Available online at www.sciencedirect.
com
Genetic variation in human muscle strength — opportunities for
therapeutic interventions?
Martine A Thomis1 and Jeroen Aerssens2
Inter-individual variation in muscle mass and muscular fitness is
broad; being at the upper tail of the distribution not only
contributes to improve elite sport performance, but is also
associated with longer independent living and higher quality-
of-life in the aging population. Heritability estimates of muscle
phenotypes are substantial and warrant the search for genetic
components underlying this individual variability. The
‘kinesiogenomics’ field is young, but genetic associations with
muscle strength-related phenotypes have been reported
already for more than 40 candidate genes, and genome-wide
scans revealed several additional regions of interest in the
genome. Although genetic findings may reveal attractive
targets for novel muscle atrophy therapy, the benefit of
exercise as a major stimulus for natural muscle mass
enhancement or maintenance cannot be underestimated.
Addresses
1
Department of Kinesiology, Faculty of Kinesiology and Rehabilitation
Sciences, Katholieke Universiteit Leuven, Tervuursevest 101, B-3001
Leuven, Belgium
2
Department of Translational Genomics & Genetics, Janssen
Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30,
B-2340 Beerse, Belgium
Corresponding author: Thomis, Martine A
(martine.thomis@faber.kuleuven.be)
Current Opinion in Pharmacology 2012, 12:355–362
This review comes from a themed issue on
Musculoskeletal
Edited by Martin Hohenegger
Available online 23rd March 2012
1471-4892/$ – see front matter
# 2012 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coph.2012.03.003
Introduction
A sufficient amount of muscle mass is an essential con-
dition for attaining healthy muscular fitness. Muscle mass
can be estimated indirectly through regional measures
(e.g., circumferences corrected for subcutaneous fat),
radiological techniques (e.g., ultrasound-thickness, CT/
MRI scans) or whole body lean mass measurements (e.g.,
DEXA scan). Muscle strength can be assessed through
many different methods, each measuring specific aspects
of this complex phenotype. Muscular strength pheno-
types are often subdivided in static strength (e.g., hand-
grip strength), dynamic strength (e.g., torque delivered
during isokinetic concentric and eccentric contractions of
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the knee), explosive strength or power (e.g., jump test)
and muscular endurance (e.g., decrease in strength over
25 maximal contractions) [1].
Heritability of muscular strength phenotypes
and muscle mass
The relative contribution of an individual’s genetic back-
ground to the observed variation in several muscular
strength phenotypes and muscle mass has been quanti-
fied in twin and family studies [2]. Heritability estimates
for muscle mass or cross-sectional area range between
0.20 and 0.95, with several studies reporting heritabilities
at about 0.85 [3]. Estimates based on structural equation
modeling in twins suggested a slight decrease in herit-
ability for static strength from adolescence (0.52–0.82) to
young adulthood (0.50–0.70) and old age (0.49). However,
heritability estimates based on data from longitudinal
studies are scarce, and often focus primarily on the fast
growing period during adolescence rather than during
aging of elderly. In these studies where gender was a
significant factor, heritability was lower in females as
compared to males. Heritability estimates for dynamic
strength measurements range between 0.46 and 0.87.
Studies on explosive strength have been performed
particularly in young twins, and demonstrated higher
heritability estimates as compared to other strength
measures. Estimation of the (upper-limit) heritability
of muscular endurance — or resistance to fatigue — is
limited to one sibling study, which revealed lower esti-
mates compared to other strength phenotypes within the
range of 0.21–0.61 [4]. Together, the relatively high
heritability estimates for the various muscle strength
phenotypes warrant searches for genetic determinants
in the human genome that contribute to the large
inter-individual variation in muscle strength.
Genetic diversity contributes to inter-
individual variation in muscular mass and
strength
Candidate gene approach
Several case–control and population-based studies have
examined specific candidate gene variants for associ-
ations with muscle strength and size characteristics
[5,6]. In the design of these studies, the focus has often
been toward comparison of elite athletes versus less-
trained controls, thereby assessing specific variations in
candidate genes. For example, the frequencies of poten-
tial muscular strength-increasing alleles have been com-
pared between elite power athletes (e.g., sprinters) and
controls and/or elite endurance-type athletes [7]. Reports
Current Opinion in Pharmacology 2012, 12:355–362
356 Musculoskeletal
of population-based genetic studies on muscular
strength, on the other hand, are usually targeting a
population of young adults, or comprise a sample with
large age ranges. In general, sample sizes in these geno-
type–phenotype association studies have been rather
small to modest, which implies that the statistical power
is unfortunately often rather limited. Especially the
samples size of studies designed to assess the influence
of genetic variability on phenotypes that are more chal-
