Abstract
The number of adult stem cells (ASCs) is very small, limiting the regenerative potential of tissues. One of the most studied ASCs in humans is the satellite cell (SC), which proliferates and increases pool size under exercise stress and muscle damage. This review examines the growth factor response to specific types of exercise to show the potential of exercise to stimulate not only SC self-renewal, but also other ASCs. We postulate that the same factors that stimulate a high proliferation of SCs in skeletal muscle after physical exercise should also stimulate the proliferation of ASCs in the tissue in which they reside, such as heart, bone, liver and etc. Regular exercise should be promoted, not only for disease prevention, but to maintain a high ASCs reserve and progenitor cell potential for rapid activation in response to future stressors and damage.
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Introduction
Adult stem cells (ASCs) also known as somatic stem cells, are undifferentiated cells found in many specialised tissues throughout the body after embryonic development. Their primary role is to maintain and repair the tissue in which they are resident. ASCs, have been identified in many tissues and organs, including skeletal muscle, bone, cartilage, skin, blood vessels, teeth, heart, liver, gut, peripheral blood, ovarian epithelium, testis and bone marrow. At least eight different types of ASCs have been isolated: haematopoietic stem cells, mammary stem cells, mesenchymal stem cells, endothelial stem cells, neural stem cell, olfactory ASCs, neural crest stem cells, testicular cells.
ASC pools reside in a specific area called a “stem cell niche”, which has been described as a specialised local microenvironment that can be anatomically defined. It includes specific extracellular matrix and supporting cells and is enriched with growth modulating potential to signal stem cell self-renewal or differentiation (Greco and Guo 2010; Di Felice et al. 2009). During daily life a limited number of ASCs need to be activated in order to maintain the homeostasis of the tissue, while the remaining ASCs remain in a quiescent phase; both cells coexist in the same “stem cell zone” (Li and Clevers 2010). This system prevents stem cell exhaustion that will lead to a premature failure of the organ, and enables the regeneration of new tissue to proceed rapidly in the scenario of an injury. Many different aspects of ASCs, such as the physiological role that they play in daily tissue renewal and in regeneration after injury, have been, and are being investigated in scientific models. However, we maintain that there is one aspect of ASCs that seems to be neglected: is it possible to purposefully increase the number of resident ASCs to improve the potential capacity for future episodes of regeneration required in various organs? The myogenic progenitor cell niche, is an ideal system in which to address the question of whether the number of ASCs in the pool can be increased, not only in response to an acute stimulus, but also a chronic stimulus such as endurance and resistance training.
In this review, molecular mechanisms regulating the satellite cell (SC) niche will be elucidated. Firstly, factors that stimulate self-renewal of SCs will be described and secondly, the effects of acute and chronic physical activity on these factors and hence on SC pool size will be discussed. Finally, we briefly outline new developments on the potential of physical activity to modify the balance of factors in various ASC niches in favour of an increase in the number of ASCs in the specific organs.
The SC niche
Skeletal muscle is a perfect example of a tissue that relies on life-long maintenance of its ASC pool (Mauro 1961). The regeneration abilities of adult skeletal muscle can be attributed almost exclusively to SCs (Hawke and Garry 2001), although other ASCs (such as pericytes, mesoangioblasts, side population cells, muscle-derived stem cells, haematopoietic cells, CD133+ cells) are involved in skeletal muscle regeneration (Ten Broek et al. 2010; Schabort et al. 2009). The ability to stimulate myogenesis in human models in order to study muscle regeneration and to access tissue and SCs by muscle biopsy, makes the SC and its niche the most studied adult stem cell population in humans. In fact many studies have been published since 1976 when Schmalbruch and Hellhammer (1976) confirmed that SCs are present in human skeletal muscle at all ages. SC proliferation is influenced by many factors, which directly or indirectly affect the niche. These factors can be divided into three groups: local, mechanical and systemic factors. This division is convenient to explain the factors that modulate self-renewal of SCs more clearly, but in the live niche all these factors interact with each other.
Local factors
The SC niche is delineated by the sarcolemma of the myofibre and the basal membrane (Mauro 1961). The basal side of an SC expresses integrin α7β1, which links the SC with laminin in the basal membrane. The apical side expresses M-cadherin, which attaches the SC to the adjacent myofibre. Different markers have been used to identify SCs in different functional phases (quiescent, activated, proliferating, differentiating), although to date there is no known unique marker of quiescent SCs and our understanding of how SC pool size is maintained is still expanding at both experimental and theoretical levels (Boldrin et al. 2010; Gnocchi et al. 2009).
Two different mechanisms have been proposed for self-renewal of SCs to maintain the same number of this type of ASCs in skeletal muscle: asymmetric and symmetric division (Ten Broek et al. 2010; Cossu and Tajbakhsh 2007; Kuang et al. 2008). During asymmetric division two daughter cells with unequal characteristics are generated: one destined to self-renew and the other to differentiate; in contrast, during symmetric division two identical daughter cells are generated—two self-renewing cells or two differentiating cells (Fig. 1). Although scientific results obtained from in vitro and in vivo animal models seem to indicate that the asymmetric division of SCs is the fundamental self-renewal mechanism (Shinin et al. 2006; Ten Broek et al. 2010), this can only explain the maintenance of SC number but cannot explain the expansion of the SC pool which is observed after an acute bout of strenuous exercise or after training (see “Effect of physical exercise on SC proliferation in humans” section). Therefore, in addition to the highly controlled studies in a cell culture environment, a further understanding of the mechanisms influencing proliferation in vivo is required.
SCs but not muscle fibres express caveolin-1 (Volonte et al. 2005), which maintains a quiescent state by inhibiting the sphingomyelin signaling cascade (Nagata et al. 2006). Sphingomyelin is located in the inner leaflet of the plasma membrane and it has been hypothesised that disruption of laminin–integrin adhesion regulates SC activation/proliferation through the activation of the sphingolipid signaling cascade initiated by the release of hepatocyte growth factor (HGF). Consequently, sphingolipid signaling initiates cell cycle entry but also activates the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway which may down-regulate caveolin-1 in a feedback loop (Volonte et al. 2005). In fact, Nagata et al. (2006) demonstrated high levels of sphingosine-1-phosphate, after injury, and this may be the stimulus for ERK–MAPK activation, already shown by others to be involved in SC activation (Yablonka-Reuveni et al. 1999; Jones et al. 2005).
Mechanical factors
Recently, Tatsumi et al. (2010) reviewed the results obtained over the last few years by his research group, and by others, on the mechanical factors that trigger activation of SCs, describing a possible mechanism of activation in response to stretch: influx of calcium into the SC and the synthesis of nitric oxide (NO−) radicals by a calcium-calmodulin-dependent mechanism (Tatsumi et al. 2009) that will then activate metallo proteinases (Yamada et al. 2006; 2008). These proteases induce the liberation of HGF from the extracellular matrix with subsequent binding of HGF to its receptor, c-met, which generates a signal for SC activation (Allen et al. 1995; Gal-Levi et al. 1998). HGF is the only growth factor with the established ability to stimulate specifically the activation of quiescent SCs in vitro and in vivo (Allen et al. 1995, 1997; Tatsumi et al. 1998) and its expression is increased in proportion to the degree of injury during the early proliferation phase of muscle regeneration (Tatsumi et al. 1998, 2001; Suzuki et al. 2002).
