Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

Jones, Garan; Trajanoska, Katerina; Santanasto, Adam J; Stringa, Najada; Kuo, Chia Ling; Atkins, Janice L.; Lewis, Joshua R.; Duong, ThuyVy; Hong, Shengjun; Biggs, Mary L.; Luan, Jian’an; Sarnowski, Chloé; Lunetta, Kathryn L.; Tanaka, Toshiko; Wojczynski, Mary K.; Cvejkus, Ryan; Nethander, Maria; Ghasemi, Sahar; Yang, Jingyun; Zillikens, M. Carola; Walter, Stefan; Sicinski, Kamil; Kague, Érika; Ackert‐Bicknell, Cheryl; Arking, Dan E.; Windham, B. Gwen; Boerwinkle, Eric; Grove, Megan L.; Graff, Misa; Spira, Dominik; Demuth, Ilja; Velde, Nathalie van der; Groot, Lisette C. P. G. M. de; Psaty, Bruce M.; Odden, Michelle C.; Fohner, Alison E.; Langenberg, Claudia; Wareham, Nicholas J.; Bandinelli, Stefania; Schoor, Natasja M. van; Huisman, Martijn; Tan, Qihua; Zmuda, Joseph M.; Mellström, Dan; Karlsson, Magnus K.; Bennett, David A.; Buchman, Aron S.; Jager, Philip L. De; Uitterlinden, André G.; Völker, Uwe; Kocher, Thomas; Teumer, Alexander; Rodríguez‐Mañas, Leocadio; Garcı́a, Francisco; Carnicero, José Antonio Carranza; Herd, Pamela; Bertram, Lars; Ohlsson, Claes; Murabito, Joanne M.; Melzer, David; Kuchel, George A.; Ferrucci, Luigi; Karasik, David; Rivadeneira, Fernando; Kiel, Douglas P.; Pilling, Luke C.

doi:10.1038/s41467-021-20918-w

Cited by 83 publications

(41 citation statements)

References 75 publications

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“…Moreover, because ageing is associated with a progressive loss of subcutaneous fat and the accumulation of visceral and ectopic fat [ 68 ], it is important to elucidate how not only markers of total adiposity which distinguish between fat and muscle but also more specific adiposity markers influence strength. While acknowledging that relationships between adiposity and strength may vary with age and could be bi-directional [ 69 ], our consistent findings using different methodological approaches strengthens the evidence base for causal links between total adiposity and grip strength in males and females and between central adiposity and grip strength in males. We found that for both sexes, higher BF% and (in males only) WHR was associated with weaker grip strength.…”

Section: Discussionsupporting

confidence: 77%

Adiposity and grip strength: a Mendelian randomisation study in UK Biobank

Pereira

Garfield

Farmaki

et al. 2022

BMC Med

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Background Muscle weakness, which increases in prevalence with age, is a major public health concern. Grip strength is commonly used to identify weakness and an improved understanding of its determinants is required. We aimed to investigate if total and central adiposity are causally associated with grip strength. Methods Up to 470,786 UK Biobank participants, aged 38–73 years, with baseline data on four adiposity indicators (body mass index (BMI), body fat percentage (BF%), waist circumference (WC) and waist-hip-ratio (WHR)) and maximum grip strength were included. We examined sex-specific associations between each adiposity indicator and grip strength. We explored whether associations varied by age, by examining age-stratified associations (< 50 years, 50–59 years, 60–64 years,65 years +). Using Mendelian randomisation (MR), we estimated the strength of the adiposity–grip strength associations using genetic instruments for each adiposity trait as our exposure. Results In males, observed and MR associations were generally consistent: higher BMI and WC were associated with stronger grip; higher BF% and WHR were associated with weaker grip: 1-SD higher BMI was associated with 0.49 kg (95% CI: 0.45 kg, 0.53 kg) stronger grip; 1-SD higher WHR was associated with 0.45 kg (95% CI:0.41 kg, 0.48 kg) weaker grip (covariate adjusted observational analyses). Associations of BMI and WC with grip strength were weaker at older ages: in males aged < 50 years and 65 years + , 1-SD higher BMI was associated with 0.93 kg (95% CI: 0.84 kg, 1.01 kg) and 0.13 kg (95% CI: 0.05 kg, 0.21 kg) stronger grip, respectively. In females, higher BF% was associated with weaker grip and higher WC was associated with stronger grip; other associations were inconsistent. Conclusions Using different methods to triangulate evidence, our findings suggest causal links between adiposity and grip strength. Specifically, higher BF% (in both sexes) and WHR (males only) were associated with weaker grip strength.

