Article

Gene transcripts associated with muscle strength: A CHARGE meta-analysis of 7,781 persons

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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.

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... 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. ...
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... 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. ...
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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]. ...
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... 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. ...
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... 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]. ...
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... 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. ...
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... 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]. ...
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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.
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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.
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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.
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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).
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
Article
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
Article
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.
Article
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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Article
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.
Article
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.
Article
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.
Article
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.