Ageing Research Reviews 8 (2009) 328–338

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Ageing Research Reviews

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Review

The impact of sarcopenia and exercise training on skeletal muscle satellite cells
Tim Snijders, Lex B. Verdijk, Luc. J.C. van Loon *
Department of Human Movement Sciences, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University Medical Centre+, Maastricht, The Netherlands

A R T I C L E I N F O A B S T R A C T

Article history: It has been well-established that the age-related loss of muscle mass and strength, or sarcopenia, impairs
Received 29 January 2009 skeletal muscle function and reduces functional performance at a more advanced age. Skeletal muscle
Received in revised form 4 May 2009 satellite cells (SC), as precursors of new myonuclei, have been suggested to be involved in the
Accepted 13 May 2009
development of sarcopenia. In accordance with the type II muscle fiber atrophy observed in the elderly,
recent studies report a concomitant fiber type specific reduction in SC content. Resistance type exercise
Keywords: interventions have proven effective to augment skeletal muscle mass and improve muscle function in
Aging
the elderly. In accordance, recent work shows that resistance type exercise training can augment type II
Elderly
Atrophy
muscle fiber size and reverse the age-related decline in SC content. The latter is supported by an increase
Resistance exercise in SC activation and proliferation factors that generally appear following exercise training. Present
Muscle hypertrophy findings strongly suggest that the skeletal muscle SC control myogenesis and have an important, but yet
Muscle stem cells unresolved, function in the loss of muscle mass with aging. This review discusses the contribution of
skeletal muscle SC in the age-related loss of muscle mass and the efficacy of exercise training as a means
to attenuate and/or reverse this process.
ß 2009 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Since myonuclei are post-mitotic, the regenerative capacity of

muscle fibers depends on a pool of undifferentiated myogenic
Aging is characterized by a gradual decline in the regenerative precursor cells, also known as satellite cells (SC) (Mauro, 1961;
properties of cell tissue, consequently reducing cognitive, motor Moss and Leblond, 1970, 1971). During postnatal development, SC
and/or sensory function. Though skeletal muscle tissue is known to proliferate and differentiate into new myonuclei to support the
have a slow cellular turnover rate, the regenerative capacity of increasing needs of the growing myofibers. In mature muscle
myofibers in response to injury is remarkably high (Whalen et al., fibers, SC are typically quiescent but can become activated in
1990). Yet, the effectiveness by which skeletal muscle regenerates response to trauma. After proliferation, SC will fuse together with
itself seems to be reduced with aging (Grounds, 1998). The gradual existing myofibers. However, upon damage they will fuse with
loss of muscle mass and strength with aging, or sarcopenia, results each other forming new myofibers, replacing damaged fibers and/
in a reduction in muscle function and performance (Evans, 1997; or myonuclei (Hawke and Garry, 2001; Mauro, 1961; Moss and
Porter et al., 1995). On a myocellular level sarcopenia is Leblond, 1970, 1971). During normal muscle activity subtle
characterized by a reduction in muscle fiber number as well as myofiber injury habitually occurs, especially with increasing age
fiber size, with specific type II muscle fiber atrophy (Charette et al., (Brooks and Faulkner, 1996). Hence, ongoing muscle repair is
1991; Dreyer et al., 2006; Kim et al., 2005b; Kosek et al., 2006; needed for muscle fiber maintenance, and requires a continuous
Larsson et al., 1978; Lexell and Downham, 1992; Lexell et al., 1988; supply of functional SC throughout life. A decline in the number of
Martel et al., 2006; Petrella et al., 2006; Verdijk et al., 2007). SC (Kadi et al., 2004a; Renault et al., 2002; Verdijk et al., 2007) and/
Though the age-related reduction in muscle cross-sectional area is or their inability to become active and proliferate in response to
mainly attributed to the loss of muscle fibers (Lexell et al., 1988), anabolic stimuli (Conboy et al., 2003; Conboy and Rando, 2002)
this review will mainly focus on the age-related reduction in may contribute to the age-related loss of muscle mass and
muscle fiber size. strength. Exercise training represents an effective interventional
strategy to attenuate and/or even reverse the age-related loss of
muscle mass and function (Charette et al., 1991; Esmarck et al.,
2001; Fiatarone et al., 1994; Frontera et al., 1988; Hikida et al.,
2000; Ivey et al., 2000; Kosek et al., 2006; Martel et al., 2006;
* Corresponding author at: Department of Human Movement Sciences, Faculty of
Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD
Verdijk et al., 2009a,b). Recent studies show that the increase in
Maastricht, The Netherlands. Tel.: +31 43 3881397; fax: +31 43 3670976. muscle mass and myonuclear content in response to exercise is
E-mail address: [email protected] (Luc. J.C. van Loon). accompanied by an increase in SC number and SC activation status

1568-1637/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.arr.2009.05.003
 T. Snijders et al. / Ageing Research Reviews 8 (2009) 328–338 329