Recently it has been discovered that leukemia inhibitory factor (LIF), a member of the interleukin (IL)-6 superfamily known to influence SCs in vitro, is activated by mechanical strain. Broholm et al. (2011) reported an increase in LIF mRNA in response to resistance exercise and further reported that contracting human myotubes produce and secrete LIF in a PI3K-dependent manner, also inducing increased expression of the transcription factors: JunB and c-Myc. These are known to increase myoblast proliferation.
Systemic factors
Besides local and mechanical factors, systemic factors also have to be considered in order to understand the mechanisms underlying SC self-renewal, especially in light of the fact that in older individuals, despite low SC number, their intrinsic myogenic potential and self-renewal capacity remain unaltered (Shefer et al. 2006). In vitro and in vivo experiments have shown that the sera from young animals can restore Notch activation in old SCs restoring their capacity to proliferate and differentiate similarly to young cells; on the other hand old sera rapidly decreased the regenerative response of young SCs (Conboy et al. 2005; Carlson and Conboy 2007; Silva and Conboy 2008). Growth factors, controlling the up- and down regulation of muscle-specific genes, regulate SC behaviour (Charge and Rudnicki 2004). They are secreted by active immune cells, by muscle cells after injury, by the vascular system, by motor neurons and by the SC themselves (Cannon and St Pierre 1998; Hawke and Garry 2001).
Many growth factors have been studied over the last two decades to understand the roles they are playing in muscle regeneration, but overall, insulin-like growth factor-1 (IGF-1) seems to be the main growth factor that stimulates SC proliferation. Administration of IGF-1 to a rat primary SC culture altered the expression of myogenic regulatory factors promoting, first their proliferation, but also subsequently their differentiation (Allen and Boxhorn 1989). In transgenic mice over expressing IGF-1, Chakravarthy et al. (2000) observed high levels of SC proliferation associated with the activation of the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) signaling pathway, the up-regulation of cyclin-dependent kinase-2 kinase activity and the down-regulation of the cell-cycle inhibitor p27kip1. In a feedback loop to control this process, the repression of IGF-1 signaling is also mediated through phosphorylation of Akt, but via its downstream effects on forkhead transcription factor FoxO1 (Machida et al. 2003).
As reviewed by Smith et al. (2008), studies that investigated muscle regeneration after injury provided important information on the role of cytokines in SC proliferation. Several cytokines have been proved to stimulate SC proliferation. For example, interferon-gamma (IFN-γ), an inflammatory cytokine which is released primarily by activated T lymphocytes and natural killer cells, is also released by macrophages and SCs in the injured environment (Cheng et al. 2008). The multi-functional cytokine, interleukin-6 (IL-6), is also released by skeletal muscle fibres and SCs (Serrano et al. 2008) in damaged muscle. IFN-γ and IL-6 activate the Janus kinase 1–signal transducer and activator of transcription (JAK–STAT) pathway (Serrano et al. 2008; Cheng et al. 2008), which is involved in SC proliferation and the prevention of premature differentiation (Sun et al. 2007; Trenerry et al. 2011b). Although bone morphogenetic proteins (BMPs) have been considered, in the past, as inhibitors of SC proliferation (Ten Broek et al. 2010), new evidence suggests that BMPs play a critical role in balancing proliferation and differentiation of SCs and their descendents (Friedrichs et al. 2011). In fact, BMP signals maintain SC descendants in a proliferating state thereby expanding cell numbers, while the daughter cells committed to differentiation up-regulate the expression of chordin, a BMP inhibitor, to support terminal differentiation and myotube formation (Friedrichs et al. 2011).
As underlined by Carlson and Conboy (2007), the self-renewal ability of young SC were negatively affected when exposed to the old sera. It can be hypothesised that SC proliferation is not simply influenced by a lack of proliferating factors but also the presence of inhibitory factors. These include chordin (as mentioned above) and also members of the transforming growth factor superfamily, such as myostatin and transforming growth factor beta 1 (TGF-β1). Myostatin may repress activation and self-renewal of SC by the induction of p21kip (McCroskery et al. 2003), which is an inhibitor of cyclin-dependent protein kinase and a cell cycle inhibitor (Jaumot et al. 1997). High levels of TGF-β1 (in serum and locally in the muscle) induce an excessive expression of CDK inhibitors in SCs, thereby interfering negatively with productive myogenic responses (Carlson et al. 2009). This process may work through the TGF-β receptor and P-Smad signaling in a threshold-dependant manner (Carlson et al. 2009). Different isoforms of TGF-β play a role in the balance between proliferation and differentiation (Schabort et al. 2011). A certain level of TGF-β I is required not only for a normal SC response but also to prevent immune disorders, inflammation and organ dysfunction (Dunker and Krieglstein 2000).
Effect of physical exercise on SC proliferation in humans
Since the first study on SC and exercise, undertaken in 1987 in rats, the connection between an acute bout of exercise that induces muscle damage (discernible at high magnification but not by light microscopy) and SC activation was clear (Darr and Schultz 1987). Exercise-induced activation of SCs can be attributed to specific types of exercise intervention, such as maximal eccentric contraction, that activates the muscle while it is stretched. This type of exercise has been shown to induce a large (over 80 %) increase in SC number 5–8 days after the exercise intervention (Crameri et al. 2004, 2007; O’Reilly et al. 2008). During maximal eccentric contraction the sarcomeres are extended to a range where there is little or no overlap of actin and myosin filaments despite a high external load, leading to severe ultrastructural damage with a very high percentage of hypercontracted myofibrils and necrotic fibre segments (Lauritzen et al. 2009). This type of exercise is frequently prescribed for the purpose of scientific investigation and is not undertaken as a common training method except in bodybuilders. Although downhill running and plyometric jumping, exercise methods commonly used by elite and recreational athletes, the eccentric component is not as extreme as during maximal eccentric resistance exercise and they induce much less severe ultrastructural damage (Macaluso et al. 2012). Moreover preliminary evidence from our laboratory indicated that the skeletal muscle fibre type characteristics influence SC count expansion after a downhill running intervention: a greater SC count expansion was observed in the participants with higher fast twitch fibre percentage (unpublished observations). Therefore, higher mechanical strain experienced in the fast twitch fibres, without extensive damage, was sufficient to activate SC proliferation.
Although, no studies have been conducted to evaluate the acute or chronic effect of stretching or flexibility training on SC behaviour in humans, a few studies in vitro and in animal models suggest that this type of exercise should be able to stimulate SC proliferation through NO-induced mechanisms (Soltow et al. 2010; Leiter and Anderson 2010; Turtikova et al. 2007; Wozniak and Anderson 2007). However, at the moment there is no evidence to support that flexibility exercises may increase SC pool size in humans. The question therefore arises: is damaging exercise the only method to improve SC pool size?
