Sarcopenia Age-Related Muscle Wasting and Weakness: Mechanisms and Treatments P26 ppsx

236 S.M. Roth
analysis revealed a significant association with handgrip strength that was completely
explained by the rs1800169 A-allele, such that A/A individuals exhibited lower
handgrip strength compared to G-allele carriers. In a follow-up study, Roth et al.
(2008) examined multiple polymorphisms in the CNTFR gene in association with
strength variables in 465 men and women (20–90 year). For the C174T polymor-
phism, T-allele carriers exhibited significantly higher quadriceps and hamstrings
concentric and eccentric isokinetic strength at both 30 and 180 deg/s compared
to C/C carriers, but these differences were not significant after adjustment for
lower limb lean mass. No differences were observed for polymorphisms in the
promoter region or elsewhere in the gene. De Mars and coworkers (2007) exam-
ined polymorphisms in both the CNTF and the CNTFR genes in 493 middle-aged
and older men and women with measures of knee flexor and extensor strength.
T-allele carriers of the C-1703T polymorphism in CNTFR exhibited higher
strength levels for multiple measures compared to C/C homozygotes, including all
knee flexor torque values. In middle-aged women, A-allele carriers at the T1069A
locus in CNTFR exhibited lower concentric knee flexor isokinetic and isometric
torque compared to T/T homozygotes. The CNTF null allele was not associated
with any strength measures, nor were any CNTF*CNTFR interactions observed.
These findings indicate the potential for significant influences of CNTF and
CNTFR gene variants on skeletal muscle strength, though inconsistencies have
been noted for CNTFR. The frequency of the rare A/A genotype in CNTF is so low
that, despite some consistent findings of lower muscle strength, public health sig-
nificance is uncertain, though clinical importance may be had for those particular
individuals.
Estrogen Receptor (ESR1) The estrogen receptor alpha is expressed in skeletal
muscle, indicating a potential sensitivity to estrogen signaling (Wiik et al. 2009).
While several studies have examined genetic variation in the ESR1 gene in relation
to muscle strength measures, none have confirmed any association. Salmen et al.
(2002) examined 331 early postmenopausal women during a 5-year hormone
replacement therapy trial for associations with the ESR1 gene. Neither baseline nor

5-year grip strength values were associated with ESR1 genotype. Vandevyver and
colleagues (1999) examined 313 postmenopausal Caucasian women with measures
of grip and quadriceps strength and reported no associations with ESR1 genotype.
Grundberg et al. (2005) reported no association between a TA-repeat polymor-
phism in the ESR1 gene and several muscle strength measures in 175 Swedish
women (20–39 year). Ronkainen and co-workers (2008) examined ESR1 genotype
in 434 older women (63–76 year) and found no significant association with hand
grip or knee extension strength or leg extension power.
Insulin-like Growth Factor 2 (IGF2) Two studies have examined the IGF2
gene in relation to strength phenotypes. Sayer et al. (2002) performed grip strength
analysis in 693 older men and women and examined association with the IGF2
ApaI polymorphism. IGF2 genotype was associated with grip strength in men but
not women, with G/G genotype having lower strength compared to A/A genotype
carriers. Interestingly, an independent but additive effect of birth weight on grip
strength values was also noted in men. Schrager and colleagues (2004) examined
237Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia
the same ApaI polymorphism in relation to muscle strength and power phenotypes
in 485 men and women. They reported significantly lower arm and leg isokinetic
strength measures in A/A women compared to G/G women, differences that were
not observed in men. IGF2 is imprinted in mammals such that only the paternal
allele is transcribed (Zemel et al. 1992), thus analyses in these studies focused on
comparing homozygote groups rather than heterozygotes. The results of these stud-
ies stand in direct contrast to each other, and indicate that any influence of IGF2
genotype on strength-related traits is going to be minor or the result of interaction
with other yet-to-be identified factors.
Myostatin-Related Genes After myostatin’s discovery in the late 1990s, it
emerged as a potential target of gene association studies and multiple polymor-
phisms were identified in the human gene (MSTN) (Ferrell et al. 1999). Initial
investigations reported associations with skeletal muscle strength, but the sample
sizes were very small owing in part to low allele frequencies of the common poly-