(Hikida et al., 1998; Kadi et al., 2004c; Kadi and Thornell, 2000; consider the role of the myonuclei in muscle fiber atrophy and
Kosek et al., 2006; Mackey et al., 2007; Olsen et al., 2006; Petrella exercise induced muscle hypertrophy.
et al., 2006; Roth et al., 2001; Verdijk et al., 2009a). The latter has
resulted in a renewed interest in the physiological function of SC in 2.1. Myonuclei
the skeletal muscle adaptive response to exercise in the young and
elderly. Despite the proposed regulatory function of SC in skeletal Myofibers contain hundreds of myonuclei and it is generally
muscle fiber hypertrophy, there is considerable debate on the believed that each myonucleus controls the gene expression over a
functional role of changes in SC content in the etiology of muscle certain amount of cytoplasm. The latter is referred to as the
atrophy and muscle wasting. The behaviour of SC in the skeletal myonuclear domain (Cheek, 1985; Hall and Ralston, 1989). It has
muscle adaptive response to anabolic stimuli has been well- been hypothesized that changes in muscle fiber size, i.e. muscle
described (Kadi, 2008; Kadi et al., 2005). The present review fiber atrophy or hypertrophy, are accompanied by changes in the
provides an updated view on the proposed contribution of skeletal number of myonuclei, the myonuclear domain size, or both (Allen
muscle SC in regulating skeletal muscle mass. As such, changes in et al., 1999; Edgerton and Roy, 1991) (Fig. 1). Although changes in
muscle fiber SC content in the age-related loss of muscle mass and myonuclear number have been presented in animal models (Allen
strength and the efficacy of exercise intervention to attenuate and/ et al., 1995, 1996, 1997; Hikida et al., 1997; Wada et al., 2002;
or reverse this process will be evaluated. Zhong et al., 2005), human data generally fail to show any changes
in myonuclear content in response to muscle fiber atrophy (Ohira
2. Satellite cells et al., 1999). Recent findings suggest that an increase in
myonuclear number will only occur when muscle fiber size
During myogenesis, multinucleated skeletal muscle fibers are increases substantially (Kadi and Thornell, 2000; Petrella et al.,
formed by the fusion of large numbers of mononucleated 2006). No changes are to be expected when changes in muscle fiber
myoblasts (Cooper and Konigsberg, 1961; Stockdale and Holtzer, size are below 15% (Kadi and Thornell, 2000). It is hypothesized
1961). Because myonuclei are unable to proliferate (i.e. post- that in response to resistance type exercise, the myonuclear
mitotic), repair and renewal of myofibers is designated to a pool of domain size can increase to a certain extent (i.e. 2250 mm2
SC (Hawke and Garry, 2001; Mauro, 1961; Moss and Leblond, 1970, (Petrella et al., 2008)) by the upregulation of protein synthesis.
1971). In adult muscle, SC are in a quiescent state, residing in a Thereafter, the incorporation of new myonuclei seems to be
niche between the basal lamina and the sarcolemma of their required to allow further hypertrophy. This ‘‘ceiling theory’’
associated muscle fiber (Mauro, 1961). These myogenic progenitor implies that myonuclear domain size has a threshold, beyond
cells do not exhibit gene expression and/or protein synthesis when which additional nuclei are prerequisite (Petrella et al., 2006,
residing in such a quiescent state. However, SC will become 2008). The latter is consistent with the idea that myonuclei support
activated in response to stress induced by weight bearing activities gene expression for a finite volume of cytoplasm. Because
and/or trauma (Hawke and Garry, 2001) (Fig. 1). To elucidate the myonuclei are post-mitotic, SC are required to provide additional
behaviour of SC in skeletal muscle hypertrophy we first need to myonuclei when needed.

Fig. 1. Myonuclei and satellite cells (SC) in the skeletal muscle adaptive response. (A) muscle cross section of a muscle fiber containing several myonuclei. Muscle hypertrophy
is associated with an increase in myonuclear domain size (due to increased protein synthesis induced by the existing myonuclei) and/or an increase in myonuclear number. In
contrast, muscle atrophy is associated with a reduced myonuclear number and/or domain size. (B) Longitudinal section of a muscle fiber containing several myonuclei and a
SC. Skeletal muscle SC normally lie quiescent between the basal lamina and the plasma membrane of the associated myofiber. Upon injury or mechanical loading, SC are
activated and proliferate. Following differentiation, new myonuclei will be incorporated into the myofiber to allow muscle hypertrophy. In addition, part of the proliferated SC
will return to quiescence to replenish the SC pool. Alternatively, differentiated cells can fuse together to generate new myofibers in case of significant myofiber damage (not
shown).
330 T. Snijders et al. / Ageing Research Reviews 8 (2009) 328–338