Recently we pointed out the large variability in SC count between healthy young male individuals irrespective of recent exercise and without the presence of damage or aging-induced changes (Macaluso et al. 2011). Some of these subjects were sedentary and others led an active lifestyle, without training systematically. Those with higher maximal oxygen consumption (VO2max) had a greater SC pool size. Furthermore, it seems clear from other research that the basal SC pool size makes a difference in the hypertrophic response to a resistance training intervention (Petrella et al. 2008). It is possible that systemic factors may influence basal SC pool size, even in young adults. We showed that the level of stress induced by daily life activities was higher in the individuals with low levels of physical fitness (low VO2max) and was associated with a higher basal activation of p38-mitogen-activated protein kinase (MAPK), an intracellular stress signaling kinase which enhances the differentiation of SC, which may explain their reduced SC pool size (Macaluso et al. 2011). Higher levels of p38-MAPK activation have been observed in previous studies after a single bout of non-eccentric exercise in untrained humans (Yu et al. 2003) and rat (Lee et al. 2002) compared to trained controls. Together, these results indicate the behavior of SCs, and provide some insight into one of the mechanisms responsible for influencing the SC pool size, despite no acutely damaging events.
One of the adverse effects associated with aging is a progressive loss of muscle mass (loss of muscle fibres and reduced muscle fibre cross-sectional area) (Doherty 2003) and lower regenerative efficiency of muscle (Grounds 1998). Table 1 presents the results of different studies on elderly people showing that SC pool size can be enhanced after endurance (Charifi et al. 2003; Verney et al. 2008) or resistance exercise training (Verney et al. 2008; Verdijk et al. 2009; Mackey et al. 2007), although a few discrepancies are observed due to the type of exercise or subjects’ pathology (Snijders et al. 2011). The self-renewal capacity of the SC, reported as the percentage increase in Pax7 or N-CAM positive cells after the training intervention, in elderly individuals in response to resistance training seems to be similar to that reported for younger individuals (Mackey et al. 2010; Kadi et al. 2004; Brooks et al. 2010). These results concur with the idea, developed from studies conducted in animal models and in vitro, that the myogenic potential of SCs remain unaltered with age, despite their lower number (Shefer et al. 2006), but growth factors in sera may influence the proliferation capacity either positively or negatively (Conboy et al. 2005; Carlson and Conboy 2007; Silva and Conboy 2008) with or without the mechanical strain imposed by exercise.
In light of the fact that the systemic growth factors play a key role in SC self-renewal promoting symmetrical division to expand the SC pool size after exercise intervention (Fig. 1), it is essential to study the level of these systemic factors in relation to the physical activity prescribed to the individuals. In other words, it is necessary to test a new hypothesis that any physical activity that will stress the full organism will alter the balance of specific growth factors that directly or indirectly increase the self-renewal capacity of the SCs in skeletal muscle. Since all organs are exposed to systemic stimuli, this hypothesis could also include ASCs in any tissue.
Human ASC classification
Stem cells can be divided into four groups on the basis of their origin: embryonic stem cells, fetal stem cells, umbilical stem cells and ASCs (Schabort et al. 2009). ASCs evolved from embryonic stem cells, and it is believed that they are embryonic stem cells that ‘gave up in the race to differentiate’, became quiescent and remained in cell niches of organs. Currently, more than 14 subtype of ASCs have been described (Schabort et al 2009): haematopoietic and mesenchymal stem cells residing in bone marrow; gut stem cells located in the crypts of Lieberhahn; liver stem cells; bone and cartilage stem cells (although their niches have not been defined yet); skin and hair stem cells; neuronal stem cells; pancreatic stem cells; retinal stem cells; cardiac stem cells; dental pulp stem cells and skeletal muscle SCs. Other potential muscle progenitors include side population cells and pericytes, whilst cardiovascular stem cells also include mesangioblasts and vascular endothelial progenitor cells.
Much research has been done on the regenerative potential of these ASCs in animal models of tissue damage. Similarly, their ability to trans-differentiate in vitro, has been investigated with a view to ex vivo cell expansion and manipulation for transplant. However, in humans mainly skeletal muscle and dermal ASCs have been studied extensively, but the latter without any emphasis on exercise.
The effects and the potential effect of growth factors released by exercise on ASC
Taking in account the potential capacity of exercise activity to affect the levels of specific growth factors and mitogens positively, we can speculate that physical exercise may stimulate many of these different adult stem cell niches promoting ASC proliferation. Increases in the resident pool size would allow the organs a higher potential to maintain and repair themselves. This section examines the current knowledge on the growth factors released during or after different types of exercise, mentioning mainly the in vivo studies in humans, since contradictory results have sometimes been described in animal studies. The focus is on those already reported to have effects on ASCs or with potential to affect ASCs. In view of the fact that the number of these studies is very limited for some of the growth factors, evidence obtained from in vitro studies on primary cell culture of ASCs, treated with different growth factors to stimulate self-renewal, will also be mentioned. The growth factors will be discussed starting from those that have been investigated more in humans to those with a high potential to increase the self-renewal of ASCs in humans, although at the moment only indirect evidence (mainly from in vitro studies) exists. Figure 2 presents a flow diagram of the different ASCs assessed in the studies quoted below.
Vascular endothelial growth factor (VEGF)
VEGF is released by ischemic tissue stimulating the expression of matrix metalloproteinase-9 in the bone marrow, which results in an increased bioavailability of soluble Kit-ligand cytokines (Wahl et al. 2008). These cytokines enhance the mobility of c-kit+ stem cells (c-kit is the receptor for Kit-ligand cytokines), and play a role in translocating them to a vascular-enriched niche thus favouring proliferation and mobilisation to peripheral circulation (Wahl et al. 2008). Endurance exercise induces an increase in VEGF concentration in the circulation, which is sufficient to act as a trigger for release of haematopoietic and endothelial progenitor cells from the bone marrow (Mobius-Winkler et al. 2009). It is important to note that there is a time delay before significant mobilisation is observed. However, it is not only a response to an acute exercise bout, but regular exercise training also increases the numbers of circulating haematopoietic stem and progenitor cells mobilised at the end of the exercise session in healthy individuals, athletes, and in individuals with high risk for cardiovascular disease (Laufs et al. 2004; Steiner et al. 2005; Morici et al. 2005). Moreover it has been shown that individuals who exercise regularly and systematically (training), have a higher level of circulating haematopoietic stem and progenitor cells in the blood stream than sedentary individuals under resting conditions, which may suggest a positive adaptation to the recurrent stress of habitual exercise (Bonsignore et al. 2002).
Declining learning and memory functions have been associated with the attenuation of adult hippocampal neurogenesis. Animal studies suggest that VEGF is an important factor for stimulating adult neurogenesis, and in running animals elevated circulating levels of VEGF as well as a doubling neurogenesis capacity were observed (Cotman et al. 2007; Fabel et al. 2003). In particular, (Fabel et al. 2003) observed that mice with unlimited access to a running wheel presented an increase in proliferative activity of uncommitted neuronal progenitor cells and in accumulation of neuron-committed progenitors compared to the animals caged with a immobilized wheel. Moreover, the blockage of peripheral VEGF, by a single injection of adenovirus encoding for receptor of VEGF, induced a return of neurogenesis to baseline value in running animals but did not suppress neurogenesis below baseline in either running or non-running mice (Fabel et al. 2003) (see further information on neurogenesis in “Brain derived neurotrophic factor (BDNF)” section).
