Contribution of Heritability and Epigenetic Factors to Skeletal Muscle Mass Variation in United Kingdom Twins

Abstract Context: Skeletal muscle mass (SMM) is one of the major components of human body composition, with deviations from normal values often leading to sarcopenia. Objective: Our major aim was to conduct a genome-wide DNA methylation study in an attempt to identify potential genomic regions associated with SMM. Design: This was a mixed cross-sectional and longitudinal study. Setting: Community-based study. Participants: A total of 1550 middle-aged United Kingdom twins (monozygotic [MZ] and dizygotic [DZ]), 297 of which were repeatedly measured participated in the study. Main Outcome Measure: Appendicular lean mass assessed using dual-energy X-ray absorptiometry technology, and methylated DNA immunoprecipitation sequencing DNA methylation profiling genome-wide were obtained from each individual. Results: Heritability estimate of SMM, with simultaneous adjustment for covariates obtained using variance decomposition analysis, was h2 = 0.809 ± 0.050. After quality control and analysis of longitudinal stability, the DNA methylation data comprised of 723 029 genomic sites, with positive correlations between repeated measurements (Rrepeated = 0.114–0.905). Correlations between MZ and DZ twins were 0.51 and 0.38 at a genome-wide average, respectively, and clearly increased with Rrepeated. Testing for DNA methylation association with SMM in 50 discordant MZ twins revealed 36 081 nominally significant results, of which the top-ranked 134 signals (P < .01 and Rrepeated > 0.40) were subjected to replication in the sample of 1196 individuals. Seven SMM methylation association signals replicated at a false discovery rate less than 0.1, and these were located in or near genes DNAH12, CAND1, CYP4F29P, and ZFP64, which have previously been highlighted in muscle-related studies. Adjusting for age, smoking, and blood cell heterogeneity did not alter significance of these associations. Conclusion: This epigenome-wide study, testing longitudinally stable methylation sites, discovered and replicated a number of associations between DNA methylation at CpG loci and SMM. Four replicated signals were related to genes with potential muscle functions, suggesting that the methylome of whole blood may be informative of SMM variation.

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Variants in NEB and RIF1 genes on chr2q23 are associated with skeletal muscle index in Koreans: genome-wide association study

Scientific Reports ◽

10.1038/s41598-021-82003-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kyung Jae Yoon ◽

Youbin Yi ◽

Jong Geol Do ◽

Hyung-Lae Kim ◽

Yong-Taek Lee ◽

...

Keyword(s):

Skeletal Muscle ◽

Association Study ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Genome Wide Association Study ◽

Genetic Locus ◽

Genome Wide Association ◽

Skeletal Muscle Index ◽

Genome Wide ◽

A Genome

AbstractAlthough skeletal muscle plays a crucial role in metabolism and influences aging and chronic diseases, little is known about the genetic variations with skeletal muscle, especially in the Asian population. We performed a genome-wide association study in 2,046 participants drawn from a population-based study. Appendicular skeletal muscle mass was estimated based on appendicular lean soft tissue measured with a multi-frequency bioelectrical impedance analyzer and divided by height squared to derive the skeletal muscle index (SMI). After conducting quality control and imputing the genotypes, we analyzed 6,391,983 autosomal SNPs. A genome-wide significant association was found for the intronic variant rs138684936 in the NEB and RIF1 genes (β = 0.217, p = 6.83 × 10–9). These two genes are next to each other and are partially overlapped on chr2q23. We conducted extensive functional annotations to gain insight into the directional biological implication of significant genetic variants. A gene-based analysis identified the significant TNFSF9 gene and confirmed the suggestive association of the NEB gene. Pathway analyses showed the significant association of regulation of multicellular organism growth gene-set and the suggestive associations of pathways related to skeletal system development or skeleton morphogenesis with SMI. In conclusion, we identified a new genetic locus on chromosome 2 for SMI with genome-wide significance. These results enhance the biological understanding of skeletal muscle mass and provide specific leads for functional experiments.

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Body composition and energy intake — skeletal muscle mass is the strongest predictor of food intake in obese adolescents: The HEARTY trial

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2015-0479 ◽

2016 ◽

Vol 41 (6) ◽

pp. 611-617 ◽

Cited By ~ 37

Author(s):

Jameason D. Cameron ◽

Ronald J. Sigal ◽

Glen P. Kenny ◽

Angela S. Alberga ◽

Denis Prud’homme ◽

...