lenging to measure, such as responses to resistance
strength training (i.e., neuromuscular adaptations and
muscle hypertrophy responses), have been relatively
small.
The underlying drivers leading to the choice of specific
candidate genes in these studies is not always clear.
Recently two reviews of studies on genetic associations
of candidate genes with muscular strength characteristics
were published [5,6]. Figure 1 represents a chromosome
map of the human genome that depicts the candidate
genes that have been reported in studies on muscle
strength and muscle size. The majority of the examined
candidate genes can be categorized according to either
their involvement in the structural muscle function or
their influencing role in muscle physiology.
The ACTN3 gene exemplifies candidate genes with func-
tional involvement in sarcomeric structures; the a-acti-
nin-3 protein that is encoded by this gene is a major actin-
anchoring component of fast muscle fiber Z-line. Genetic
studies have revealed a R577X stopcodon polymorphism
in the ACTN3 gene, and demonstrated that approximately
18% of a Caucasian population carries the XX homozy-
gote genotype and hence lacks the protein [8]. Mean-
while, at least 15 reports have been published on the
ACTN3 polymorphism. A meta-analysis concluded that
the RR genotype is associated with elite power athlete
status, but only in European athlete groups. The XX
genotype is, however, not significantly associated with
elite endurance-type status, as was initially suggested and
also explored in phenotypes of the Actn3/ mouse model
[9]. The specific location of a-actinin-3 as Z-line protein
probably indicates a role in adaptation or protection of the
sarcomere against damage when performing eccentric
muscle contraction (e.g. action of the knee quadriceps
extension muscles when descending stairs), as reported in
both human [10] and mouse studies [11]. Other sarco-
meric structural genes that have been associated with
strength are MYLK (myosin light-chain kinase) and COL1-
A1 (collagen a-1 chain type I).
The majority of examined candidate genes encode
proteins with a functional role in the anabolic pathways
of muscle hypertrophy, and include cell differentiation
regulators, growth factors, and other anabolic and cata-
bolic factors. These candidates often belong to either the
family of insulin-like growth factor (IGF)-related genes
Current Opinion in Pharmacology 2012, 12:355–362
(IGF1, IGF2, IGF2AS, IGFBP3 and PPP3R1) or the path-
way of myostatin-related genes (e.g., MSTN, FST,
ACVR1B, ACVR2B). Mutations in the myostatin (MSTN)
gene result in double-muscle phenotypes in Belgian Blue
cattle [12], dogs [13,14], porcine breeds [15], however, its
role in lower vertebrates like fish needs to be established
[16]. The economic importance of optimizing meat-pro-
duction in livestock explains the high focus on myostatin
in many farm animals. In humans, however, only one
mutation (a guanine to adenine transition at position +5 in
intron 1) has been described that lead to a severely
truncated myostatin protein, and hence hypermuscular
phenotype, in a single child (muscle cross-sectional area
of the quadriceps was 7.2 SD above age-matched and sex-
matched control children) [17]. Among other sequence
variants in MSTN, the low frequent K153R polymorphism
has been assessed most often, albeit that association
findings with muscle mass, muscular strength, responses
to strength training and related phenotypes turned out
being inconsistent [5]. Recent reports suggested a role
for myostatin in adipose tissue and muscle metabolism-
related protection against insulin resistance [18–20], as
well as in tendon characteristics [21]. Interestingly, the R-
allele of the K153R polymorphism has also been associ-
ated with lower performance in different jumps which are
partly determined by the stiffness of the muscle-tendon
unit [22].
Furthermore, inflammatory factors – such as cytokines
and neurotrophic factors – also play an important role in
the muscle’s response to resistance exercise, through the
promotion of protein breakdown or the inhibition of
protein synthesis, or at the opposite, through the pro-
motion of cell growth by stimulating satellite cell pro-
liferation and differentiation. It is therefore not surprising
that genetic variations in the genes encoding TNFa,
TNFR2, IL-6, IL-15, IL-15Ra, CCL2, CCR2, CNTF
and CNTFR have been studied in order to identify
potential associations with phenotypes of muscle mass,
strength and responses to strength training (reviewed in
[6]).
Complementary to the rationales for candidate gene
selection as described above, several other genes have
been selected and examined in association studies on
muscle phenotypes, including ACE, VDR, ESR1, COMT,
NR3C1, AMPD1, CKM and AK1M (reviewed in [5]).
Although a functional relationship of muscle phenotypes
with the proteins encoded by these genes could be
envisioned, the evidence gained from the reports avail-
able today is limited to warrant a prominent role for these
genes as predictors of muscle strength. The value of
candidate gene association studies is often somewhat
hampered because of lacking knowledge of the functional
role and significance at the molecular or cellular level of
the specific gene variant found to be associated with the
examined muscle phenotype. Also, few studies in the
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 Genetic variation in human muscle strength Thomis and Aerssens 357