IGF-I
IGF-1 regulates skeletal muscle growth by binding to its receptor localised in the sarcolemma, initiating the PI3K/Akt signaling cascade to promote protein synthesis. Circulating concentrations of IGF-1 are affected by many lifestyle factors, such as exercise and nutrition. Resistance exercise increases IGF-1 concentration in the blood stream (Kraemer et al. 1990) and in skeletal muscle (Bamman et al. 2001). Although, recent results seem to suggest that resistance exercise triggers IGF-1 production mainly in muscle cells themselves, without altering the plasma levels (Gundersen 2011), the production of IGF-1 in the liver is dependent on the exercise intensity (Rubin et al. 2005). This growth hormone-induced IGF-1 synthesis can change in relation to the fitness level of the subjects (Hasani-Ranjbar et al. 2011). IGF-1 is encoded by the igf1 gene, which undergoes alternative splicing producing multiple isoforms (Barton et al. 2010). Three isoforms have been observed in humans and primates (Wallis 2009), while only two in most of the vertebrates (Shimatsu and Rotwein 1987). Human and rodent IGF-1A is virtually identical; human IGF-1C and rodent IGF-1B bear high homology, while human IGF-1B seems to be unique to primates. Each isoform seems to play a different role in tissue growth, in particular, IGF-1A has consistently increased muscle mass (Adams and McCue 1998; Barton 2006; Schertzer and Lynch 2006), whilst human IGF-1C (homologous to rodent IGF-1B) induces hypertrophy only in young animals in the growing phase, where there is an active SC pool (Barton 2006).
IGF-1 appears to have a major role in cardiac adaptation induced by endurance training, namely development of the “athlete’s heart” (cardiomyocyte hypertrophy and neoangiogenesis). In fact, it has been hypothesised previously that endurance exercise may determine the formation of new cardiomyocytes through the activation of circulating and resident stem cells, the latter through the IGF-1/AkT pathway (Ellison et al. 2011). In transgenic mice it has been demonstrated that human IGF-1B causes cardiomyocyte proliferation, resulting in cardiomegaly (enlargement of heart) (Reiss et al. 1996). However, these studies are not definitive since an appropriate lineage-tracing model in humans is not currently possible and these observations are limited to the animal model (Beltrami et al. 2003). Nevertheless, human cardiac stem cells (c-kit+) isolated from old patients, still present with the receptor for IGF-1 on their membranes. These cells had a young cell phenotype defined by long telomeres, high telomerase activity, high proliferation rate in vitro, and attenuated apoptosis (Ellison et al. 2011).
Brain derived neurotrophic factor (BDNF)
The term ‘neuroplasticity’ describes the ability of the brain and cental nervous system (CNS) to adapt to their in vivo environment, respond to injury and acquire information. These responses are mediated by neurotrophins, which stimulate neuronal cell survival, differentiation or growth. Among all neurotrophins, BDNF, produced by neuronal (brain and CNS) and non-neuronal tissues (vascular human endothelial cells, T lymphocytes, B lymphocytes, eosinophils, monocytes, pituitary gland and skeletal muscle fibres), seems to be the most affected by exercise (Knaepen et al. 2010). BDNF can cross the blood–brain barrier and the main cellular origin of BDNF in response to exercise seems to be the brain (estimated to contribute almost 75 % of circulating BDNF). Currently, it is not thought that muscle-derived BDNF is released into the blood stream. It has been proved that the magnitude of increase in serum BDNF concentration during exercise is dependent on the intensity of the stress induced by exercise (Zoladz and Pilc 2010). Normalisation of the circulating BDNF concentration occurs quite quickly once exercise has stopped, indicating that BDNF enters tissue environments. These may be peripheral tissues or it may be transported back into the brain, once more crossing the blood–brain barrier, and potentially enhancing the health and plasticity of central neural progenitor cells. During endurance or resistance training programs that maintain the same exercise stimulus, the subjects became accustomed to the stress, a homeostatic condition developed again and the specific exercise no longer presented as a stressor of sufficient intensity to increase the level of BDNF in the serum (Zoladz and Pilc 2010).
LIF
Broholm and Pedersen (2010) suggested that the oscillation in Ca2+ concentration in skeletal muscle after 3 h of cycling at 60 % of VO2max (concentric contraction) is responsible for inducing a fourfold increase in muscular LIF mRNA expression measured immediately after and that it declines gradually throughout the post-exercise period. Although the LIF mRNA levels were responsive to this intensity of aerobic exercise, LIF protein levels remained unaltered in the muscle of these subjects (Broholm et al. 2008). A longer duration of aerobic exercise, 6 h of running, also did not change LIF protein levels in the serum of ultra-endurance athletes (Donnikov et al. 2009). In a recent study the same authors showed that 20 min of heavy resistance exercise induced a much higher (about ninefold) increase in the expression of LIF mRNA in the vastus lateralis muscle than the aerobic exercise (Broholm and Pedersen 2010). The authors suggested that this difference was not caused by the exercise intensity but rather by the mechanical characteristics of the exercise (Broholm and Pedersen 2010), because of the eccentric phase possibly resulting in structural and ultrastructural damage, thus inducing the calcium influx into the fibre. However, it was observed that LIF protein level remain unaltered in the muscle after an acute bout of downhill running (Malm et al. 2004) which also exploits the eccentric component of muscle contraction, but perhaps not to a sufficient extent in the protocol used. These conflicting data, particularly the apparent lack of translation of LIF mRNA and no assessment of SC responses, lead us to report the in vitro evidence that LIF does indeed influence ASCs. In vitro LIF had a growth stimulating effect on human colony-forming units, both eosinophil and erythroid (Mathieu et al. 2011 Moreau et al. 1987). In contrast, no effect was observed on human neural stem cells treated with LIF (Sun et al. 2008), while rat neural precursor cells proliferated after treatment (Covey and Levison 2007).
Platelet-derived growth factor (PDGF)
PDGF, during early and later development stages, induces the proliferation and migration of mesenchymal stem cells (Hoch and Soriano 2003). Czarkowska-Paczek et al. (2006) reported an increase in PDGF and VEGF level in the circulation of young sportsmen immediately after a strenuous physical exercise session. Similarly, another research group reported a peak in circulating PDGF 3 h after resistance exercise, which also occurred in response to an acute bout after 12 weeks of resistance exercise (Trenerry et al. 2011a).
Endothelial growth factor (EGF)
EGF, seems to be dispensable for human skin-derived mesenchymal stem cell proliferation (Riekstina et al. 2008), while it may be used to induce hepatocyte differentiation in human mesenchymal-derived hepatocyte-like progenitor cells (Lysy et al. 2008).
Basic fibroblast growth factors (bFGF)
Treatment with LIF and bFGF promoted the proliferation of cultured spermatogonial stem cells isolated from human donors (Mirzapour et al. 2011).
Although some growth factors may contribute to ASC regulation, their effects may require additional mitogenic stimulation. For example, human pluripotent stem cells, isolated from dental pulp, required the presence of LIF, EGF and PDGF to ensure proliferation (Atari et al. 2011).