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Section: Discussionsupporting

confidence: 77%

Adiposity and grip strength: a Mendelian randomisation study in UK Biobank

Pereira

Garfield

Farmaki

et al. 2022

BMC Med

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“…The loss of muscle mass and strength or physical function (sarcopenia) is one of the common disabilities in the elderly [ 1 ]. It occurs under various conditions, such as aging [ 2 ], cancer [ 3 ], cardiovascular diseases [ 4 ], and drug treatment [ 5 ]. Glucocorticoids are known to have catabolic effects on skeletal muscle, either as an endogenous endocrine hormone released in response to various stressful conditions or as a drug given exogenously to treat inflammation [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis

Wang

Jiao

et al. 2021

Cell Death Discov.

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Skeletal muscle atrophy is one of the major side effects of high dose or sustained usage of glucocorticoids. Pyroptosis is a novel form of pro-inflammatory programmed cell death that may contribute to skeletal muscle injury. Trimetazidine, a well-known anti-anginal agent, can improve skeletal muscle performance both in humans and mice. We here showed that dexamethasone-induced atrophy, as evidenced by the increase of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) expression, and the decrease of myotube diameter in C2C12 myotubes. Dexamethasone also induced pyroptosis, indicated by upregulated pyroptosis-related protein NLR family pyrin domain containing 3 (NLRP3), Caspase-1, and gasdermin-D (GSDMD). Knockdown of NLRP3 or GSDMD attenuated dexamethasone-induced myotube pyroptosis and atrophy. Trimetazidine treatment ameliorated dexamethasone-induced muscle pyroptosis and atrophy both in vivo and in vitro. Activation of NLRP3 using LPS and ATP not only increased the cleavage and activation of Caspase-1 and GSDMD, but also increased the expression levels of atrophy markers MuRF1 and Atrogin-1 in trimetazidine-treated C2C12 myotubes. Mechanically, dexamethasone inhibited the phosphorylation of PI3K/AKT/FoxO3a, which could be attenuated by trimetazidine. Conversely, co-treatment with a PI3K/AKT inhibitor, picropodophyllin, remarkably increased the expression of NLRP3 and reversed the protective effects of trimetazidine against dexamethasone-induced C2C12 myotube pyroptosis and atrophy. Taken together, our study suggests that NLRP3/GSDMD-mediated pyroptosis might be a novel mechanism for dexamethasone-induced skeletal muscle atrophy. Trimetazidine might be developed as a potential therapeutic agent for the treatment of dexamethasone-induced muscle atrophy.

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“…The findings revealed that several genetic variants related to metabolism could be of importance in determining the pathogenesis of sarcopenia. Previous sarcopenia GWAS for European descendants showed association with FTO 22 , 27 , 28 and several loci, including TGFA and HLA-DRB1 29 .…”

Section: Discussionmentioning

confidence: 93%

Unveiling genetic variants for age-related sarcopenia by conducting a genome-wide association study on Korean cohorts

Jin

Yoo

Kim

et al. 2022

Sci Rep

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Sarcopenia is an age-related disorder characterised by a progressive decrease in skeletal muscle mass. As the genetic biomarkers for sarcopenia are not yet well characterised, this study aimed to investigate the genetic variations related to sarcopenia in a relatively aged cohort, using genome-wide association study (GWAS) meta-analyses of lean body mass (LBM) in 6961 subjects. Two Korean cohorts were analysed, and subgroup GWAS was conducted for appendicular skeletal muscle mass (ASM) and skeletal muscle index. The effects of significant single nucleotide polymorphisms (SNPs) on gene expression were also investigated using multiple expression quantitative trait loci datasets, differentially expressed gene analysis, and gene ontology analyses. Novel genetic biomarkers were identified for LBM (rs1187118; rs3768582) and ASM (rs6772958). Their related genes, including RPS10, NUDT3, NCF2, SMG7, and ARPC5, were differently expressed in skeletal muscle tissue, while GPD1L was not. Furthermore, the ‘mRNA destabilisation’ biological process was enriched for sarcopenia. Our study identified RPS10, NUDT3, and GPD1L as significant genetic biomarkers for sarcopenia. These genetic loci were related to lipid and energy metabolism, suggesting that genes involved in metabolic dysregulation may lead to the pathogenesis of age-related sarcopenia.

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Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

Cited by 83 publications

References 75 publications

Adiposity and grip strength: a Mendelian randomisation study in UK Biobank

Adiposity and grip strength: a Mendelian randomisation study in UK Biobank

Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis

Unveiling genetic variants for age-related sarcopenia by conducting a genome-wide association study on Korean cohorts

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