morphisms. Seibert et al. (2001) reported lower strength in older African American
women (70–79 year) with the R-allele compared to K/K genotype at the MSTN
K153R polymorphism, but the sample size was quite low (n = 55). Corsi et al.
(2002) reported lower isometric muscle strength (averaged across eight muscle
groups) in R-allele carriers of the K153R polymorphism in 450 older men and
women. Though consistent with the findings of Seibert (2001), the sample size of
R-allele carriers was only seven making the findings inconclusive. Because the
common polymorphisms have rare allele frequencies, the clinical significance of
MSTN genetic variation is unlikely. Two groups have recently examined genes
within the myostatin signaling pathway, including the myostatin receptor (activin-
type II receptor B; ACVR2B) and follistatin (FST), a myostatin inhibitor. Walsh
et al. (2007) examined the genetic association of ACVR2B and FST with muscle
strength in 593 men and women across the adult age span. In women but not men,
ACVR2B haplotype was significantly associated with knee extensor concentric peak
torque. FST haplotype was not associated with muscle strength. Kostek et al. (2005)
reported significant associations with the MSTN gene in 23 African Americans for
biceps isometric strength. The FST gene was also associated with baseline one-
repetition maximum strength levels. Again, the sample sizes of the genotype groups
with significant findings were small making the clinical relevance of these findings
uncertain but generally not compelling.
Vitamin D Receptor (VDR) Vitamin D deficiency has been consistently
associated with lower muscle strength (Ceglia 2008) and has been discussed as
a potential mechanism of sarcopenia (Montero-Odasso and Duque 2005). In one
of the first gene associations for skeletal muscle traits, Geusens et al. (1997)
demonstrated a significant relationship between the VDR BsmI polymorphism
and both isometric quadriceps and hand grip strength in 501 elderly, healthy
women, with 23% higher quadriceps strength and 7% higher grip strength in the
b/b compared to B/B genotype carriers. These findings were subsequently sup-
ported in a subgroup of these same women (Vandevyver et al. 1999). In contrast,
Grundberg et al. (2005) examined two polymorphisms (poly A repeat and BsmI)

within VDR in relation to muscle strength in 175 women aged 20–39 year.
238 S.M. Roth
They found greater hamstrings isokinetic muscle strength in women homozygous
for the shorter poly A repeat (ss) compared to women homozygous for the long
poly A repeat (LL). No associations were reported with quadriceps or grip
strength. Similar findings were reported for the BsmI variant (b and B alleles)
given the significant linkage disequilibrium between the s and B alleles. Thus,
the B/B genotype group exhibited higher hamstrings strength in contrast to the
Geusens et al. findings. Roth and colleagues (2008) reported significant associa-
tions with the VDR FokI polymorphism (f and F alleles) and knee extensor iso-
metric strength in 302 older Caucasian men (f/f higher than F/F), but these
associations were no longer significant once leg FFM was accounted for in the
models, suggesting that the genotype-strength associations were explained by
differences in muscle mass. Wang et al. (2006) examined the ApaI, BsmI, and
TaqI VDR polymorphisms in 109 young Chinese women in relation to knee and
elbow torque measures. At the ApaI locus, A/A women exhibited lower elbow
flexor concentric peak torque and lower knee extensor eccentric peak torque
compared to either A/a or a/a carriers. For the BsmI locus, the b/b carriers dem-
onstrated lower knee flexor concentric peak torque than the B-allele carriers. No
associations were observed for the TaqI locus. Windelinckx and colleagues
(2007) examined the BsmI, TaqI, and FokI VDR polymorphisms in 493 middle-
aged and older men and women for association with various muscle strength
phenotypes, with BsmI and TaqI combined in a haplotype analysis. In women,
the FokI polymorphism was associated with quadriceps isometric and concentric
strength, with higher levels in f/f homozygotes compared to F-allele carriers. In
men, the BsmI/TaqI haplotype was associated with quadriceps isometric strength
with Bt/Bt homozygotes exhibiting greater strength than bT haplotype carriers.
In a study involving 107 COPD patients and 104 healthy controls, Hopkinson
et al. (2006) reported Fok1 F/F carriers had lower quadriceps isometric strength
than f-allele carriers. The b-allele of the Bsm1 polymorphism was associated