Conclusion
ASCs resident in tissue niches require a stimulus to become activated and to proceed to proliferation. That such stimuli can be provided by localised damage is without doubt. Whether or not exercise may be used to improve the repair process of damaged tissue induced by chronic disease, such as cardiovascular diseases, is currently under investigation. Exercise can, in fact, provide a physiological stimulus to enhance cell signaling to activate resident ASCs and to mobilise haematopoetic stem cells into circulation, with some evidence of myocardial regeneration in patients. The same concept has been used to prescribe exercise to obtain a rejuvenation effect in elderly people.
We propose the following new concept: physical exercise is an important factor to increase the number of ASCs in various organs without any evidence of localised damage. The exercise stimulus primes the ASC niches and generates a naturally engineered “super hero” with the capacity to easily heal and regenerate body tissue.
References
Adams GR, McCue SA (1998) Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats. J Appl Physiol 84(5):1716–1722
Allen RE, Boxhorn LK (1989) Regulation of skeletal muscle satellite cell proliferation and differentiation by transforming growth factor-beta, insulin-like growth factor I, and fibroblast growth factor. J Cell Physiol 138(2):311–315. doi:10.1002/jcp1041380213
Allen RE, Sheehan SM, Taylor RG, Kendall TL, Rice GM (1995) Hepatocyte growth factor activates quiescent skeletal muscle satellite cells in vitro. J Cell Physiol 165(2):307–312. doi:10.1002/jcp1041650211
Allen RE, Temm-Grove CJ, Sheehan SM, Rice G (1997) Skeletal muscle satellite cell cultures. Methods Cell Biol 52:155–176
Atari M, Barajas M, Hernandez-Alfaro F, Gil C, Fabregat M, Padro EF, Giner L, Casals N (2011) Isolation of pluripotent stem cells from human third molar dental pulp. Histol Histopathol 26(8):1057–1070
Bamman MM, Shipp JR, Jiang J, Gower BA, Hunter GR, Goodman A, McLafferty CL Jr, Urban RJ (2001) Mechanical load increases muscle IGF-I and androgen receptor mRNA concentrations in humans. Am J Physiol Endocrinol Metab 280(3):E383–E390
Barton ER (2006) Viral expression of insulin-like growth factor-I isoforms promotes different responses in skeletal muscle. J Appl Physiol 100(6):1778–1784
Barton ER, DeMeo J, Lei H (2010) The insulin-like growth factor (IGF)-I E-peptides are required for isoform-specific gene expression and muscle hypertrophy after local IGF-I production. J Appl Physiol 108(5):1069–1076
Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114(6):763–776
Boldrin L, Muntoni F, Morgan JE (2010) Are human and mouse satellite cells really the same? J Histochem Cytochem 58(11):941–955. doi:10.1369/jhc.2010.956201
Bonsignore MR, Morici G, Santoro A, Pagano M, Cascio L, Bonanno A, Abate P, Mirabella F, Profita M, Insalaco G, Gioia M, Vignola AM, Majolino I, Testa U, Hogg JC (2002) Circulating hematopoietic progenitor cells in runners. J Appl Physiol 93(5):1691–1697. doi:10.1152/japplphysiol.00376.2002
Broholm C, Pedersen BK (2010) Leukaemia inhibitory factor—an exercise-induced myokine. Exerc Immunol Rev 16:77–85
Broholm C, Mortensen OH, Nielsen S, Akerstrom T, Zankari A, Dahl B, Pedersen BK (2008) Exercise induces expression of leukaemia inhibitory factor in human skeletal muscle. J Physiol 586(8):2195–2201. doi:10.1113/jphysiol.2007.149781
Broholm C, Laye MJ, Brandt C, Vadalasetty R, Pilegaard H, Pedersen BK, Scheele C (2011) LIF is a contraction-induced myokine stimulating human myocyte proliferation. J Appl Physiol 111(1):251–259. doi:10.1152/japplphysiol.01399.2010
Brooks NE, Cadena SM, Vannier E, Cloutier G, Carambula S, Myburgh KH, Roubenoff R, Castaneda-Sceppa C (2010) Effects of resistance exercise combined with essential amino acid supplementation and energy deficit on markers of skeletal muscle atrophy and regeneration during bed rest and active recovery. Muscle Nerve 42(6):927–935. doi:10.1002/mus.21780
Cannon JG, St Pierre BA (1998) Cytokines in exertion-induced skeletal muscle injury. Mol Cell Biochem 179(1–2):159–167
Carlson ME, Conboy IM (2007) Loss of stem cell regenerative capacity within aged niches. Aging Cell 6(3):371–382. doi:10.1111/j.1474-9726.2007.00286.x
Carlson ME, Conboy MJ, Hsu M, Barchas L, Jeong J, Agrawal A, Mikels AJ, Agrawal S, Schaffer DV, Conboy IM (2009) Relative roles of TGF-beta1 and Wnt in the systemic regulation and aging of satellite cell responses. Aging Cell 8(6):676–689. doi:10.1111/j.1474-9726.2009.00517.x
Chakravarthy MV, Abraha TW, Schwartz RJ, Fiorotto ML, Booth FW (2000) Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3’-kinase/Akt signaling pathway. J Biol Chem 275(46):35942–35952. doi:10.1074/jbc.M005832200
Charifi N, Kadi F, Feasson L, Denis C (2003) Effects of endurance training on satellite cell frequency in skeletal muscle of old men. Muscle Nerve 28(1):87–92. doi:10.1002/mus.10394
Charge SB, Rudnicki MA (2004) Cellular and molecular regulation of muscle regeneration. Physiol Rev 84(1): 209–238. doi:10.1152/physrev.00019.200384/1/209
Cheng M, Nguyen MH, Fantuzzi G, Koh TJ (2008) Endogenous interferon-gamma is required for efficient skeletal muscle regeneration. Am J Physiol Cell Physiol 294(5):C1183–C1191. doi:10.1152/ajpcell.00568.2007
Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433(7027):760–764. doi:10.1038/nature03260
Cossu G, Tajbakhsh S (2007) Oriented cell divisions and muscle satellite cell heterogeneity. Cell 129(5):859–861. doi:10.1016/j.cell.2007.05.029
Cotman CW, Berchtold NC, Christie LA (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30(9):464–472
Covey MV, Levison SW (2007) Leukemia inhibitory factor participates in the expansion of neural stem/progenitors after perinatal hypoxia/ischemia. Neuroscience 148(2):501–509. doi:10.1016/j.neuroscience.2007.06.015
Crameri RM, Langberg H, Magnusson P, Jensen CH, Schroder HD, Olesen JL, Suetta C, Teisner B, Kjaer M (2004) Changes in satellite cells in human skeletal muscle after a single bout of high intensity exercise. J Physiol 558(Pt 1):333–340. doi:10.1113/jphysiol.2004.061846