Figure 1

1 2 3 4 5 6
rs9328112
rs1445128
rs714513
ACVR2B D6S1051
rs1039559
CCR2 TNF
DIO1 EPAS1

FST
PPP3R1

AMPD1
IL1RN
rs477499 MYLK
NR3C1

rs13320 IL15
ESR1

183 Mb
TTN
194 Mb
MSTN 203 Mb
D2S118
214 Mb

255 Mb
263 Mb

7 8 9 10 IGF2AS
11 12
IGF2
IL15RA INS
IL6 D11S4138
D12S1042
CNTFR
D12S85
IGFBP3
VDR
ACVR1B
CNTF
rs7845911

ACTN3
IGF1
D12S7
NUAK1
CFTR TRHR PPP1CC
ATP2A2
rs4962424
143 Mb
145 Mb 144 Mb
155 Mb 144 Mb

171 Mb
Current Opinion in Pharmacology

Human genome ideogram with indication of association and linkage based QTLs/candidate genes for muscular strength phenotypes. Markers for
linkage-based gene regions are indicated with D# and rs# for locations with LOD-peaks > 2.0 in the Leuven Genes for Muscular Strength Study
[4,40,41] or the Finnish Twin Study on Aging [42] (genomic region indicated by dashed line). Gene symbols indicate candidate genes for which
association with sequence variant(s) and strength phenotypes have been reported in literature. Ideogram is based on review information in [5,6].

www.sciencedirect.com Current Opinion in Pharmacology 2012, 12:355–362

358 Musculoskeletal

Figure 1 ( Continued ).