Keyword(s):

Skeletal Muscle ◽

Body Composition ◽

Body Weight ◽

Muscle Mass ◽

Energy Intake ◽

Skeletal Muscle Mass ◽

Fat Free Mass ◽

Cross Sectional ◽

Percentage Body Fat ◽

Obese Adolescents

There has been renewed interest in examining the relationship between specific components of energy expenditure and the overall influence on energy intake (EI). The purpose of this cross-sectional analysis was to determine the strongest metabolic and anthropometric predictors of EI. It was hypothesized that resting metabolic rate (RMR) and skeletal muscle mass would be the strongest predictors of EI in a sample of overweight and obese adolescents. 304 post-pubertal adolescents (91 boys, 213 girls) aged 16.1 (±1.4) years with body mass index at or above the 95th percentile for age and sex OR at or above the 85th percentile plus an additional diabetes risk factor were measured for body weight, RMR (kcal/day) by indirect calorimetry, body composition by magnetic resonance imaging (fat free mass (FFM), skeletal muscle mass, fat mass (FM), and percentage body fat), and EI (kcal/day) using 3 day food records. Body weight, RMR, FFM, skeletal muscle mass, and FM were all significantly correlated with EI (p < 0.005). After adjusting the model for age, sex, height, and physical activity, only FFM (β = 21.9, p = 0.007) and skeletal muscle mass (β = 25.8, p = 0.02) remained as significant predictors of EI. FFM and skeletal muscle mass also predicted dietary protein and fat intake (p < 0.05), but not carbohydrate intake. In conclusion, with skeletal muscle mass being the best predictor of EI, our results support the hypothesis that the magnitude of the body’s lean tissue is related to absolute levels of EI in a sample of inactive adolescents with obesity.

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Cutoff values for appendicular skeletal muscle mass and strength in relation to fear of falling among Brazilian older adults: cross-sectional study

Sao Paulo Medical Journal ◽

10.1590/1516-3180.2017.0049030517 ◽

2017 ◽

Vol 135 (5) ◽

pp. 434-443 ◽

Cited By ~ 5

Author(s):

Ricardo Aurélio Carvalho Sampaio ◽

Priscila Yukari Sewo Sampaio ◽

Luz Albany Arcila Castaño ◽

João Francisco Barbieri ◽

Hélio José Coelho Júnior ◽

...

Keyword(s):

Older Adults ◽

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Fear Of Falling ◽

Cross Sectional Study ◽

Sectional Study ◽

Cross Sectional ◽

Appendicular Skeletal Muscle ◽

Appendicular Skeletal Muscle Mass

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Relation of serum 25-hydroxyvitamin D status with skeletal muscle mass by sex and age group among Korean adults

British Journal Of Nutrition ◽

10.1017/s0007114515003633 ◽

2015 ◽

Vol 114 (11) ◽

pp. 1838-1844 ◽

Cited By ~ 9

Author(s):

Min Jung Ko ◽

Sungha Yun ◽

Kyungwon Oh ◽

Kirang Kim

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Age Groups ◽

Mean Value ◽

High Serum ◽

Cross Sectional ◽

Mean Values ◽

Hydroxyvitamin D ◽

25 Hydroxyvitamin D

AbstractThe objective of this study was to examine whether high serum 25-hydroxyvitamin D (25(OH)D) concentration was associated with high skeletal muscle mass, taking into account the effects of sex and age among the participants of the Korea National Health and Nutrition Examination Survey (KNHANES) aged 40 years or older. This was a cross-sectional study using data from the 2009 to 2010 KNHANES; a total of 8406 subjects (3671 men and 4735 women) were included. The appendicular skeletal muscle mass index (ASMMI, kg/m2) was estimated to measure the skeletal muscle mass. Hypovitaminosis was classified when the level of serum 25(OH)D was <20 ng/ml. The general linear model adjusted for confounding factors was used to determine differences in means of ASMMI by 25(OH)D status. The mean values of ASMMI were higher for men when compared with women. Women had a greater proportion of hypovitaminosis (71·1 %) compared with men (53·2 %). After adjusting for multiple factors, men were seen to have significant differences in ASMMI based on 25(OH)D status regardless of age, showing a lower mean value of ASSMI in those with hypovitaminosis. However, there was no difference in ASMMI by 25(OH)D status among women in both younger and older age groups. In conclusion, we found that there might be a positive relationship between 25(OH)D and skeletal muscle mass in men, indicating that interventions to improve 25(OH)D levels that are aimed at increasing muscle mass could be beneficial for men with more rapid decreased rate of skeletal muscle mass.