Crameri RM, Aagaard P, Qvortrup K, Langberg H, Olesen J, Kjaer M (2007) Myofibre damage in human skeletal muscle: effects of electrical stimulation versus voluntary contraction. J Physiol 583(Pt 1):365–380. doi:10.1113/jphysiol.2007.128827
Czarkowska-Paczek B, Bartlomiejczyk I, Przybylski J (2006) The serum levels of growth factors: PDGF, TGF-beta and VEGF are increased after strenuous physical exercise. J Physiol Pharmacol 57(2):189–197
Darr KC, Schultz E (1987) Exercise-induced satellite cell activation in growing and mature skeletal muscle. J Appl Physiol 63(5):1816–1821
Di Felice V, De Luca A, Colorito ML, Montalbano A, Ardizzone NM, Macaluso F, Gammazza AM, Cappello F, Zummo G (2009) Cardiac stem cell research: an elephant in the room? Anat Rec (Hoboken) 292(3):449–454. doi:10.1002/ar.20858
Doherty TJ (2003) Invited review: aging and sarcopenia. J Appl Physiol 95(4):1717–1727. doi:10.1152/japplphysiol.00347.2003
Donnikov AE, Shkurnikov MY, Akimov EB, Grebenyuk ES, Khaustova SA, Shahmatova EM, Tonevitsky AG (2009) Effect of a six-hour marathon ultra-race on the levels of IL-6, LIF, and SCF. Bull Exp Biol Med 148(5):819–821
Dunker N, Krieglstein K (2000) Targeted mutations of transforming growth factor-beta genes reveal important roles in mouse development and adult homeostasis. Eur J Biochem 267(24):6982–6988
Ellison GM, Waring CD, Vicinanza C, Torella D (2011) Physiological cardiac remodelling in response to endurance exercise training: cellular and molecular mechanisms. Heart. doi:10.1136/heartjnl-2011-300639
Fabel K, Fabel K, Tam B, Kaufer D, Baiker A, Simmons N, Kuo CJ, Palmer TD (2003) VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci 18(10):2803–2812
Friedrichs M, Wirsdorfer F, Flohe SB, Schneider S, Wuelling M, Vortkamp A (2011) Bmp-signaling balances proliferation and differentiation of muscle satellite cell descendants. BMC Cell Biol 12(1):26. doi:10.1186/1471-2121-12-26
Gal-Levi R, Leshem Y, Aoki S, Nakamura T, Halevy O (1998) Hepatocyte growth factor plays a dual role in regulating skeletal muscle satellite cell proliferation and differentiation. Biochim Biophys Acta 1402(1):39–51
Gnocchi VF, White RB, Ono Y, Ellis JA, Zammit PS (2009) Further characterisation of the molecular signature of quiescent and activated mouse muscle satellite cells. PLoS ONE 4(4):e5205. doi:10.1371/journal.pone.0005205
Greco V, Guo S (2010) Compartmentalized organization: a common and required feature of stem cell niches? Development 137(10):1586–1594. doi:10.1242/dev.041103
Grounds MD (1998) Age-associated changes in the response of skeletal muscle cells to exercise and regeneration. Ann N Y Acad Sci 854:78–91
Gundersen K (2011) Excitation-transcription coupling in skeletal muscle: the molecular pathways of exercise. Biol Rev Camb Philos Soc 86(3):564–600. doi:10.1111/j.1469-185X.2010.00161.x
Hasani-Ranjbar S, Soleymani Far E, Heshmat R, Rajabi H, Kosari H (2011) Time course responses of serum GH, insulin, IGF-1, IGFBP1, and IGFBP3 concentrations after heavy resistance exercise in trained and untrained men. Endocrine. doi:10.1007/s12020-011-9537-3
Hawke TJ, Garry DJ (2001) Myogenic satellite cells: physiology to molecular biology. J Appl Physiol 91(2):534–551
Hoch RV, Soriano P (2003) Roles of PDGF in animal development. Development 130(20):4769–4784. doi:10.1242/dev.00721
Jaumot M, Estanol JM, Casanovas O, Grana X, Agell N, Bachs O (1997) The cell cycle inhibitor p21CIP is phosphorylated by cyclin A-CDK2 complexes. Biochem Biophys Res Commun 241(2):434–438. doi:10.1006/bbrc.1997.7787
Jones NC, Tyner KJ, Nibarger L, Stanley HM, Cornelison DD, Fedorov YV, Olwin BB (2005) The p38alpha/beta MAPK functions as a molecular switch to activate the quiescent satellite cell. J Cell Biol 169(1):105–116. doi:10.1083/jcb.200408066
Kadi F, Schjerling P, Andersen LL, Charifi N, Madsen JL, Christensen LR, Andersen JL (2004) The effects of heavy resistance training and detraining on satellite cells in human skeletal muscles. J Physiol 558(Pt 3):1005–1012. doi:10.1113/jphysiol.2004.065904
Knaepen K, Goekint M, Heyman EM, Meeusen R (2010) Neuroplasticity-exercise-induced response of peripheral brain-derived neurotrophic factor: a systematic review of experimental studies in human subjects. Sports Med 40(9):765–801. doi:10.2165/11534530-000000000-00000
Kraemer WJ, Marchitelli L, Gordon SE, Harman E, Dziados JE, Mello R, Frykman P, McCurry D, Fleck SJ (1990) Hormonal and growth factor responses to heavy resistance exercise protocols. J Appl Physiol 69(4):1442–1450
Kuang S, Gillespie MA, Rudnicki MA (2008) Niche regulation of muscle satellite cell self-renewal and differentiation. Cell Stem Cell 2(1):22–31. doi:10.1016/j.stem.2007.12.012
Laufs U, Werner N, Link A, Endres M, Wassmann S, Jurgens K, Miche E, Bohm M, Nickenig G (2004) Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 109(2):220–226. doi:10.1161/01.CIR.0000109141.48980.37
Lauritzen F, Paulsen G, Raastad T, Bergersen LH, Owe SG (2009) Gross ultrastructural changes and necrotic fiber segments in elbow flexor muscles after maximal voluntary eccentric action in humans. J Appl Physiol 107(6):1923–1934. doi:10.1152/japplphysiol.00148.2009
Lee JS, Bruce CR, Spurrell BE, Hawley JA (2002) Effect of training on activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase pathways in rat soleus muscle. Clin Exp Pharmacol Physiol 29(8):655–660
Leiter JR, Anderson JE (2010) Satellite cells are increasingly refractory to activation by nitric oxide and stretch in aged mouse-muscle cultures. Int J Biochem Cell Biol 42(1):132–136. doi:10.1016/j.biocel.2009.09.021
Li L, Clevers H (2010) Coexistence of quiescent and active adult stem cells in mammals. Science 327(5965):542–545. doi:10.1126/science.1180794
Lysy PA, Smets F, Najimi M, Sokal EM (2008) Leukemia inhibitory factor contributes to hepatocyte-like differentiation of human bone marrow mesenchymal stem cells. Differentiation 76(10):1057–1067. doi:10.1111/j.1432-0436.2008.00287.x