2.2. Satellite cell activation 2006). However, whether NO, Notch or other growth factors
determine the activation of the intrinsic cell signal S1P remains to
The first step in the process of supplying new myonuclei (which be established. Moreover, it remains to be elucidated whether the
either fuse to form new myofibers, or allow extensive hypertrophy function of S1P, Notch, and NO is operative in humans.
of existing muscle fibers) is the activation of SC. In an elegant
overview, Kadi et al. (2005) previously described a range of auto-/ 2.3. Satellite cell proliferation and differentiation
paracrine as well as endocrine factors (i.e. IGF-I, IGF-Iea, FGF, MGF
and HGF) that are likely to contribute to the control of SC To regenerate skeletal muscle fibers, SC are required to activate,
activation. More recently, the potential role of nitric oxide and proliferate, and differentiate to generate new myonuclei. The latter
Notch signaling in SC activation has gained much interest. Nitric either fuse into pre-existing myofibers or fuse together to form
oxide (NO) is normally produced in low-level pulses (Tidball et al., new myofibers to repair muscle damage. The extent to which SC
1998) by NO-synthase (NOS) in skeletal muscle tissue under respond to damage induced myogenesis, relies on the expression of
conditions where SC are quiescent (Alderton et al., 2001). However, Pax and the myogenic regulatory factors (MRFs) comprising Myf5,
NOS is upregulated by exercise, stretch, loading, and injury, leading MyoD, myogenin, and MRF4 (Zammit et al., 2006). Sequential
to the release of NO (Anderson and Meyer, 2000; Balon and Nadler, suppression and/or activation of Pax3/7 and MRFs is necessary for
1997; Fujii et al., 1998; Roberts et al., 1999; Tidball, 2005; Tidball the progression of skeletal myoblasts through the different stages
et al., 1998, 1999). The latter has been reported to activate SC of the cell cycle. In rodent muscle, it has been observed that
(Anderson, 2000; Wozniak and Anderson, 2007). SC activation by expression of Myf5 and/or MyoD is required to commit SC to the
NO is mediated through the activation of guanylate cyclase and myogenic lineage, and both factors are then co-expressed during
generation of cyclic guanosine monophosphate (cGMP). Together, proliferation (Sabourin and Rudnicki, 2000). Subsequently, under
cGMP and NO induce the expression of follistatin in adult muscle the action of myogenin and MRF4, the committed cells (myoblasts)
tissue, which mediates myogenic stimuli (Pisconti et al., 2006). In can enter the process of terminal differentiation into myotubes
addition, follistatin has been shown to inhibit myostatin, a and/or mature myofibers (Sabourin and Rudnicki, 2000). Alter-
negative regulator of myogenesis (Amthor et al., 2007; Lee and natively, SC can escape the route of terminal differentiation and
McPherron, 2001; Matsakas and Diel, 2005; Thomas et al., 2000). return to a quiescent state (Moss and Leblond, 1971). The latter is
Interestingly, Wozniak and Anderson (2007) reported an increase thought to be facilitated by the expression of Pax7 in SC (Kuang
in SC activity in unstretched muscle of mdx and NOS-I(/) mice. et al., 2006; Seale et al., 2000), and causes the pool of
The latter implies that NO might also play a role in maintaining SC undifferentiated quiescent SC to remain balanced and prepared
quiescence. Together, these results suggest that large fluctuations for additional myogenesis (Moss and Leblond, 1971; Olguin and
in NO concentration modulate SC activation. Olwin, 2004; Zammit et al., 2002). This is in line with recent in vivo
The NO-dependent release of hepatocyte growth factor (HGF) is data by Crameri et al. (2007), who suggested that the increase in
also thought to activate SC. Upon muscle fiber damage a bolus of Pax7 expression following electrical stimulation is associated with
NO is released, resulting in the rapid release of HGF on the part of the SC pool returning to quiescence. In addition, increased
extracellular matrix of the surrounding myofibers (Tatsumi et al., myogenin expression was proposed to be associated with a certain
2002, 2006). The latter tends to be proportional to the amount of part of SC progressing through terminal differentiation (Crameri
injury (Hawke, 2005). HGF then binds to its receptor, c-met, on the et al., 2007). These findings suggest that MRFs as well as Pax7 have
SC plasma membrane, thereby promoting SC activation and a decisive role in SC lineage determination. Although SC are
proliferation (Tatsumi et al., 2002; Wozniak and Anderson, thought to be responsible for the upregulation of MRFs in skeletal
2007) and inhibiting differentiation (Gal-Levi et al., 1998). The muscle, recent studies in humans show that the upregulation of
proposed role of HGF in SC activation is thought to be mediated myogenin expression following a single bout of endurance type
through the mitogen-activated protein kinase (MAPK) signaling exercise occurs within the myonuclei as opposed to the SC (Kadi
cascade. In accordance, mechanical loading (Jones et al., 2005; et al., 2004b). The latter tends to be in line with previous work in
Williamson et al., 2003; Wretman et al., 2001) and HGF (Recio and animal muscle tissue, suggesting that myonuclei play a decisive
Merlino, 2002) have been reported to activate the p38a/b MAPK role in the increase in MRF expression following electrical
cascade. stimulation, stretch and/or fiber damage (Eppley et al., 1993;
Besides NO-mediated SC activation, Notch signaling might also Jacobs-El et al., 1995; Koishi et al., 1995). Overall, MRFs are thought
regulate SC activation. Upon muscle fiber damage, an upregulation to represent key regulators in myogenesis. However, the specific
of Notch ligand-delta expression is followed by SC activation time course, pattern, location, and function of the MRF protein
(Conboy et al., 2003). Notch ligands on adjacent cells bind to expression remain to be further elucidated.
Notch-1 receptors on quiescent SC (Conboy and Rando, 2002). The
latter releases the intracellular domain of Notch protein which is 3. Aging
transmitted to the cell nucleus where it regulates gene expression
by activating myogenic transcription factors (Carlson and Conboy, The gradual loss of muscle mass and strength is one of the more
2007). In accordance with the proposed role of Notch in SC consistent hallmarks of normal aging. In many cases, the loss of
activation, gene expression of the Notch-1 antagonist Numb has muscle mass and strength impairs functional capacity leading to
been shown to be reduced following muscle fiber damage in mice disability and the subsequent loss of independence. These age-
(Conboy et al., 2003; Conboy and Rando, 2002). Based on animal related changes in muscle mass can, at least partly, be attributed to
studies and in vitro experiments, Notch is now considered critical a decline in physical activity, a less than optimal diet and the
in muscle fiber maintenance, playing a regulating role in the prevalence of disease. Understanding the etiology of sarcopenia in
progression of SC through the cell cycle. the elderly will help to define more effective exercise, nutritional
Though both NO and Notch seem to play a key role in SC and/or pharmaceutical strategies to prevent, delay and/or reverse
activation, the exact triggers that set off the process of SC the loss of muscle mass and strength with aging. SC play a key role
activation remain to be determined. For example, it has been in the maintenance, growth and repair of myofibers (Heslop et al.,
proposed that the intrinsic cell signal sphingosine-1-phosphate 2001; Mauro, 1961; Moss and Leblond, 1970, 1971). As such, a
(S1P), which is produced in the inner leaflet of the SC’s plasma decline in the number of SC and/or their ability to become
membrane, is essential for SC to enter the cell cycle (Nagata et al., activated might contribute to the development of sarcopenia.
 T. Snijders et al. / Ageing Research Reviews 8 (2009) 328–338 331