with greater strength compared to B-allele carriers in COPD patients but not in
controls. In summary, VDR genetic variation has been associated with muscle
strength variables in numerous studies, though inconsistencies have been noted.
Studies having examined the BsmI locus are mixed with regard to their findings
and future studies need to incorporate the haplotype of BsmI and TaqI rather
than looking at either site independently. The VDR FokI site is considered func-
tional (Arai et al. 1997; Jurutka et al. 2000) and two studies reported higher
strength in f/f compared to F/F carriers, so this site should be investigated more
thoroughly for possible clinical significance.
In summary, several genes have been associated with skeletal muscle strength
phenotypes in multiple studies. While none of these genes can yet be tagged as
conclusively contributing to inter-individual variation in strength phenotypes, their
consistency across multiple studies is encouraging. These genes will require
additional validation and clarification as to their specific roles in modifying
strength-related traits, with the eventual goal to determine their clinical importance
to sarcopenia.
239Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia
4.2 Genetic Variation and Skeletal Muscle Mass
Table 3 summarizes the genes that have been studied in relation to skeletal muscle
mass measurements, focusing on genes associated with baseline muscle mass
values; genes related to muscle mass adaptation to exercise training are discussed
in a later section. Genes that have been studied in only one paper or that have not
been replicated in some way and are not discussed here include: MTHFR (Liu et al.
2008b); CNTF and CNTFR (Roth et al. 2000, 2008); COL1A1 (Van Pottelbergh
et al. 2001); TNF (Liu et al. 2008a); IL15 and IL15RA (Pistilli et al. 2008); COMT
(Ronkainen et al. 2008); ESR1 (Ronkainen et al. 2008); NR3C1 (Peeters et al.
2008); and IGF2 (Schrager et al. 2004).
Angiotensin Converting Enzyme (ACE) The majority of papers examining the
ACE I/D polymorphism have been focused on muscle strength rather than muscle
mass phenotypes, though some studies have examined both. Most have shown no

significant association (Thomis et al. 1998a; Pescatello et al. 2006), though
Charbonneau et al. (2008) reported higher quadriceps muscle volume in D/D com-
pared to I/I carriers in a study of 225 older men and women (50–85 year). Thus, it
appears unlikely that ACE genotype contributes significantly to muscle mass phe-
notypes, which is similar to the conclusion for muscle strength traits.
Alpha Actinin 3 (ACTN3) As discussed above, several studies have examined
the potential for the ACTN3 R577X polymorphism to explain variability in muscle
strength measures. Many of those same papers have also examined muscle mass
variables, though the results are less consistent. Vincent and colleagues (2007) did
not observe any genotype difference in FFM determined by bioelectrical imped-
ance in their study of 90 young men. Norman et al. (2009) reported no significant
genotype associations with FFM determined by skinfold measurements in 120
young men and women. Delmonico et al. (2008) reported no significant genotype
associations with DXA-measured FFM in their study of 1,367 older adults (70–79
year). Walsh et al. (2008) examined 848 adult men and women (22–90 year) and
found that X/X women displayed lower levels of both total body FFM and lower
limb FFM compared with R/X + R/R women. Concomitant differences were noted
for muscle strength that were explained by the FFM differences, as discussed in the
previous section. No genotype-related differences were observed in men. Thus,
only Walsh et al. (2008) have found evidence of an association between muscle
mass and the ACTN3 null allele, indicating at best a minor role for this polymor-
phism in explaining inter-individual variability in this trait.
Androgen Receptor (AR) Walsh and colleagues (2005) examined the associa-
tion between the AR CAG-repeat polymorphism with muscle strength and mass
variables in two cohorts of older men and women. Though they found no associa-
tion between muscle strength and AR genotype, significant genotype associations
with FFM were observed in the men of both cohorts. The androgen receptor is a
nuclear transcription factor, for which testosterone is an important ligand. The
CAG-repeat sequence in exon 1 of the AR gene appears to modulate receptor tran-
scriptional activity (Chamberlain et al. 1994). Subjects were grouped according to