Macaluso F, Brooks NE, van de Vyver M, Van Tubbergh K, Niesler CU, Myburgh KH (2011) Satellite cell count, VO(2max), and p38 MAPK in inactive to moderately active young men. Scand J Med Sci Sports. doi:10.1111/j.1600-0838.2011.01389.x
Macaluso F, Isaacs AW, Myburgh KH (2012) Preferential type II muscle fiber damage from plyometric exercise. J Athl Train 47(4)
Machida S, Spangenburg EE, Booth FW (2003) Forkhead transcription factor FoxO1 transduces insulin-like growth factor’s signal to p27Kip1 in primary skeletal muscle satellite cells. J Cell Physiol 196(3):523–531. doi:10.1002/jcp10339
Mackey AL, Esmarck B, Kadi F, Koskinen SO, Kongsgaard M, Sylvestersen A, Hansen JJ, Larsen G, Kjaer M (2007) Enhanced satellite cell proliferation with resistance training in elderly men and women. Scand J Med Sci Sports 17(1):34–42. doi:10.1111/j.1600-0838.2006.00534.x
Mackey AL, Holm L, Reitelseder S, Pedersen TG, Doessing S, Kadi F, Kjaer M (2010) Myogenic response of human skeletal muscle to 12 weeks of resistance training at light loading intensity. Scand J Med Sci Sports. doi:10.1111/j.1600-0838.2010.01178.x
Malm C, Sjodin TL, Sjoberg B, Lenkei R, Renstrom P, Lundberg IE, Ekblom B (2004) Leukocytes, cytokines, growth factors and hormones in human skeletal muscle and blood after uphill or downhill running. J Physiol 556(Pt 3):983–1000. doi:10.1113/jphysiol.2003.056598
Mathieu ME, Saucourt C, Mournetas V, Gauthereau X, Theze N, Praloran V, Thiebaud P, Boeuf H (2011) LIF-Dependent Signaling: new Pieces in the Lego. Stem Cell Rev. doi:10.1007/s12015-011-9261-7
Mauro A (1961) Satellite cell of skeletal muscle fibers. J Biophys Biochem Cytol 9:493–495
McCroskery S, Thomas M, Maxwell L, Sharma M, Kambadur R (2003) Myostatin negatively regulates satellite cell activation and self-renewal. J Cell Biol 162(6):1135–1147. doi:10.1083/jcb.200207056
Mirzapour T, Movahedin M, Tengku Ibrahim TA, Haron AW, Nowroozi MR, Rafieian SH (2011) Effects of basic fibroblast growth factor and leukaemia inhibitory factor on proliferation and short-term culture of human spermatogonial stem cells. Andrologia. doi:10.1111/j.1439-0272.2010.01135.x
Mobius-Winkler S, Hilberg T, Menzel K, Golla E, Burman A, Schuler G, Adams V (2009) Time-dependent mobilization of circulating progenitor cells during strenuous exercise in healthy individuals. J Appl Physiol 107(6):1943–1950. doi:10.1152/japplphysiol.00532.2009
Moreau JF, Bonneville M, Godard A, Gascan H, Gruart V, Moore MA, Soulillou JP (1987) Characterization of a factor produced by human T cell clones exhibiting eosinophil-activating and burst-promoting activities. J Immunol 138(11):3844–3849
Morici G, Zangla D, Santoro A, Pelosi E, Petrucci E, Gioia M, Bonanno A, Profita M, Bellia V, Testa U, Bonsignore MR (2005) Supramaximal exercise mobilizes hematopoietic progenitors and reticulocytes in athletes. Am J Physiol 289(5):R1496–R1503. doi:10.1152/ajpregu.00338.2005
Nagata Y, Partridge TA, Matsuda R, Zammit PS (2006) Entry of muscle satellite cells into the cell cycle requires sphingolipid signaling. J Cell Biol 174(2):245–253. doi:10.1083/jcb.200605028
O’Reilly C, McKay B, Phillips S, Tarnopolsky M, Parise G (2008) Hepatocyte growth factor (HGF) and the satellite cell response following muscle lengthening contractions in humans. Muscle Nerve 38(5):1434–1442. doi:10.1002/mus.21146
Petrella JK, Kim JS, Mayhew DL, Cross JM, Bamman MM (2008) Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis. J Appl Physiol 104(6):1736–1742. doi:10.1152/japplphysiol.01215.2007
Reiss K, Cheng W, Ferber A, Kajstura J, Li P, Li B, Olivetti G, Homcy CJ, Baserga R, Anversa P (1996) Overexpression of insulin-like growth factor-1 in the heart is coupled with myocyte proliferation in transgenic mice. Proc Natl Acad Sci USA 93(16):8630–8635
Riekstina U, Muceniece R, Cakstina I, Muiznieks I, Ancans J (2008) Characterization of human skin-derived mesenchymal stem cell proliferation rate in different growth conditions. Cytotechnology 58(3):153–162. doi:10.1007/s10616-009-9183-2
Rubin MR, Kraemer WJ, Maresh CM, Volek JS, Ratamess NA, Vanheest JL, Silvestre R, French DN, Sharman MJ, Judelson DA, Gomez AL, Vescovi JD, Hymer WC (2005) High-affinity growth hormone binding protein and acute heavy resistance exercise. Med Sci Sports Exerc 37(3):395–403
Schabort EJ, Myburgh KH, Wiehe JM, Torzewski J, Niesler CU (2009) Potential myogenic stem cell populations: sources, plasticity, and application for cardiac repair. Stem cells and development 18(6):813–830. doi:10.1089/scd.2008.0387
Schabort EJ, van der Merwe M, Niesler CU (2011) TGF-beta isoforms inhibit IGF-1-induced migration and regulate terminal differentiation in a cell-specific manner. J Muscle Res Cell Motil 31(5–6):359–367. doi:10.1007/s10974-011-9241-1
Schertzer JD, Lynch GS (2006) Comparative evaluation of IGF-I gene transfer and IGF-I protein administration for enhancing skeletal muscle regeneration after injury. Gene Ther 13(23):1657–1664
Schmalbruch H, Hellhammer U (1976) The number of satellite cells in normal human muscle. Anat Rec 185(3):279–287. doi:10.1002/ar.1091850303
Serrano AL, Baeza-Raja B, Perdiguero E, Jardi M, Munoz-Canoves P (2008) Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metab 7(1):33–44. doi:10.1016/j.cmet.2007.11.011
Shefer G, Van de Mark DP, Richardson JB, Yablonka-Reuveni Z (2006) Satellite-cell pool size does matter: defining the myogenic potency of aging skeletal muscle. Dev Biol 294(1):50–66. doi:10.1016/j.ydbio.2006.02.022
Shimatsu A, Rotwein P (1987) Mosaic evolution of the insulin-like growth factors. Organization, sequence, and expression of the rat insulin-like growth factor I gene. J Biol Chem 262(16):7894–7900
Shinin V, Gayraud-Morel B, Gomes D, Tajbakhsh S (2006) Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Nat Cell Biol 8(7):677–687. doi:10.1038/ncb1425
Silva H, Conboy IM (2008) Aging and stem cell renewal. StemBook [Internet]. Harvard Stem Cell Institute, Cambridge
Smith C, Kruger MJ, Smith RM, Myburgh KH (2008) The inflammatory response to skeletal muscle injury: illuminating complexities. Sports Med 38(11):947–969
