Quantitative trait loci for human muscle strength: linkage analysis of myostatin pathway genes

Abstract

This study reports the results of a multipoint linkage study that aims to unravel the genetic basis of muscle strength and muscle mass in humans. Myostatin (GDF8) is known to be a strong inhibitor of muscle growth in animals. However, studies examining human myostatin polymorphisms are rare and are limited to the GDF8 gene itself. Here, the contribution to isometric and concentric knee strength of nine key proteins involved in the myostatin pathway is studied in a nonparametric multipoint linkage analysis by means of a variance components and regression method. A sample of 367 healthy young male siblings was phenotyped on an isokinetic dynamometer and genotyped for markers of the myostatin pathway genes. Three of the loci were found significantly linked with a quantitative trait locus (QTL) for knee muscle strength. First, D13S1303 showed replication of an explorative single-point linkage study with a maximum LOD score of 2.7 (P = 0.0002). Second, maximum LOD scores of 3.4 (P = 0.00004) and 3.3 (P = 0.00005) were observed for markers D12S1042 and D12S85, respectively, at 12q12-14. Finally, marker D12S78 showed an LOD score of 2.7 at 12q22-23. We conclude that several genes involved in the myostatin pathway, but not the myostatin gene itself, are important QTLs for human muscle strength. An additional set of valuable candidate genes that were not part of the myostatin pathway was found in the chromosome 12 and 13 genomic regions.

Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene

“…11 This is consistent with the observation that the importance of genetic factors decreases with increasing velocities in concentric torques due to genetic variation in contractile and elastic components, which contribute differently to strength production at different velocities. 47 It could be argued that the currently applied two-stage strategy infers a bias toward genes with a known function in (the regulation of) muscle strength.…”

“…The recruitment protocol and subject characteristics have been described elsewhere. 9,11 For stage 1, a total of 500 individuals were included (169 subjects overlap with the microsatellite-based linkage study 11 ). For stage 2, a total of 536 subjects were included with an overlap of 464 subjects with stage 1.…”

“…Genetic linkage studies regarding muscle strength are even scarcer. To date, only Tiainen et al 8 and our research group [9][10][11][12][13][14] reported results on genetic linkage for skeletal muscle strength characteristics. We were the first to perform linkage analyses on a unique collection of young male Caucasian siblings drawn from the Leuven Genes for Muscular Strength study (LGfMS).…”

“…9 Single and multipoint microsatellite marker-based linkage analyses revealed significant or suggestive linkage of chromosomal regions 12q12-14, 12q22-23 and 13q14.2 to knee muscle strength. 9,11 It can, however, not be excluded that genes other than the original myostatin pathway genes underlie these linkage findings and further fine mapping of the region surrounding these candidate genes is therefore warranted.…”

Heritability of somatotype components: a multivariate analysis

“…In many of the studies, irrespective of the methodology that is used, mesomorphy tends to be the most heritable of the three components or it has the highest familial correlations, although there are exceptions. This trend is confirmed in the present study and also parallels the high (upper-limit) heritabilities for several muscle and muscle-bone measures reported in young Flemish men by Huygens et al 27,28 The lower heritability of the endomorphy component found in the present study intuitively makes sense as fat tissue is relatively prone to environmental variation in, for example, nutrition and physical activity. Huygens et al, 27 however, reported upper-limit heritability estimates for adiposity indicators in young adult Flemish brothers which were situated between 50 and 70%.…”