240 S.M. Roth
Table 3 Genes and gene sequence variants associated with skeletal muscle mass phenotypes in multiple studies
Gene References Variants Examined Subjects
Skeletal Muscle Mass
Measurements
AR
Walsh et al. (2005) CAG repeat 295 men (cohort 1) and 202 men
and women (cohort 2)
FFM (DXA) in men in both
cohorts
FST Walsh et al. (2007) Haplotype analysis 593 men and women FFM (DXA) in men
Kostek et al. (2009) A-5003T 23 young African American Biceps cross-sectional area
TRHR Liu et al. (2009) rs16892496, rs7832552 1,000 men women (cohort 1); 1,488 men
and women (cohort 2); 2,955 Chinese
men and women (cohort 3); 1,972
men and women from 593 families
(cohort 4)
LBM (DXA) in all four cohorts
VDR
Van Pottelbergh et al. (2002) TaqI, ApaI, FokI 271 older men FFM (DXA)
Roth et al. (2004) FokI, BsmI 302 older men FFM (DXA)
FFM, fat-free mass; LBM, lean body mass; DXA, dual-energy X-ray absorptiometry. Gene abbreviations are defined in the text.
241Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia
the length of the CAG repeat, with subjects grouped for short and long fragments.
Men in both cohorts with the long fragment lengths demonstrated significantly
greater appendicular skeletal muscle mass and higher relative total lean mass. The
results could not be explained by genotype-based differences in either bioavailable
or total testosterone. Additional work is required to determine the extent to which
the AR CAG-repeat polymorphism contributes to muscle mass variation, though
these consistent findings in two cohorts is encouraging.

Myostatin-Related Genes Despite the strong physiological evidence behind
myostatin as a candidate gene for muscle mass traits, genetic variation in the MSTN
gene has not been associated with muscle mass (Ivey et al. 2000; Kostek et al.
2005). Kostek et al. (2009) did report strength differences for MSTN in a small
number of African American subjects, as noted above. Two studies have examined
myostatin-related genes in relation to muscle mass phenotypes. In 593 men and
women across the adult age span, Walsh et al. (2007) reported significant associa-
tions between follistatin (FST) haplotype and leg FFM in men but not women, but
no association with FFM and haplotype structure in the myostatin receptor,
ACVR2B. Strength differences were discussed in the previous section. Kostek et al.
(2005) also examined the FST gene and found that African Americans carriers of
the FST T-allele had greater biceps CSA than A/A genotype carriers for the
A-5003T polymorphism, but sample sizes were small. There is little compelling
evidence that MSTN or myostatin-related genes are major contributors to skeletal
muscle mass, though minor contributions are indicated.
Thyrotropin-Releasing Hormone Receptor (TRHR) As described above, Liu
and colleagues (2008a) identified TRHR as a potential candidate gene for skel-
etal muscle mass from the first genome-wide association study for this trait.
After the initial genome-wide analysis that identified two polymorphisms in the
TRHR locus, the authors performed separate replication studies in three cohorts
consisting of over 6,000 total white and Chinese subjects and consistent signifi-
cant associations with LBM were observed in those analyses. Importantly, inter-
actions between TRHR and genes in the growth hormone/insulin-like growth
factor (GH/IGF1) pathway were explored and tentative connections were indi-
cated. Though only a single paper, the multiple replications pointing to TRHR
provide strength for this as a potentially important candidate gene for muscle
mass variation.
Vitamin D Receptor (VDR) VDR genetic variation has been studied fairly
extensively for muscle strength phenotypes, as described above, but fewer studies
have focused on skeletal muscle mass. Van Pottelbergh and colleagues (2001)