3.1. Structural changes in myofiber properties with aging skeletal muscle groups respond similarly to the aging process. The
diversity between muscle groups and individual variability should
The structural changes in muscle fiber type characteristics with be kept in mind when discussing different aspects of sarcopenia.
human aging have been well-described (Porter et al., 1995). Post-
mortem analyses of human vastus lateralis muscle has shown that 3.2. Myonuclei in aging muscle
by the ninth decade 50% fewer type I and type II muscle fibers are
present when compared with muscle tissue in 20 yr old subjects Sarcopenia is characterized by a progressive but more
(Lexell et al., 1988). Furthermore, a shift in muscle fiber type prolonged time course of muscle wasting when compared with
distribution towards a higher percentage type I vs type II muscle other muscle atrophy models (e.g. bed rest, space flight, hindlimb
fibers becomes apparent at a more advanced age (Charifi et al., suspension). Therefore, it is questionable whether similar myo-
2003; Dreyer et al., 2006; Frontera et al., 2000; Hameed et al., 2003; cellular events as established in other muscle atrophy models also
Kim et al., 2005b; Larsson et al., 1978; Verdijk et al., 2007). Yet, apply to the process of sarcopenia. Unfortunately, only few data
others failed to observe any significant changes in muscle fiber exist on the changes in myonuclear number and domain size with
type composition with age (Grimby et al., 1984; Kosek et al., 2006; aging. An apparent discrepancy exists between findings reported
Lexell et al., 1986, 1988; Sato et al., 1984). Studies performing in different human studies (Dreyer et al., 2006; Kadi et al., 2004a;
histochemical analyses of muscle biopsies generally agree that Manta et al., 1987; Petrella et al., 2006; Roth et al., 2000; Verdijk
type II muscle fiber size diminishes with age, whereas type I et al., 2007). Some report an age-related reduction in muscle fiber
muscle fiber size tends to remain rather constant (Charette et al., size without any changes in myonuclear number, resulting in a
1991; Coggan et al., 1992; Dreyer et al., 2006; Frontera et al., 2008; decline in myonuclear domain size (Dreyer et al., 2006; Manta
Kim et al., 2005b; Larsson et al., 1978; Lexell et al., 1988; Martel et al., 1987; Petrella et al., 2006; Roth et al., 2000). In contrast,
et al., 2006; Petrella et al., 2006; Sato et al., 1984; Verdijk et al., others have reported an increase in the number of myonuclei with
2007) (Table 1). Although type II muscle fiber atrophy has been increasing age (Kadi et al., 2004a; Verdijk et al., 2007). These
found to be consistent in timing and magnitude with the loss of inconsistent results might be attributed to a lack of muscle fiber
muscle strength observed with aging, the loss of muscle fibers type specific data. Because age-related atrophy is generally
represents the main factor responsible for the decline in muscle restricted to the type II muscle fibers, it would be sensible to
CSA with age (Doherty, 2003; Lexell et al., 1988). assume that changes in myonuclear number and domain size occur
Human aging has also been associated with fiber type grouping. specifically in type II muscle fibers in elderly muscle. In
It appears that especially type II muscle fibers are associated with accordance, we recently observed a more pronounced reduction
an increased amount of denervation (Roos et al., 1997; Vander- in type II vs type I muscle fiber myonuclear domain size in elderly
voort, 2002). In an attempt to minimize fiber loss, collaterals from vs young adults (type I: 16%, and type II: 31%). The latter
the type I motor neurons expand to some of the denervated type II resulted from a lower type II muscle fiber size in the elderly, which
fibers (Kirkendall and Garrett, 1998; Roos et al., 1997; Vander- was accompanied by a larger myonuclear number of both type I
voort, 2002). The latter will enlarge the type I motor unit territory (+17%) and type II (+13%) muscle fibers (Verdijk et al., 2007). The
at the expense of the type II muscle fibers. Consequently the underlying mechanisms of the increase in the number of
muscle tends to loose its typical chessboard configuration myonuclei with age and the specific decrease of type II muscle
(Kirkendall and Garrett, 1998; Roos et al., 1997; Vandervoort, fiber myonuclear domain size remain unclear. It could be
2002), due to the grouping of fibers expressing the same MHC hypothesized that the changes in myonuclear number and/or
isoforms. It has been hypothesized that this age-related fiber type domain size might be a compensatory response, directly or
grouping contributes to the loss of muscle mass and/or strength in indirectly related to changes in SC number with age.
the elderly (Kirkendall and Garrett, 1998). It is worth noting that
the effect of aging on skeletal muscle has primarily been 3.3. Satellite cells in aging muscle
investigated in the lower extremities, particularly the vastus
lateralis muscle. As such, it remains to be determined if other At birth, SC account for 15% of the entire myofiber nuclei
population (Thornell et al., 2003). The latter decreases to 1–6% of
Table 1 total myonuclear content in mature muscle fibers (Roth et al.,
Impact of age on human muscle fiber size. 2000; Schmalbruch and Hellhammer, 1976). As SC are essential for
Study Sex Age (yrs) Muscle Muscle fiber size muscle fiber maintenance, growth and regeneration, an age-
related decline in the number of SC and/or their inability to become
Type I Type II
activated and proliferate upon stimuli might contribute to muscle
Coggan et al. (1992) M 26  1 vs 64  1 gastrocnemius $ # (13%) fiber atrophy observed in the elderly. So far, no consensus has been
F 23  1 vs 63  1 gastrocnemius $ # (24%) reached on whether SC numbers decline with a more advancing
Dreyer et al. (2006) M 21–35 vs >60 vastus lateralis $ # (25%) age. Some reports have shown an age-related decline in SC content
Frontera et al. (2008) M/F 71  5 vs 80  5 vastus lateralis $ " (NS) in rat tibialis anterior (Brack et al., 2005; Dedkov et al., 2003) and
Kim et al. (2005b) M/F 20–35 vs 60–75 vastus lateralis $ # (18%) extensor digitorum longus muscle of mice (Gibson and Schultz,
Kosek et al. (2006) M/F 20–35 vs 60–75 vastus lateralis $ # (19%)
1983; Shefer et al., 2006), while others did not observe any decline
Larsson et al. (1978) M 20–29 vs 60–65 vastus lateralis $ # (33%)
Lexell et al. (1988) M 15–22 vs 80–83 vastus lateralis $ # (26%) in SC number in rat levator (Nnodim, 2000) or mice soleus muscle
with increasing age (Schafer et al., 2005). Similar to the rodent
Petrella et al. (2006) M 20–35 vs 60–75 vastus lateralis $ # (14%)
F 20–35 vs 60–75 vastus lateralis $ # (27%)
studies, no conclusive evidence has been generated from human
studies. Some report a reduction in skeletal muscle SC content in
Sato et al. (1984) F 39 vs 70 pectoralis minor " (8%) # (12%) the vastus lateralis (Sajko et al., 2004; Verdijk et al., 2007), biceps
Verdijk et al. (2007) M 20  1 vs 76  1 vastus lateralis $ # (27%)
brachii (Renault et al., 2002), tibialis anterior (Kadi et al., 2004a),
Note: This table provides an overview of the impact of aging on muscle fiber size, in and masseter (Renault et al., 2002) muscle in the elderly, whereas
both type I and type II muscle fibers. Only studies that have determined the effects others report no age-related changes (Dreyer et al., 2006; Hikida
of aging on muscle fiber size in a fiber type specific manner are included. Type
I = slow twitch muscle fibers; Type II = fast twitch muscle fibers; M = male;
et al., 1998; Petrella et al., 2006; Roth et al., 2000; Verney et al.,
F = female; " = significant increase compared with young subjects; $ = no change; 2008) (Table 2). The apparent discrepancy is likely attributed to the
# = significant reduction compared with young subjects; NS = not significant. different age-categories of the subjects assessed in these studies. In
332 T. Snijders et al. / Ageing Research Reviews 8 (2009) 328–338