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Alternate Mediterranean diet score is positively associated with skeletal muscle mass index in middle-aged adults

British Journal Of Nutrition ◽

10.1017/s0007114517001118 ◽

2017 ◽

Vol 117 (8) ◽

pp. 1181-1188 ◽

Cited By ~ 9

Author(s):

Hui-yuan Tian ◽

Rui Qiu ◽

Li-peng Jing ◽

Zhan-yong Chen ◽

Geng-dong Chen ◽

...

Keyword(s):

Skeletal Muscle ◽

Mediterranean Diet ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

General Information ◽

Whole Body ◽

Cross Sectional ◽

Mediterranean Diet Score ◽

Skeletal Muscle Mass Index ◽

Diet Score

AbstractResearches have suggested Mediterranean diet might lower the risk of chronic diseases, but data on skeletal muscle mass (SMM) are limited. This community-based cross-sectional study examined the association between the alternate Mediterranean diet score (aMDS) and SMM in 2230 females and 1059 males aged 40–75 years in Guangzhou, China. General information and habitual dietary information were assessed in face-to-face interviews conducted during 2008–2010 and 3 years later. The aMDS was calculated by summing the dichotomous points for the items of higher intakes of whole grain, vegetables, fruits, legumes, nuts, fish and ratio of MUFA:SFA, lower red meat and moderate ethanol consumption. The SMM of the whole body, limbs, arms and legs were measured using dual-energy X-ray absorptiometry during 2011–2013. After adjusting for potential covariates, higher aMDS was positively associated with skeletal muscle mass index (SMI, SMM/height2, kg/m2) at all of the studied sites in males (all Ptrend<0·05). The multiple covariate-adjusted SMI means were 2·70 % (whole body), 2·65 % (limbs), 2·50 % (arms) and 2·70 % (legs) higher in the high (v. low) category aMDS in males (all P<0·05). In females, the corresponding values were 1·35 % (Ptrend=0·03), 1·05, 0·52 and 1·20 %, (Ptrend>0·05). Age-stratified analyses showed that the favourable associations tended to be more pronounced in the younger subjects aged less than the medians of 59·2 and 62·2 years in females and males (Pinteraction>0·10). In conclusion, the aMDS shows protective associations with SMM in Chinese adults, particularly in male and younger subjects.

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Prevalence of Sarcopenia and Association with Lifestyle Patterns in Patients with Type 2 Diabetes Mellitus (P01-025-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz028.p01-025-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Tatiana de Paula ◽

Mauren de Freitas ◽

Vanessa Lopes ◽

Maria Elisa Miller ◽

Karen Araujo ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Meta Analysis ◽

Cross Sectional Study ◽

Cross Sectional ◽

Logistic Regression Models ◽

Type 2 Dm

Abstract Objectives The aim of the study was to establish the prevalence of sarcopenia and associated factors in elderly with type 2 diabetes (DM) in southern Brazil. Methods A cross-sectional study was performed in 240 patients with type 2 DM. The diagnosis of sarcopenia was performed according to EWGSOP criteria. Muscle mass was calculated by skeletal muscle mass index (appendicular skeletal muscle mass/height² - Inbody® bioimpendance). Muscle strength was assessed by manual grip strength (Jamar® dynamometer) and physical performance was assessed by the sit and lift test. Patients with type 2 DM with age ≥60 years and with the ability to ambulate were selected. Patients with recent cardiovascular events, serum creatinine >2.0 mg/dl, use of corticosteroids and BMI >40 kg/m² were excluded. The sample size was 240 patients based on meta-analysis who found 17% sarcopenia in elderly patients without DM. Results We included 240 patients aged 68.4 ± 5.5 years, 53.2% were women and the duration of DM was 15 (8–22) years, the BMI was 29.4 ± 4.4 kg/m². The prevalence of sarcopenia was 21% and men had more sarcopenia (75%). Patients with sarcopenia walk less [3541 (2227–4574) vs. 4521 (3037–5678) steps, P = 0.013], drink more alcohol [21 (56.8%) vs. 71 (31.8%); P < 0.034] and have lower total cholesterol levels [146 ± 41 Vs. 168 ± 43; P = 0.007] than the group without sarcopenia. In multivariate logistic regression models, walking < 3760 steps [OR = 2868; CI 95% 1.331–6.181] and male [OR = 5285; CI 95% 2261–12,350], were associated with sarcopenia. Conclusions The prevalence of sarcopenia was 21%, higher than in patients without diabetes (17%). In this group of patients, lower physical activity, and male sex were associated with sarcopenia. Funding Sources FIPE n. 160467; CAPES.