Snijders T, Verdijk LB, Hansen D, Dendale P, van Loon LJ (2011) Continuous endurance-type exercise training does not modulate satellite cell content in obese type 2 diabetes patients. Muscle Nerve 43(3):393–401. doi:10.1002/mus.21891
Soltow QA, Lira VA, Betters JL, Long JH, Sellman JE, Zeanah EH, Criswell DS (2010) Nitric oxide regulates stretch-induced proliferation in C2C12 myoblasts. J Muscle Res Cell Motil 31(3):215–225. doi:10.1007/s10974-010-9227-4
Steiner S, Niessner A, Ziegler S, Richter B, Seidinger D, Pleiner J, Penka M, Wolzt M, Huber K, Wojta J, Minar E, Kopp CW (2005) Endurance training increases the number of endothelial progenitor cells in patients with cardiovascular risk and coronary artery disease. Atherosclerosis 181(2):305–310. doi:10.1016/j.atherosclerosis.2005.01.006
Sun L, Ma K, Wang H, Xiao F, Gao Y, Zhang W, Wang K, Gao X, Ip N, Wu Z (2007) JAK1-STAT1-STAT3, a key pathway promoting proliferation and preventing premature differentiation of myoblasts. J Cell Biol 179(1):129–138. doi:10.1083/jcb.200703184
Sun Y, Pollard S, Conti L, Toselli M, Biella G, Parkin G, Willatt L, Falk A, Cattaneo E, Smith A (2008) Long-term tripotent differentiation capacity of human neural stem (NS) cells in adherent culture. Mol Cell Neurosci 38(2):245–258. doi:10.1016/j.mcn.2008.02.014
Suzuki S, Yamanouchi K, Soeta C, Katakai Y, Harada R, Naito K, Tojo H (2002) Skeletal muscle injury induces hepatocyte growth factor expression in spleen. Biochem Biophys Res Commun 292(3):709–714. doi:10.1006/bbrc.2002.6706
Tatsumi R (2010) Mechano-biology of skeletal muscle hypertrophy and regeneration: possible mechanism of stretch-induced activation of resident myogenic stem cells. Anim Sci J 81(1):11–20. doi:10.1111/j.1740-0929.2009.00712.x
Tatsumi R, Anderson JE, Nevoret CJ, Halevy O, Allen RE (1998) HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells. Dev Biol 194(1):114–128. doi:10.1006/dbio.1997.8803
Tatsumi R, Sheehan SM, Iwasaki H, Hattori A, Allen RE (2001) Mechanical stretch induces activation of skeletal muscle satellite cells in vitro. Exp Cell Res 267(1):107–114. doi:10.1006/excr.2001.5252
Tatsumi R, Wuollet AL, Tabata K, Nishimura S, Tabata S, Mizunoya W, Ikeuchi Y, Allen RE (2009) A role for calcium-calmodulin in regulating nitric oxide production during skeletal muscle satellite cell activation. Am J Physiol Cell Physiol 296(4):C922–C929. doi:10.1152/ajpcell.00471.2008
Ten Broek RW, Grefte S, Von den Hoff JW (2010) Regulatory factors and cell populations involved in skeletal muscle regeneration. J Cell Physiol 224(1):7–16. doi:10.1002/jcp.22127
Trenerry MK, Della Gatta PA, Larsen AE, Garnham AP, Cameron-Smith D (2011a) Impact of resistance exercise training on interleukin-6 and JAK/STAT in young men. Muscle Nerve 43(3):385–392. doi:10.1002/mus.21875
Trenerry MK, Gatta PA, Cameron-Smith D (2011b) JAK/STAT signaling and human in vitro myogenesis. BMC Physiol 11:6. doi:10.1186/1472-6793-11-6
Turtikova OV, Altaeva EG, Tarakina MV, Malashenko AM, Nemirovskaya TL, Shenkman BS (2007) Muscle progenitor cell proliferation during passive stretch of unweighted soleus in dystrophin deficient mice. J Gravit Physiol 14(1):P95–P96
Verdijk LB, Gleeson BG, Jonkers RA, Meijer K, Savelberg HH, Dendale P, van Loon LJ (2009) Skeletal muscle hypertrophy following resistance training is accompanied by a fiber type-specific increase in satellite cell content in elderly men. J Gerontol A Biol Sci Med Sci 64(3):332–339. doi:10.1093/gerona/gln050
Verney J, Kadi F, Charifi N, Feasson L, Saafi MA, Castells J, Piehl-Aulin K, Denis C (2008) Effects of combined lower body endurance and upper body resistance training on the satellite cell pool in elderly subjects. Muscle Nerve 38(3):1147–1154. doi:10.1002/mus.21054
Volonte D, Liu Y, Galbiati F (2005) The modulation of caveolin-1 expression controls satellite cell activation during muscle repair. FASEB J 19(2):237–239. doi:10.1096/fj.04-2215fje
Wahl P, Brixius K, Bloch W (2008) Exercise-induced stem cell activation and its implication for cardiovascular and skeletal muscle regeneration. Minim Invasive Ther Allied Technol 17(2):91–99. doi:10.1080/13645700801969816
Wallis M (2009) New insulin-like growth factor (IGF)-precursor sequences from mammalian genomes: the molecular evolution of IGFs and associated peptides in primates. Growth Horm IGF Res 19(1):12–23
Wozniak AC, Anderson JE (2007) Nitric oxide-dependence of satellite stem cell activation and quiescence on normal skeletal muscle fibers. Dev Dyn 236(1):240–250. doi:10.1002/dvdy.21012
Yablonka-Reuveni Z, Seger R, Rivera AJ (1999) Fibroblast growth factor promotes recruitment of skeletal muscle satellite cells in young and old rats. J Histochem Cytochem 47(1):23–42
Yamada M, Tatsumi R, Kikuiri T, Okamoto S, Nonoshita S, Mizunoya W, Ikeuchi Y, Shimokawa H, Sunagawa K, Allen RE (2006) Matrix metalloproteinases are involved in mechanical stretch-induced activation of skeletal muscle satellite cells. Muscle Nerve 34(3):313–319. doi:10.1002/mus.20601
Yamada M, Sankoda Y, Tatsumi R, Mizunoya W, Ikeuchi Y, Sunagawa K, Allen RE (2008) Matrix metalloproteinase-2 mediates stretch-induced activation of skeletal muscle satellite cells in a nitric oxide-dependent manner. Int J Biochem Cell Biol 40(10):2183–2191. doi:10.1016/j.biocel.2008.02.017
Yu M, Stepto NK, Chibalin AV, Fryer LG, Carling D, Krook A, Hawley JA, Zierath JR (2003) Metabolic and mitogenic signal transduction in human skeletal muscle after intense cycling exercise. J Physiol 546(Pt 2):327–335
Zoladz JA, Pilc A (2010) The effect of physical activity on the brain derived neurotrophic factor: from animal to human studies. J Physiol Pharmacol 61(5):533–541
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Macaluso, F., Myburgh, K.H. Current evidence that exercise can increase the number of adult stem cells. J Muscle Res Cell Motil 33, 187–198 (2012). https://doi.org/10.1007/s10974-012-9302-0
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DOI: https://doi.org/10.1007/s10974-012-9302-0