13 14 15 16 17 18
rs1941487

rs1010800
CCL2
D13S153
D13S1303 COL1A1

KBTBD13 ACE rs1866338

rs760267
X 85 Mb
92 Mb
98 Mb
BDKRB2 rs7175643
89 Mb
93 Mb
98 Mb

19
20
21 22
RETN

Y
COMT

CKM
PPARA
67 Mb 72 Mb 34 Mb 34.5 Mb 35 Mb 164 Mb
Current Opinion in Pharmacology

field have focused on more than one gene variant and very
few studies have tested gene–gene interactions or
examined genes within a larger physiological pathway
[23]. Yet, some studies have proposed a theoretical esti-
mate of the distribution of optimal polygenic profiles for
muscle strength and calculated the distribution of total
genotypic scores – both in a theoretical population [24] as
well as in an attempt to predict elite power athlete versus
endurance-athlete types [25]. The application of genetic
predisposition scores in non-athlete populations is scarce
and limited to hand grip strength [26].
Pathways to guide for success
Rather than assessing the impact of genetic diversity on
muscle phenotypes gene by gene, the simultaneous study
of a set of genes belonging to a common protein pathway
appears to be an attractive alternative and more coherent
approach. For example, linkage analysis for 10 genes
within the myostatin-pathway has been applied in a
sib-pair study aiming to identify genetic factors contri-
buting to variation in muscular strength [27]. In single-
point linkage analyses, suggestive evidence for linkage
was found for genetic markers near MSTN, CDKN1A, and
MYOD1 with slow contraction strength phenotypes. In
the multi-point phase, 39 microsatellite markers were
genotyped within the following genetic regions: myosta-
tin (MSTN); muscle regulatory factors MyoD (MYOD1),
Myf5 (MYF5), and Myf6 (MYF6); p21 (CDKN1A); retino-
blastoma (RB1); insulin-like growth factor-1 (IGF1);
cyclin-dependent kinase-2 (CDK2); and titin (TTN)
[28]. Significant or suggestive linkage at chromosomal
regions 12q12–14, 13q14.2–21, and 12q22–23 pointed to
CDK2, RB1, and IGF1 — or other neighboring genes on
the chromosome — as potentially potent Quantitative
Trait Loci (QTLs) for muscle strength. Next, a two-
staged gene-centered fine mapping approach was applied
to investigate candidate genes located in the genomic
regions 12q12–14 and 12q22–23 and prioritized based on
bioinformatics tools (Endeavor) in 2 consecutive geno-
typing rounds using Single Nucleotide Polymorphisms
(SNPs) [29].
Family-based combined linkage and association analyses
provided evidence for an association of rs2854464 in the
ACVR1B gene at 12q12–14 with knee strength. This
finding was independently replicated in the Baltimore
Longitudinal Study of Aging and Flemish Policy
Research Center of Sport, Physical Activity and Health

