Polymorphisms in PTK2 are associated with skeletal muscle specific force: an independent replication study

Morse

et al. 2022

Genes

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Background: Heritability explains 45-82% of muscle mass and strength variation, yet polygenic models for muscle phenotypes in older women are scarce. Therefore, the objective of the present study was to (1) assess if total genotype predisposition score (GPSTOTAL) for a set of polymorphisms differed between older women with low and high muscle mass, and (2) utilise a data-driven GPS (GPSDD) to predict the variance in muscle size and strength-related phenotypes. Methods: In three-hundred 60- to 91-year-old Caucasian women (70.7 ± 5.7 years), skeletal muscle mass, biceps brachii thickness, vastus lateralis anatomical cross-sectional area (VLACSA), hand grip strength (HGS), and elbow flexion (MVCEF) and knee extension (MVCKE) maximum voluntary contraction were measured. Participants were classified as having low muscle mass if the skeletal muscle index (SMI) < 6.76 kg/m2 or relative skeletal muscle mass (%SMMr) < 22.1%. Genotyping was completed for 24 single-nucleotide polymorphisms (SNPs). GPSTOTAL was calculated from 23 SNPs and compared between the low and high muscle mass groups. A GPSDD was performed to identify the association of SNPs with other skeletal muscle phenotypes. Results: There was no significant difference in GPSTOTAL between low and high muscle mass groups, irrespective of classification based on SMI or %SMMr. The GPSDD model, using 23 selected SNPs, revealed that 13 SNPs were associated with at least one skeletal muscle phenotype: HIF1A rs11549465 was associated with four phenotypes and, in descending number of phenotype associations, ACE rs4341 with three; PTK2 rs7460 and CNTFR rs2070802 with two; and MTHFR rs17421511, ACVR1B rs10783485, CNTF rs1800169, MTHFR rs1801131, MTHFR rs1537516, TRHR rs7832552, MSTN rs1805086, COL1A1 rs1800012, and FTO rs9939609 with one phenotype. The GPSDD with age included as a predictor variable explained 1.7% variance of biceps brachii thickness, 12.5% of VLACSA, 19.0% of HGS, 8.2% of MVCEF, and 9.6% of MVCKE. Conclusions: In older women, GPSTOTAL did not differ between low and high muscle mass groups. However, GPSDD was associated with muscle size and strength phenotypes. Further advancement of polygenic models to understand skeletal muscle function during ageing might become useful in targeting interventions towards older adults most likely to lose physical independence.

Section: Discussionsupporting

confidence: 92%

Polygenic Models Partially Predict Muscle Size and Strength but Not Low Muscle Mass in Older Women

Morse

et al. 2022

Genes

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“…Where p < 0.15, the rarer homozygotes were combined with heterozygotes (in both dominant and recessive models) and two-group analysis was performed. Similarly, when very few participants were in one of the homozygous groups, the group was combined with the heterozygotes [55]. Odds ratio (OR) was used to estimate effect size for significant SNP-groups associations.…”

Section: Statisticsmentioning

confidence: 99%

Sarcopenia, Obesity, and Sarcopenic Obesity: Relationship with Skeletal Muscle Phenotypes and Single Nucleotide Polymorphisms