Table 2 for SC to enter and/or complete their cell cycle. In rodent muscle,
Impact of aging on skeletal muscle satellite cell content.
the magnitude of upregulation of MRF mRNA expression appears
Study Sex Age (yrs) Muscle Satellite cell to be proportional to the degree of sarcopenia (Edstrom and
content Ulfhake, 2005). This suggests that senescent muscle remains in a
Dreyer et al. (2006) M 21–35 vs >60 vastus lateralis $ state of failing regenerative effort (Kosek et al., 2006; Musaro et al.,
Hikida et al. (1998) M 23  6 vs 65  6 vastus lateralis $ 1995). In contrast to the upregulated basal MRF mRNA expression,
Kadi et al. (2004a) M 20–32 vs 70–83 tibialis anterior # (37%)
Notch signaling has been reported to decline at a more advanced
F 20–32 vs 70–83 tibialis anterior # (25%) age. Notch activation seems essential in the regulation of SC
activation, proliferation and differentiation (Conboy and Rando,
Renault et al. (2002) M/F 23  1 vs 74  4 biceps brachii # (62%)
M/F 23  1 vs 74  4 masseter # (70%)
2002; Nofziger et al., 1999). Conboy et al. (2003) showed that the
regenerative potential of SC is not triggered by injury in old mice
Roth et al. (2000) M 25  3 vs 69  3 vastus lateralis $
due to attenuated Notch activation. In line, Schubert (2004)
F 26  1 vs 67  3 vastus lateralis $
reported more pronounced upregulation of Notch delta expression
Sajko et al. (2004) M/F 29  2 vs 71  1 vastus lateralis # (36%)z in response to muscle injury in young vs old mice. In humans,
Petrella et al. (2006) M 20–35 vs 60–75 vastus lateralis $ Notch mRNA expression has been shown to increase following
F 20–35 vs 60–75 vastus lateralis $ 12 wks of resistance type exercise training in both young and older
Verdijk et al. (2007) M 20  1 vs 76  1 vastus lateralis # (44%) y
subjects (Carey et al., 2007). However, the same study reported
that young subjects showed an absolute higher Notch gene
Note: This table provides an overview of the studies that have assessed the effects of expression at all time points when compared with the elderly.
aging on satellite cell content. Only studies that have compared the effects of aging
on satellite cell content between two (or more) different age-categories within one
Both SC number and their activation appear to be altered in
study have been included in this table. M = male; F = female; $ = no change; aged muscle. Therefore, future studies should not only focus on
# = significant reduction compared with young subjects; NS = not significant. increasing the SC pool but also investigate effective strategies to
Satellite cell content: measured as mean number of satellite cells per fiber cross- stimulate SC activation. Both strategies may be of vital importance
section; ySignificant lower number of SC in specifically type II muscle fibers.
to prevent, delay, and/or even reverse the loss of muscle mass with
zMuscle samples were excised post-mortally. All studies determined satellite cells
content per muscle fiber by means of immunohistochemical analysis, except for aging.
Roth et al. (2000) who used electron microscopy.
4. Satellite cell adaptive response
human skeletal muscle, the pool of SC appears to be maintained
into the seventh decade of life (Hikida et al., 1998; Petrella et al., Resistance and endurance type exercise training have been
2006; Roth et al., 2000), but seems to decline thereafter (Kadi et al., shown to improve muscle mass and strength, and increase
2004a; Renault et al., 2002; Verdijk et al., 2007). performance capacity in both the young and elderly. However,
As sarcopenia is generally associated with type II muscle fiber the mechanism(s) by which exercise induces skeletal muscle
specific atrophy, recent work from our lab aims to assess muscle hypertrophy remain poorly understood. Kadi et al. (1999a,b) were
characteristics in a fiber type specific manner (Koopman et al., the first to associate muscle fiber hypertrophy with an increase in
2006b; Stellingwerff et al., 2007; van Loon and Goodpaster, 2006; both myonuclei number and SC content. The latter renewed the
Verdijk et al., 2007) (Fig. 2). In accordance with previous findings interest in the involvement of SC in the skeletal muscle adaptive
(Kadi et al., 2006) and in contrast with animal models (Gibson and response to exercise. SC recruitment is now generally believed to
Schultz, 1983; Schmalbruch and Hellhammer, 1977) we recently be imperative for substantial skeletal muscle hypertrophy to occur.
showed that SC content in the vastus lateralis is similar between The impact of exercise training on SC content has been reviewed
type I and type II muscle fibers in healthy, young adults. extensively by Kadi et al. (2005). We will provide a further update
Interestingly though, we observed that type II muscle fiber atrophy on recent work on the proposed involvement of SC in regulating
in the elderly is accompanied by a type II muscle fiber specific the skeletal muscle adaptive response to exercise training.
reduction in SC content (Verdijk et al., 2007). A 44% lower SC
content was observed specifically in the type II muscle fibers in old 4.1. Resistance type exercise
(76  1 yr) vs young (20  1 yr) males (Verdijk et al., 2007). A recent
study by Verney et al. (2008) confirmed these findings. In their study, Resistance type exercise training has been proven a practical
the authors assessed type I and type II muscle fiber SC content in both and effective interventional strategy to increase muscle mass and
the vastus lateralis and deltoideus muscle. In contrast to the vastus strength in the elderly (Charette et al., 1991; Esmarck et al., 2001;
lateralis muscle, no differences were observed between type I and Fiatarone et al., 1994; Frontera et al., 1988; Kosek et al., 2006;
type II muscle fiber SC content in the deltoideus muscle (Verney et al., Mackey et al., 2007; Martel et al., 2006; Roth et al., 2001; Verdijk
2008). The latter was in line with the observation that the vastus et al., 2009a,b). As mentioned previously, for muscle fiber
lateralis muscle showed type II muscle fiber specific atrophy, while hypertrophy to occur beyond a certain threshold, the addition of
this was not observed in the deltoideus muscle. Interestingly, this new myonuclei is essential. The latter is facilitated by the
study reported a larger type II muscle fiber size compared to type I proliferation of SC and the differentiation of their progeny into
fibers in the deltoideus muscle (Verney et al., 2008). Thus, in the same new myonuclei that fuse with existing muscle fibers (Hawke and
elderly individual it appears that type II muscle fiber atrophy and an Garry, 2001). SC proliferation and/or differentiation are controlled
accompanying decline in SC content can occur in lower limb muscle, by the sequential activation and/or suppression of MRFs (i.e. Myf5,
whereas no such changes are evident in upper limb muscle. The latter MyoD, Myogenin, and Mrf4). Interestingly, MRF mRNA expression
implies that there can be substantial differences in the impact of aging appears to increase following resistance type exercise in both
on muscle atrophy and SC content between different muscle groups young and older adults (Costa et al., 2007; Kim et al., 2005b; Kosek
and/or extremities. et al., 2006; McKay et al., 2008; Psilander et al., 2003; Raue et al.,
Although the number of skeletal muscle SC appears to decline 2006; Yang et al., 2005). In addition, the impaired Notch signaling
with an increasing age, basal MRF mRNA expression appears to be in the elderly has been reported to be modulated by strenuous
upregulated in senescent muscle (Edstrom and Ulfhake, 2005; exercise (Carey et al., 2007). In contrast with the upregulation of
Hameed et al., 2003; Kim et al., 2005b; Kosek et al., 2006; Raue MRFs, myostatin mRNA expression is found to be downregulated
et al., 2006). The activation and/or suppression of MRFs is required in response to exercise training in both the young and elderly
 T. Snijders et al. / Ageing Research Reviews 8 (2009) 328–338 333