reported associations between the TaqI (T and t alleles)/ApaI (A and a alleles)
haplotypes and lean mass in 271 older men (>70 year). The highest lean mass was
observed in the At-At haplotype group, which differed most from haplotypes con-
taining T-allele homozygosity (e.g., aT-aT, AT-aT, and AT-AT haplotypes). This
relationship was not observed, however, in a group of younger men from the same
study. Roth et al. (2008) reported significant associations with the VDR FokI poly-
morphism (f and F alleles) and leg FFM in 302 older Caucasian men, with con-
comitant differences in muscle strength as noted above. No significant differences
242 S.M. Roth
were associated with the VDR BsmI site. This study is described in more detail in
the section on genes specifically associated with sarcopenia. Thus, only two studies
have examined VDR genotype in relation to skeletal muscle mass phenotypes, but
the results provide some evidence for positive association.
In summary, remarkably few studies have provided evidence of genetic associa-
tion of specific candidate genes with muscle mass phenotypes despite the strong
heritability of the trait. The strongest findings are perhaps those with the least evi-
dence, as TRHR and AR have at least been replicated, but only one research group
has contributed to each of those studies. Presumably the advent of genome-wide
association studies will provide a greater push for identifying potential candidate
genes with relevance to skeletal muscle mass.
4.3 Genetic Variation and Sarcopenia
While a number of studies have addressed specific genes and genetic variants in
relation to skeletal muscle strength and mass phenotypes, only one study to date has
specifically targeted a measure of sarcopenia per se. Roth and colleagues (2004)
analyzed the influence of the VDR BsmI and FokI variants on muscle strength and
mass in a cohort of 302 older (58–93 year) Caucasian men with measures of FFM
by DXA. VDR FokI genotype was significantly associated with total lean mass,
appendicular lean mass, and normalized appendicular lean mass (all P < 0.05), with
the F/F group demonstrating significantly lower mass than the F/f and f/f groups.
In addition, the group categorized the men as normal or sarcopenic based on the

definition of Baumgartner et al. (1998), which relies on a cutoff value based on
appendicular FFM relative to body weight (kg/m
2
). Logistic regression revealed a
significant 2-fold higher risk for sarcopenia in VDR Fok I F/F homozygotes than
carriers of the f-allele (OR = 2.17; 95%CI = 1.19–3.85; P = 0.03). Quadriceps mus-
cle strength was also significantly lower in the F/F group compared to the F/f and
f/f groups, but this association was eliminated when the analysis controlled for dif-
ferences in total body lean mass. No significant differences were associated with
the VDR BsmI site. Thus, VDR FokI genotype was significantly associated with
lean mass and sarcopenia in this cohort of older Caucasian men, with concomitant
differences in muscle strength. Vitamin D deficiency has been consistently associ-
ated with lower muscle strength (Ceglia 2008), and appears to be related to type II
fiber atrophy (Pfeifer et al. 2002), thus making it an important potential mechanism
in the etiology of sarcopenia in some individuals (Montero-Odasso and Duque
2005). The FokI polymorphism in the VDR gene affects the translational start site
of the gene (Arai et al. 1997; Jurutka et al. 2000) thus making it a potentially func-
tional polymorphism, though other variants in the VDR gene may interact in a more
complex haplotype (Uitterlinden et al. 2004). Obviously, considerable work
remains to be done to take the many genes outlined above and address the clinical
relevance of sarcopenia in particular.
243Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia
4.4 Genetic Variation and Skeletal Muscle Adaptation
to Training
Though not an emphasis of this chapter, several studies have examined the role of
genetic variation in the adaptation of skeletal muscle to exercise training, especially
strength or resistance training. The adaptation of skeletal muscle to strength train-
ing is a heritable trait in itself (Thomis et al. 1998b) and linkage studies have been
successfully performed using such traits as outcome variables, as described above
(Chagnon et al. 2000; Sun et al. 1999). Moreover, specific genes have been studied