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 Genetic variation in human muscle strength Thomis and Aerssens 359
[30]. ACVR1B encodes the activin type I receptor ALK4
that is involved in myostatin pathway signaling [31].
Interestingly, the rs2854464 polymorphism is located
in a putative miR-24-binding site in the 30 untranslated
region (UTR) of the ACVR1B mRNA, while Wang et al.
[32] showed that miR-24 can decrease the expression of
the human ACVR1B gene and its encoded protein
(ALK4). We therefore hypothesize that the rs2854464
polymorphism may affect muscle strength by interfering
with miRNA binding. Even though miR-24 is not a
muscle-specific miRNA, it has been demonstrated by
Sun et al. [33] that miR-24 can inhibit TGF b-induced
differentiation and homeostatic maintenance of cardiac
and skeletal muscle tissue. Although supporting data are
lacking today, one could hypothesize that the effect of
miR-24 on TGF b signaling can be mediated through a
miR-24-binding site in the 30 -UTR of ACVR1B. Evi-
dence is growing, though, that altered expression of
miRNAs may affect the response of muscle mass hyper-
trophy by resistance exercise; this highlights the poten-
tial importance of miRNAs and their binding places in
the genes as new biomarkers to study the regulation of
exercise responses [34,35].
Finally, a subsequent family-based association study
was performed within linkage region 12q22–23, con-
taining 51 functional candidate genes [36]. Genotyping
122 SNPs in stage 1, identified several tagSNPs sig-
nificantly associated with knee torque production,
located in ATP2A2 (type 2 Ca2+ ATPase or SERCA2),
NUAK1 (NUAK family, SNF1-like kinase 1) and
PPP1CC (catalytic gamma subunit of protein phospha-
tase 1) [36]. These genes encode proteins relevant to
muscular mass and strength: the ATP2A2 gene product
is predominantly expressed in cardiac and slow-twitch
skeletal muscle and is involved in the calcium handling
necessary for the muscle contraction–relaxation cycle.
Darier’s disease patients with mutations in the ATP2A2
gene, have a prolonged contraction time and half re-
laxation time of the adductor pollicis muscle, indicating
altered contractile properties of muscle fibers [37].
NUAK1 and PPP1CC both play a role in contraction-
related glycogen metabolism in muscle [38,39]. In stage
2 of the same study, family-based association tests on
additional putatively functional SNPs (e.g. exonic
SNPs, SNPs in transcription factor binding sites or in
conserved regions) in an enlarged sample did, however,
not identify additional associations with muscle
strength characteristics.
Genetics outside the box: genome-wide approaches
Complementary to the studies on specific candidate
genes or pathways as described above, genome-wide
genetic studies enable to discover novel genes linked to
muscle strength phenotypes through a hypothesis free
approach. Today, muscle strength phenotypes have
been investigated in two genome-wide studies: the
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Leuven Genes for Muscular Strength Study [4,40,41]
and the Finnish Twin Study on Aging (FITSA) [42]
(Figure 1). Both studies are, however, rather small in
sample size and reveal different chromosomal regions
with little overlap between studies. Apart from these 2
studies with focus on muscular strength phenotypes, a
genome-wide linkage scan has also been performed for
lean tissue (leg lean mass), in a bivariate analysis with
femoral bone traits in the Framingham study [43]. This
analysis did not identify significant QTLs for leg lean
mass, except in covariance with bone parameters. The
observation that the linkage scans did not reveal con-
sistent chromosomal regions for muscular strength phe-
notypes may reflect the lack of genes with large effect
size underlying the genetic component for muscle
strength. In order to explain the high heritability of
muscular strength phenotypes, it is reasonable to
hypothesize that many different genes each contribut-
ing a small portion of the total genetic component
underlie inter-individual variability in muscle strength.
This view is supported by the findings of associations of
several genetic markers identified through the candi-
date gene and pathway approaches. Carefully designed
and large-scale genome-wide association studies could
have the statistical power to identify additional genetic
markers in non-obvious candidate genes with small
effect size. However, genome-wide association studies
that have been reported are all lacking any measure of
strength phenotypes; therefore no new hypothesis gen-
erating ‘hits’ associated with muscle strength have been
identified from these studies yet.
Myostatin and activin signaling pathway as
starting points for pharmacological targets
The findings of the genetic studies suggest many differ-
ent genes contributing to the inter-individual variation in
muscle strength. Indeed, especially results from candi-
date gene and pathway approaches demonstrate that
several genes from the myostatin and activin signaling
pathway are implicated to determine muscle strength
phenotypes. Hence, pharmacological intervention
through this pathway might provide opportunities for
improving muscle strength.
Myostatin has gained focus as a muscle growth inhibitory
factor, since its discovery in a knockout mouse [44]. The
impressive increase in muscle mass in mice lacking the
gene positioned MSTN as an obvious candidate gene for
muscle mass regulation in humans. Since its inhibitory
role in muscle development and maintenance became
clearer, ways to inhibit myostatin’s function became a
major target in the search for novel treatments for muscle
disease, and excessively, for stimulating muscle build in
athletes.
Different strategies aiming to block myostatin-function-
ing have been developed and tested in different models
Current Opinion in Pharmacology 2012, 12:355–362
360 Musculoskeletal
in vitro and in vivo. These inhibitors include proteins that
specifically bind myostatin (follistatin, growth and