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Reference Values for Skeletal Muscle Mass – Current Concepts and Methodological Considerations

Nutrients ◽

10.3390/nu12030755 ◽

2020 ◽

Vol 12 (3) ◽

pp. 755 ◽

Cited By ~ 6

Author(s):

Carina O. Walowski ◽

Wiebke Braun ◽

Michael J. Maisch ◽

Björn Jensen ◽

Sven Peine ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Reference Values ◽

Skeletal Muscle Mass ◽

Bioelectrical Impedance ◽

Reference Population ◽

Muscle Quality ◽

Whole Body ◽

Whole Body Imaging ◽

Cross Sectional

Assessment of a low skeletal muscle mass (SM) is important for diagnosis of ageing and disease-associated sarcopenia and is hindered by heterogeneous methods and terminologies that lead to differences in diagnostic criteria among studies and even among consensus definitions. The aim of this review was to analyze and summarize previously published cut-offs for SM applied in clinical and research settings and to facilitate comparison of results between studies. Multiple published reference values for discrepant parameters of SM were identified from 64 studies and the underlying methodological assumptions and limitations are compared including different concepts for normalization of SM for body size and fat mass (FM). Single computed tomography or magnetic resonance imaging images and appendicular lean soft tissue by dual X-ray absorptiometry (DXA) or bioelectrical impedance analysis (BIA) are taken as a valid substitute of total SM because they show a high correlation with results from whole body imaging in cross-sectional and longitudinal analyses. However, the random error of these methods limits the applicability of these substitutes in the assessment of individual cases and together with the systematic error limits the accurate detection of changes in SM. Adverse effects of obesity on muscle quality and function may lead to an underestimation of sarcopenia in obesity and may justify normalization of SM for FM. In conclusion, results for SM can only be compared with reference values using the same method, BIA- or DXA-device and an appropriate reference population. Limitations of proxies for total SM as well as normalization of SM for FM are important content-related issues that need to be considered in longitudinal studies, populations with obesity or older subjects.

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Effects of 6 months of abiraterone acetate (AA) on muscle and adipose mass in men with metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.222 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 222-222 ◽

Cited By ~ 1

Author(s):

Samuel Craig Brondfield ◽

Vivian K. Weinberg ◽

Kathryn M. Koepfgen ◽

Arturo Molina ◽

Charles J. Ryan ◽

...

Keyword(s):