Fig. 2. Representation of fiber-type specific analysis of skeletal muscle satellite cells (SC). (A) MHC-I + laminin + dapi staining from serial sections of B–D; the marked area
represents the same area as presented in frames B–D. (B) CD56 + laminin + dapi staining. (C) Only CD-56 staining. (D) CD-56 + dapi staining. Numbers indicate the muscle
fiber type I and type II. Arrows point at SC. This specific muscle cross-section was selected as an example due to the relatively high SC content.

(Costa et al., 2007; Hulmi et al., 2008; Kim et al., 2005a; Raue et al., et al. (2005)). Resistance type exercise training has been shown to
2006; Roth et al., 2003; Walker et al., 2004). Thus, whereas basal increase muscle fiber size with a concurrent increase in SC content
MRF mRNA expression has been reported to be elevated in the in both vastus lateralis (Kadi et al., 2004c; Olsen et al., 2006; Petrella
elderly, the response to resistance exercise seems to be quite et al., 2006) and trapezius (Kadi and Thornell, 2000) muscle.
similar between young and older adults. The exact implications of Whereas some studies (Kadi and Thornell, 2000; Petrella et al.,
the changes in mRNA expression of MRFs, Notch and myostatin in 2006) report a proportional increase in myonuclear content in
response to resistance type exercise, and their impact on the response to exercise induced muscle fiber hypertrophy, others fail
skeletal muscle adaptive response in the elderly muscle remain to to confirm these findings (Hikida et al., 1998; Kadi et al., 2004c;
be addressed in future research. Olsen et al., 2006). The latter might be attributed to the fact that
In addition to the exercise induced effects on SC signaling, other pre-existing myonuclei are able to increase their protein synthesis
studies have focused their attention on increasing the SC pool size. and support an exercise induced increase in cytoplasmic volume.
Recently, O’Reilly et al. (2008) observed a significant increase in In accordance, various studies have reported that muscle
mixed muscle fiber SC content following a bout of 300 eccentric hypertrophy in response to resistance type exercise training is
knee extensions in young males. Mixed muscle fiber SC content accompanied by an increase in myonuclear domain size, whereas
was shown to be increased at 24, 72 and 120 h following the myonuclear number remains equal throughout the training period
exercise bout. Others have reported similar increases in SC content (Kadi et al., 2004c; Petrella et al., 2006).
4 and 8 days after an exercise bout, but did not observe an increase Similar results have been reported when SC were studied in
in SC content after 24 h of post-exercise recovery (Crameri et al., response to resistance type exercise training in the elderly
2007, 2004). Dreyer et al. (2006) were the first to compare the (Table 3). Most (Mackey et al., 2007; Roth et al., 2001; Verdijk
acute effects of a single bout of exercise on SC content between et al., 2009a; Verney et al., 2008) but not all (Hikida et al., 1998;
young and elderly subjects. They reported an increase in SC content Petrella et al., 2006) studies report a substantial increase in SC
within 24 h following 92 eccentric contractions in both the young content following 9–16 wks of resistance type exercise training in
and elderly. However, the increase in SC content was greater in the older adults. Remarkably, some of these studies report an increase
young (141%) vs the older subjects (51%), suggesting that SC in SC content in the absence of muscle fiber hypertrophy (Mackey
recruitment in response to exercise is blunted in the elderly et al., 2007; Roth et al., 2001). To explain the apparent discrepancy
(Dreyer et al., 2006). it has been suggested that the increase in SC content represents a
Although the muscle regenerative capacity seems to decline at a physiological response to resistance exercise, preparing the muscle
more advanced age (i.e. decline in SC number and/or activation), it for adaptation. In contrast, others (Hikida et al., 1998; Petrella
is obvious that a reduced SC pool size does not prevent the capacity et al., 2006) observed a resistance exercise induced increase in
to allow extensive muscle hypertrophy even at an advanced age muscle fiber size without an increase in SC content. Therefore, it
(Dedkov et al., 2003; Shefer et al., 2006; Thornell et al., 2003). could also be hypothesized that SC content increases during the
Table 3 presents an overview of human studies that have assessed initial stages of adaptation to exercise training. Overall, these
myocellular characteristics in response to more prolonged findings suggest that SC are instrumental in the generation of new
resistance type exercise training (see also the review by Kadi myonuclei to facilitate muscle fiber hypertrophy.
334 T. Snijders et al. / Ageing Research Reviews 8 (2009) 328–338