Williams

et al. 2021

JCM

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Obesity may aggravate the effects of sarcopenia on skeletal muscle structure and function in the elderly, but no study has attempted to identify the gene variants associated with sarcopenia in obese women. Therefore, the aims of the present study were to: (1) describe neuromuscular function in sarcopenic and non-sarcopenic women with or without obesity; (2) identify gene variants associated with sarcopenia in older obese women. In 307 Caucasian women (71 ± 6 years, 66.3 ± 11.3 kg), skeletal muscle mass was estimated using bioelectric impedance, and function was tested with a 30 s one-leg standing-balance test. Biceps brachii thickness and vastus lateralis cross-sectional area (VLACSA) were measured with B-mode ultrasonography. Handgrip strength, maximum voluntary contraction elbow flexion (MVCEF), and knee extension torque (MVCKE) were measured by dynamometry, and MVCKE/VLACSA was calculated. Genotyping was performed for 24 single-nucleotide polymorphisms (SNPs), selected based on their previous associations with muscle-related phenotypes. Based on sarcopenia and obesity thresholds, groups were classified as sarcopenic obese, non-sarcopenic obese, sarcopenic non-obese, or non-sarcopenic non-obese. A two-way analysis of covariance was used to assess the main effects of sarcopenia and obesity on muscle-related phenotypes and binary logistic regression was performed for each SNP to investigate associations with sarcopenia in obesity. There were no significant obesity * sarcopenic status interactions for any of the investigated muscle-related phenotypic parameters. Neither sarcopenia nor obesity had a significant effect on biceps brachii thickness, but sarcopenia was associated with lower VLACSA (p = 0.003). Obesity was associated with lower MVCEF (p = 0.032), MVCKE (p = 0.047), and MVCKE/VLACSA (p = 0.012) with no significant effect of sarcopenia. Adjusted for age and height, three SNPs (ACTN3 rs1815739, MTHFR rs1801131, and MTHFR rs1537516) were associated with sarcopenia in obese participants. Sarcopenia was associated with a smaller muscle size, while obesity resulted in a lower muscle quality irrespective of sarcopenia. Three gene variants (ACTN3 rs1815739, MTHFR rs1801131, and MTHFR rs1537516) suspected to affect muscle function, homocysteine metabolism, or DNA methylation, respectively, were associated with sarcopenia in obese elderly women. Understanding the skeletal muscle features affected by sarcopenia and obesity, and identification of genes related to sarcopenia in obese women, may facilitate early detection of individuals at particular risk of sarcopenic obesity.

“…These genes encode for a component of muscle structural proteins and the extracellular matrix (ECM) and thus might provide strength and integrity for the muscle fibre. For example, the PTK2 rs7460 A-allele, identified here as a favourable allele, has been previously associated with higher baseline specific force in Caucasian men [42,43]. It has been speculated that PTK2 rs7460 AA might favour more integrin-ECM bonds and result in a higher costamere density [43], which may favour lateral force transmission [42].…”

Section: Structural Proteinsmentioning

confidence: 75%

“…For example, the PTK2 rs7460 A-allele, identified here as a favourable allele, has been previously associated with higher baseline specific force in Caucasian men [42,43]. It has been speculated that PTK2 rs7460 AA might favour more integrin-ECM bonds and result in a higher costamere density [43], which may favour lateral force transmission [42]. Higher gene expression has been observed with AA homozygotes compared to TT for PTK2 rs7460 [44], which may result in an increase in the number of integrin ECM bonds compared to TT genotypes and thus higher lateral force transmission with higher resultant muscle strength in the present elderly population.…”

Section: Structural Proteinsmentioning

confidence: 86%

The Association of Multiple Gene Variants with Ageing Skeletal Muscle Phenotypes in Elderly Women

Herbert

et al. 2020

Genes

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There is a scarcity of studies that have investigated the role of multiple single nucleotide polymorphisms (SNPs) on a range of muscle phenotypes in an elderly population. The present study investigated the possible association of 24 SNPs with skeletal muscle phenotypes in 307 elderly Caucasian women (aged 60–91 years, 66.3 ± 11.3 kg). Skeletal muscle phenotypes included biceps brachii thickness, vastus lateralis cross-sectional areas, maximal hand grip strength, isometric knee extension and elbow flexion torque. Genotyping for 24 SNPs, chosen on their skeletal muscle structural or functional links, was conducted on DNA extracted from blood or saliva. Of the 24 SNPs, 10 were associated with at least one skeletal muscle phenotype. HIF1A rs11549465 was associated with three skeletal muscle phenotypes and PTK2 rs7460 and ACVR1B rs10783485 were each associated with two phenotypes. PTK2 rs7843014, COL1A1 rs1800012, CNTF rs1800169, NOS3 rs1799983, MSTN rs1805086, TRHR rs7832552 and FTO rs9939609 were each associated with one. Elderly women possessing favourable genotypes were 3.6–13.2% stronger and had 4.6–14.7% larger muscle than those with less favourable genotypes. These associations, together with future work involving a broader range of SNPs, may help identify individuals at particular risk of an age-associated loss of independence.