Prostate Cancer ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Wasting ◽

Cross Sectional Area ◽

Sectional Area ◽

Cross Sectional ◽

Adipose Mass

222 Background: AA, an inhibitor of androgen biosynthesis, has been shown to prolong overall survival in patients with mCRPC who have previously been treated with chemotherapy. Androgen deprivation therapy (ADT) has been shown to result in muscle wasting in prostate cancer pts. The effects of AA on progression of muscle and fat wasting have not been characterized. We evaluated whether 6 months of AA therapy altered total skeletal muscle mass or adipose mass. Methods: 10 sequential pts who responded to AA therapy for at least 6 months and had available computed tomography (CT) scans were retrospectively selected from the phase I-II COU-AA-002 study. CT image analysis was used to quantify change from baseline in total skeletal muscle and adipose tissue after 6 months of AA treatment. Skeletal muscle and adipose tissue cross-sectional area were calculated at the L3 level using Slice-O-Matic software V4.3. Previously published regression models were used to estimate fat-free mass, fat mass and skeletal muscle mass. Paired t-tests were performed to determine the change in measurements. Results: At baseline, 7 of 10 pts were overweight or obese (body mass index [BMI] > 25 kg/m2), and none were underweight. Advanced muscle wasting (sarcopenia, previously defined as the ratio of skeletal muscle cross-sectional area at L3 level to height < 52.4 cm2/m2) was present at baseline and 6 months in 9 of 10 pts. Over 6 months of AA treatment, pts lost an average of 1.9 kg ± 1.9 kg (p = 0.13). Mean changes (kg) (±standard deviation) in total skeletal muscle mass (−0.80 ± 1.71, p = 0.18) and total non-adipose mass (−1.44 ± 3.09, p = 0.17) were not significant. A significant decrease in total adipose mass (−0.61 ± 0.84, p = 0.048) was observed. Conclusions: Sarcopenia is prevalent in pts with mCRPC. AA was not related to significantly worsening sarcopenia or overall weight loss during the first 6 months of treatment; however, this may reflect a relatively short duration of therapy and/or small sample size. A significant loss of adipose tissue was observed, which is unexpected given the known effects of ADT, which increases adipose mass. Evaluation of additional AA treated patients is ongoing.

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Body composition as a predictor of sunitinib toxicity in patients with renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e15566 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e15566-e15566

Author(s):

Samantha Cushen ◽

Aoife M Ryan ◽

MinYuen Teo ◽

Peter MacEneaney ◽

Patrick McLaughlin ◽

...

Keyword(s):

Skeletal Muscle ◽

Body Composition ◽

Muscle Mass ◽

Renal Cell ◽

Skeletal Muscle Mass ◽

Cell Cancer ◽

Drug Dose ◽

Fat Free Mass ◽

Cross Sectional ◽

Overweight Group

e15566 Background: Sunitinib is a standard first-line option for metastatic renal cell cancer (mRCC). Identification of biomarkers associated with outcome or toxicity is a challenge. Body composition is a prognostic factor in cancer and sarcopenia is associated with treatment toxicity and survival. We investigated if body composition by CT scan predicted dose limiting toxicity (DLT) from sunitinib in mRCC. Methods: Patients (pts) with mRCC receiving sunitinib 50mg as 1stline therapy between 2007-2012 were included. Ethical approval was obtained and prospectively maintained databases analysed. Skeletal muscle cross-sectional area at L3 was measured by CT. Sarcopenia was defined using published cut offs. Toxicity was assessed after 4 cycles of drug (CTCAE, v4.0). Results: 55 pts (43 male), mean age 64yrs (±10.6) were included. 67% were overweight/obese (BMI>25kg/m2). Sarcopenia was present in 33% (56% of normal BMI, 44% overweight group). Overall 40 pts (73%) experienced DLT (51% M, 100% F, p<0.016). DLT occurred in <6 months in 53% (44% M vs 83% F, p<0.016) and these pts were older (mean 68 yrs vs 60 yrs, p<0.01), had lower skeletal muscle mass (51.8 cm2/m2 vs 59.4 cm2/m2, p<0.012), and fat free mass (FFM) (51.4kg vs 57.7kg, p<0.03), and received higher drug dose in mg/kg FFM (1.01 vs 0.89, p<0.02). Common toxicities were GI (65%) and fatigue (47%). Of pts <25th percentile skeletal muscle mass 92% experienced DLT, higher than pts >75th percentile (p<0.05). Pts <25th percentile had an average of 5 toxicities vs 2 in those >75th percentile (p<0.003). All toxicities were more common in muscle wasted patients (p<0.05). 77% (n=10) of pts receiving a drug dose >75th percentile (1.105mg/FFM) experienced DLT in <6 months vs 44% (n=17) receiving a dose <75thpercentile (<1.099mg/FFM; p<0.037). Conclusions: Sarcopenia is prevalent in patients with mRCC, is easily measured, is an occult condition in pts with normal/high BMI, and is a significant predictor of DLT in pts receiving 1st line sunitinib. Our results highlight the potential use of baseline body composition to predict toxicity. The role of sarcopenia in targeted therapy is evolving and its potential to predict toxicity should be further studied.

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