Table 3
Studies on the impact of prolonged resistance type exercise training on muscle fiber characteristics.

Study Sex Age (yrs) Duration Muscle fiber size Myonuclear content Myonuclear domain Satellite cell content

Hikida et al. (1998) M 23  6 8 wks " (26%) $ $ $

M 65  6 16 wks " (37%) $ " (NS) $

Kadi and Thornell (2000) F 38  6 10 wks " (36%) " (71%) NDA " (46%)

Kadi et al. (2004c) M 20–32 30 days " (6%) $ " " (19%)
90 days " (17%) $ " " (31%)

Mackey et al. (2007) M 70–81 12 wks $ $ NDA " (36%)

F 70–82 12 wks $ " NDA " (18%)

Olsen et al. (2006) M 19–26 4 wks " (14%) $ NDA " (22%)
8 wks $ $ NDA " (40%)
16 wks $ $ NDA " (27%)
Petrella et al. (2006) M 20–35 16 wks " (32%) " (19%) $ " (49%)
F 20–35 16 wks " (21%) $ " $
M 60–75 16 wks " $ $ $
F 60–75 16 wks " (24%) $ " (NS) $

Roth et al. (2001) M/F 20–30 9 wks $ $ $ "

M/F 65–75 9 wks $ NDA $ "

Verdijk et al. (2009a) M 65–85 12 wks " (28%)a $ $ " (76%)a

Verney et al. (2008) M 73  4 14 wks " (NS)a $ $ " (73%)a

Note: this table provides an overview of studies that have assessed muscle fiber characteristics following resistance type exercise training in both young and older adults. Only
studies that have determined muscle fiber size, myonuclear and satellite cell content at baseline and following a resistance type exercise program have been included in this
table. M = male; F = female; " = significant increase compared with pre training values; $ = no change; NDA = no data available; NS = not significant. SC content: measured as
mean number of satellite cells per fiber cross-section. Myonuclear content: measured as the mean number myonuclei per muscle fiber. All data were obtained from the vastus
lateralis muscle, except for Verney et al. (2008) who studied the deltoideus muscle.
a
Increases only observed in type II muscle fibers, with no changes in type I muscle fibers.

Most studies quantify muscle fiber SC content in a non-muscle response to either acute or long-term resistance type exercise
fiber type specific manner. The latter might prevent the observa- training in the elderly vs the young. The latter might limit the
tion of specific changes in muscle fiber size and SC content. It has skeletal muscle hypertrophic response to exercise training in the
been well-established that sarcopenia is associated with specific elderly, despite the potentially compensating upregulation of
type II muscle fiber atrophy and the accompanying decline in type baseline MRF and Notch signaling. So far, no consensus has been
II muscle fiber SC content (Verdijk et al., 2007; Verney et al., 2008). reached on the proposed physiological role of SC in the skeletal
Furthermore, resistance type exercise training has been shown to muscle adaptive response to exercise. The latter is, at least partly,
typically induce type II muscle fiber hypertrophy. Therefore, it due to the lack of muscle fiber type specific data which likely
seems evident to study the skeletal muscle adaptive response to explains much of the discrepancy in the literature. In addition,
resistance type exercise training in a fiber type specific manner. genetic factors, individual training status, age of participants, and
Recently, we assessed the effects of 12 wks resistance type exercise the applied exercise modalities should be taken into account when
training in healthy, elderly men (Verdijk et al., 2009a). At baseline, evaluating the impact of exercise intervention on the skeletal
type II muscle fiber size and SC content were reduced when muscle adaptive response.
compared with the type I muscle fibers. Exercise training resulted
in a 28% increase in type II muscle fiber size and a concomitant 76% 4.2. Endurance type exercise
increase in type II muscle fiber SC content (Verdijk et al., 2009a).
The apparent differences in fiber size and/or SC content between When compared with resistance type exercise training, only
type I and type II muscle fibers prior to intervention were no longer few studies have addressed the behavior of SC in the skeletal
evident after 12 wks of training. Similar results were recently muscle adaptive response to endurance type exercise training.
reported by Verney et al. (2008), who reported a 73% increase in However, recent studies suggest that endurance type exercise
type II muscle fiber SC content in the deltoideus muscle following training also affects SC activation and proliferation. Appell et al.
resistance type exercise training. However, the increase in SC (1988) reported that skeletal muscle SC were activated following
content was not accompanied by a fiber type specific increase in 10 wks of endurance type exercise training in young males. The
fiber size or myonuclear number. So far, only one study has activation status was determined based upon the presence of an
assessed both long-term training as well as detraining effects on extensive granular endoplasmic reticulum, and the abundance of
skeletal muscle SC content. A substantial 31% increase in SC free ribosomes and mitochondria within the SC. However, it
content was observed after 3 months of exercise training (Kadi remains questionable how to define active SC. More recently, an
et al., 2004c). At 3, 10, and 60 days of detraining SC content increase in SC content in response to 14 wks endurance type
remained above baseline values, but the number of SC per muscle exercise training was reported in 11 healthy, elderly males (Charifi
fiber declined gradually (Kadi et al., 2004c). et al., 2003). A 13% increase in VO2 peak was accompanied by an
In summary, resistance type exercise training has been well- increase in both myonuclear number (6%) and muscle fiber size
established as an effective interventional strategy to counteract (13%: P = 0.05). Although the increase in myonuclear number and
the age-related loss of muscle mass. Elderly are still able to respond muscle fiber size did not reach statistical significance, SC content
to an exercise stimulus by extensive muscle hypertrophy and a had increased by 29% (from 2.4 to 3.1%; P < 0.05) (Charifi et al.,
concomitant increase in muscle strength and improved functional 2003). Similar results have recently been presented by Verney et al.
capacity. On a myocellular level, some evidence is emerging to (2008), who investigated the combined effects of upper body
suggest that SC number does not increase to the same extent in resistance and lower body endurance type exercise training in
 T. Snijders et al. / Ageing Research Reviews 8 (2009) 328–338 335