differentiation factor-associated serum protein 1
(GASP-1)), recombinant virus with mutated myostatin
propeptide, anti-myostatin monoclonal antibody (MYO-
029), or a complex of myostatin-targeting siRNA and
atelocollagen that can be locally delivered in skeletal
muscle tissue [45]. The results from clinical studies are,
however, not always in line of expectancy. For example,
the administration of MYO-029 did not improve muscle
function of treated patients during phase I/II clinical
trials in a range of muscular dystrophies [46]. However,
skinned fibers from 4 out of 5 patients treated with MYO-
029 increased specific force production, suggesting an
effect at the cellular level that could not be detected in
the whole muscle. These findings contradict some of the
mice/cell model work indicating lower specific strength
and hypertrophy without increased contractile proteins
during prolonged inhibition of myostatin functioning
[47]. They also illustrate that more detailed information
on the effect of myostatin depletion can be gained from
single muscle fiber studies compared to whole muscle
findings. Effects in whole muscle (e.g., increased sensi-
tivity of Mstn/ muscle to eccentric strain damage)
might in addition be affected by myostatin’s effect on
tendon and aponeuroses [48].
Myostatin, activin and other members of the TGF-beta
super family signal through a combination of activin type
II and type I receptors. Myostatin binds activin type II
receptor ACVR2B or ActRIIB and utilizes ALK4
(encoded by ACVR1B) as type I receptor. Upon binding
of myostatin to ActRIIB, the ALK4 receptor is recruited
to the complex and its glycine-serine rich (GS) domain is
phosphorylated by ActRIIB. This initiates a cascade
through Smad proteins that further downstream
regulates the expression of different genes [20,49]. It
has been suggested that the problem of using anti-myos-
tatin compounds may be due to the ability of myostatin
receptor ActRIIB to also bind other ligands from the
TGF-beta family, resulting in a redundancy of myostatin
[49]. Alternative pharmacological approaches therefore
target the signaling pathway downstream of myostatin,
through the inhibition of ActRIIB by means of a soluble
form of the receptor, sActRIIB (a fusion protein of the
receptor extracellular domain with immunoglobulin Fc),
or the inhibition of the ALK4 receptor (by means of a
small molecule, SB431542). This approach is also sup-
ported by the results from the genetic studies, which
show an association of the ACVR1B gene with gene
strength, and the data on the miR-24 miRNA that can
bind the 30 UTR of this gene [32,33]. Although anti-
myostatin interventions seem to show their effects
mainly in muscle tissue, without apparent adverse
effects, activins and other members of the TGF-beta
family function in almost every cell type. Pleiotropic
effects are therefore expected and concerns are raised
Current Opinion in Pharmacology 2012, 12:355–362
regarding off-target effects when their appropriateness
for treatment of disease is considered [31]. Deregulation
of activin signals contribute to pathological conditions
such as chronic inflammation, fibrosis and development
of cancer [31,50].
Another potentially interesting new target is the
mechano-growth factor (MGF), a member of the IGF1
superfamily that is responsive to mechanical stimuli
[51,52]. Because MGF has a marked ability to induce
satellite cell fusion for muscle repair and maintenance, its
administration could provide a potential therapeutic
strategy for treating age-related sarcopenia, particularly
in combination with treatment to activate satellite cells,
such as exercise. However, recent findings of up-regula-
tion of MGF in prostatic cancer cells might highlight a
role also in cancer biology [53] which jeopardizes its
application in therapeutic use of muscle mass (repair).
All together, the pharmacological options for drug de-
velopment in muscular diseases or sarcopenia are broad-
ening; the identification of additional muscle strength-
related genes from new genetic studies (e.g., whole
genome associations) might lead to the discovery of
alternative pharmacologically interesting targets.
Increasing muscle mass and strength to
prevent sarcopenia
‘Exercise is Medicine1’ [54] builds on the evidence of
the effect of both endurance type of exercise and resist-
ance training on inducing muscular hypertrophic factors.
Exercise lowers myostatin levels both in serum and in
muscle and is therefore the natural choice of anti-myos-
tatin treatment [19]. A large body of research is involved
in the optimization of training stimuli with interaction of
optimal timing of meals of optimal composition (amino
acids, protein, carbohydrates) to induce optimal protein
build [55]. For all people without muscle disease, resist-
ance training is a major way of building muscle mass and
slow down the deteriorating effects of sarcopenia [56].
However, in disease status or when exercise is contra-
indicated, use of pharmacological agents aimed at increas-
ing muscle mass, both from a prospective of better
muscular fitness as well as increased metabolic active
mass (reduced metabolic disease/type 2 diabetes) is indi-
cated.
Conclusion
Studies on genetic variation in muscle mass and strength
characteristics in elite athletes, young and older popu-
lations have been focusing on several candidate genes,
amongst which myostatin-related pathway genes, but
genome-wide association approaches are lacking. Targets
for therapeutic intervention today are focused on inhibit-
ing myostatin as a muscle growth inhibitory factor, how-
ever effects on whole muscle in muscular dystrophy
patients are not yet optimal. Optimizing strength training
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 Genetic variation in human muscle strength Thomis and Aerssens 361
for elderly will remain a main strategy to combat effects of
sarcopenia.
Acknowledgment
We thank Siacia Broos for constructing Figure 1.
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