the analyses. Those men who were in the lowest third of the distribution of grip strength at baseline were at two to three times greater risk of developing disabilities assessed 25 years later compared to the highest third. It is possible that before they reach the disability level, those with greater reserve of strength may afford to lose more strength, for example following bed rest and inactivity associated with an illness. Midlife grip strength was also found to predict long-term total mortality: those with poorer strength at baseline were more likely to die over the follow-up period of 30 years. The association between muscle strength and disability is largely explained by biomechanical mechanisms. However, the mechanism explaining the association between muscle strength and mortality risk still remains to be explored.
The minichromosome maintenance (MCM) 2-7 helicase complex functions to initiate and elongate replication forks. Cell cycle checkpoint signaling pathways regulate DNA replication to maintain genomic stability. We describe four lines of evidence that ATM/ATR-dependent (ataxia-telangiectasia-mutated/ATM- and Rad3-related) checkpoint pathways are directly linked to three members of the MCM complex. First, ATM phosphorylates MCM3 on S535 in response to ionizing radiation. Second, ATR phosphorylates MCM2 on S108 in response to multiple forms of DNA damage and stalling of replication forks. Third, ATR-interacting protein (ATRIP)-ATR interacts with MCM7. Fourth, reducing the amount of MCM7 in cells disrupts checkpoint signaling and causes an intra-S-phase checkpoint defect. Thus, the MCM complex is a platform for multiple DNA damage-dependent regulatory signals that control DNA replication.