healthy, elderly men. At baseline, type II muscle fiber size was a control group (Olsen et al., 2006). However, a more recent study
reported to be reduced when compared with the type I muscle by Verdijk et al. (2009b) showed no surplus benefits of protein
fibers in the vastus lateralis. In addition, type II muscle fiber SC supplementation in combination with 12 wks of resistance type
content was reduced when compared with the type I muscle fibers. exercise training on muscle mass, strength and muscle fiber size in
Fourteen weeks of endurance type exercise training significantly healthy, elderly males. Pharmaceutical (co-)interventions may also
increased the vastus lateralis type II muscle fiber size (+13%), which be effective to induce muscle hypertrophy. For example, testos-
was accompanied by a 58% increase in type II muscle fiber SC terone supplementation (see Kadi (2008) for an extensive review)
content (Verney et al., 2008). No changes in myonuclear number has been reported to induce muscle fiber hypertrophy and increase
and/or domain size were observed following endurance type mixed muscle fiber SC content in young adults (Sinha-Hikim et al.,
exercise training (Verney et al., 2008). Clearly, more studies are 2002) and community dwelling elderly (Sinha-Hikim et al., 2006).
warranted to address the contribution of SC in the specificity of the Yet, the fiber type specific response to such pharmaceutical
skeletal muscle adaptive response to endurance vs resistance type interventions, with and/or without exercise training, remains to be
exercise training. elucidated.
Research is warranted to evaluate the surplus benefits of
5. Future research nutritional and/or pharmaceutical intervention to augment the
gain in skeletal muscle mass and strength during exercise
Even though there has been an enormous gain in insight into intervention. Defining such interventions to further stimulate
the anatomical and physiological background of SC in skeletal skeletal muscle hypertrophy is of great clinical importance in the
muscle tissue, the molecular mechanisms that control SC elderly and/or specific patient populations (i.e. COPD, type II
activation, proliferation, differentiation and self-renewal in vivo diabetes, cachexia). The impact on SC activation, proliferation, and
in humans remain to be established. Several auto-/paracrine and/ differentiation might represent a target to maximize the clinical
or endocrine signaling pathways seem to tightly regulate each step benefits of exercise to augment skeletal muscle mass and function.
of SC lineage determination. The identification of molecular key
signatures of quiescent and activated SC may help to determine the 6. Conclusion
precise signaling pathways leading to SC activation, proliferation,
and differentiation following injury, stretch and/or mechanical It has been well-established that sarcopenia is characterized by
loading. a decline in skeletal muscle mass and strength and the loss of
Exercise intervention programs have proven to influence SC functional capacity with aging. Though the mechanisms respon-
lineage determination (Carey et al., 2007; Costa et al., 2007; Kim sible for the onset of sarcopenia remain largely unknown, it seems
et al., 2005b; Kosek et al., 2006; McKay et al., 2008; Psilander et al., evident that skeletal muscle SC play a significant role in this
2003; Raue et al., 2006; Yang et al., 2005). Muscle fiber process. Sarcopenia is characterized by type II muscle fiber
hypertrophy in response to resistance type exercise training is atrophy. The latter is accompanied by a proportionate reduction
accompanied by an increase in SC content in both the young and in type II muscle fiber SC content. Exercise training has been
elderly (Charifi et al., 2003; Dreyer et al., 2006; Hikida et al., 1998; successfully applied to augment muscle mass and improve muscle
Kadi et al., 1999b, 2004c; Kosek et al., 2006; O’Reilly et al., 2008; function in the elderly. Both resistance and endurance type
Petrella et al., 2006; Renault et al., 2002; Roth et al., 2001; Verdijk exercise training have been shown to increase skeletal muscle SC
et al., 2009a; Verney et al., 2008). Although SC have been proposed content specifically in the type II muscle fibers. The latter is
to be key players in the skeletal muscle adaptive response to generally accompanied by a further increase in SC activation and
exercise training, many questions remain unanswered. The most proliferation factors (i.e. MyoD, myogenin, Mrf4 and Myf5) in
significant question would be why SC respond to an exercise skeletal muscle tissue. Present findings suggest that skeletal
stimulus. Is it the impact of muscle fiber contraction per se and/or muscle SC co-regulate myogenesis, and have an important, but yet
are other factors responsible that might be released during and/or unresolved, function in the loss of muscle mass with aging.
following exercise? Furthermore, regarding the distinctive skeletal
muscle adaptive response to resistance vs endurance type exercise,
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