and specific gene variants identified as being potentially important to skeletal
muscle adaptation. The bulk of these studies have been described most recently in
the updated Human Gene Map for Performance and Health-Related Fitness
Phenotypes (Bray et al. 2009).
Genetic variation important to skeletal muscle adaptation has relevance for sar-
copenia in multiple contexts. First, the identification of particular genes that con-
tribute to inter-individual variation in skeletal muscle adaptation provide insights
into the basic biology of skeletal muscle, which could be exploited in multiple ways
to facilitate new or improved intervention techniques for muscle disorders and sar-
copenia in particular. Second, the possibility exists that the same gene variants
important to skeletal muscle adaptation could also be important to skeletal muscle
development and thus baseline phenotypes, though the case can equally be made
that different genetic contributions can be expected for these two different traits.
Finally, because exercise training in general and strength training in particular are
considered some of the most important interventions for the prevention and treat-
ment of sarcopenia (Roth et al. 2000), understanding the genetic contributions to
muscle adaptation, especially in older men and women, will allow improved appli-
cation of such interventions via genetic screening.
A number of genes have been identified as potentially important for skeletal
muscle adaptation, though arguably none have emerged as clinically meaningful as
of this writing. Similar to the situation with baseline skeletal muscle phenotypes,
the bulk of these genes remain unreplicated or replicated across different training
stimuli or measurement methods, making traditional genetic replication analysis
challenging. In fact, the variations on exercise training interventions are arguably
more numerous than those related to measurement of skeletal muscle strength, and
variations on both of these are often seen across different gene association studies
related to muscle strength adaptation. Genes studied in relation to skeletal muscle
adaptation include: PPARD with muscle volume response to lifestyle intervention
(Thamer et al. 2008); IGF1, IGFBP3, and PPP3R1 (calcineurin) with muscle
strength and volume responses to strength training (Kostek et al. 2005, Hand et al.

2007); RST with upper arm muscle strength and muscle CSA responses to strength
training (Pistilli et al. 2007); TNF, TNFR1, TNFR2, and IL6 with measures of
physical function before and after exercise training (Nicklas et al. 2005); IGF2,
ACTN3, and MYLK in different studies with muscle damage in response to a dam-
aging exercise protocol (Devaney et al. 2007; Clarkson et al. 2005b); ACE with
244 S.M. Roth
muscle strength and mass responses to various exercise training protocols (Folland
et al. 2000; Charbonneau et al. 2008; Thomis et al. 1998a; Williams et al. 2005;
Pescatello et al. 2006; Frederiksen et al. 2003); IL15 and IL15RA (IL-15 receptor)
with muscle strength and size responses to strength training (Riechman et al. 2004,
Pistilli et al. 2008); MSTN and FST polymorphisms with muscle strength and size
traits in response to strength training (Thomis et al. 1998b; Kostek et al. 2009; Ivey
et al. 2000); ACTN3 with muscle strength and size responses to strength training
(Clarkson et al. 2005a; Delmonico et al. 2007); and BMP2 with muscle size
response to strength training (Devaney et al. 2009).
5 Conclusions and Future Directions
Despite remarkably high heritability values, only modest progress has been made
in identifying the specific genetic contributors to skeletal muscle strength and mass
phenotypes. Only seven genes have been positively associated with strength-related
traits in multiple cohorts (Table 2), and the findings are not always consistent
within the replication analyses. Similarly, only four such genes have been identified
for muscle mass and two of those genes were internally replicated rather than being
confirmed in a second paper (Table 3). No genes have been replicated for associa-
tion with sarcopenia per se, though VDR has been associated with sarcopenia in one
study and associated with muscle mass and strength phenotypes in multiple
studies.
Not only have few genes been identified, but their contribution to genetic
variation is also generally quite small. None of the genes identified in the present
chapter have been shown to conclusively contribute more than 5% of the inter-
individual variation to their respective traits, and most are on the order of 1–3%.

These results mirror what has recently been found for other highly heritable
traits: genome-wide association studies are finding genes with relatively small
influence that in no way explain the overall genetic influence predicted by heri-
tability estimates (Maher 2008). This could reflect the major limitation of
genome-wide association studies and most genetic association studies to date in
that these have focused almost exclusively on single nucleotide polymorphisms,
which though important are not the only DNA-related components that contribute
to genetic influence. In addition to typical polymorphisms, copy number variation
(CNV; multiple copies of the same gene), epistasis (multiple genes coordinated
in a pathway), complex gene*environment interactions, and epigenetic factors are
also contributing to the genetic component of inter-individual variability
(Altshuler et al. 2008) and these more complex phenomena are just beginning to
be studied in large-scale investigations.
An important contributor to inter-individual variation in age-related muscle
traits will likely be epigenetic factors, which have already been shown to be impor-
tant to aging tissues in general (Kahn and Fraga 2009). Epigenetics generally refers
245Genetic Variation and Skeletal Muscle Traits: Implications for Sarcopenia
to chemical modifiers to DNA and histone proteins that alter DNA regulation
without a direct change to the DNA sequence itself with consequences for normal
development and disease risk (Hirst and Marra 2009). DNA methylation has been
shown to decline with aging in several species including humans (Bollati et al.
2009) and DNA methylation has important consequences for gene expression.
Importantly, modification of epigenetic factors appears to be related to environmen-
tal conditions (Foley et al. 2009; Baccarelli et al. 2009). So, both age and environ-
ment are likely to contribute to epigenetic changes in skeletal muscle tissue that will
alter gene regulation and contribute to age-related losses in strength and mass, thus
affecting physical function. How environmental conditions will alter epigenetic
factors in a way meaningful for skeletal muscle traits and sarcopenia risk is as yet
unclear, but certainly this represents another avenue of exploration for future
studies.

An underlying theme when considering the genetic aspects of skeletal muscle
traits generally and sarcopenia in particular is that of a “threshold” level for these
traits below which physical function (e.g., activities of daily living) is impaired.
Once a person’s strength falls below a certain threshold, physical function becomes
impaired. Such a threshold would surely be defined differently for each individual,
but within reason we can expect clinically meaningful thresholds to be established
across various physical characteristics, especially sex, age, height, weight, and
body composition. This threshold concept has been discussed by a number of
groups (Ferrucci et al. 1997; Walston and Fried 1999; Visser et al. 2005; McNeil
et al. 2005).
Because genetic variation (including epigenetics) will tend to have subtle
influences on skeletal muscle and sarcopenia-related traits, the general hypoth-
esis is that genetic variation will tend to push trait values closer to or farther
away from this threshold, thus altering an individual’s risk for impaired physical
function. Thus, identifying individuals with genetic susceptibility to lower levels
of skeletal muscle strength or mass who are closer to their likely threshold for
physical limitation will allow for early, targeted interventions to help prevent
early losses. This is the concept behind personalized or genetic medicine. Early
identification for individuals genetically susceptible to sarcopenia could result
in a dramatic improvement in health care costs, by introducing interventions
prior to the onset of associated infirmities. Of course, finding these genes and
developing the individualized interventions will take many years if the last
decade provides any clue to future progress. One potential approach to speed
discovery will be to examine genes related to bone structure and mass, which
may have a pleiotropic influence on skeletal muscle traits (Karasik and Kiel
2008). The development of more sophisticated genome-wide association studies
that include copy number variants may also aid in this search. Even if genes of
only minor effect are identified that don’t lend themselves to genetic screening
and personalized medicine, those genes will point to potential physiological
pathways that can be manipulated through more typical means and lend insight

into the underlying etiology of sarcopenia in different individuals (Khoury et al.
2007; Burke 2003).