Roles played by protein metabolism and myogenic progenitor … · 2019-10-26 · signaling pathway is also known to play a regulatory role in translation initiation, either dependently

J Phys Fitness Sports Med, 1(1): 83-94 (2012)

JPFSM: Review Article

Roles played by protein metabolism and myogenic progenitor cells inexercise-induced muscle hypertrophy and their relation to resistance training regimens

Naokata Ishii1,2*, Riki Ogasawara2, Koji Kobayashi 3 and Koichi Nakazato3

1 Department of Life Science, Graduate School of Arts and Sciences, The University of Tokyo, Komaba, Tokyo 153-8902, Japan2 Department of Environmental Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 227-

8653, Japan3 Graduate School of Health and Sport Sciences, Nippon Sport Science University, Fukazawa, Tokyo 153-8850, Japan

Received: March 23, 2012 / Accepted: April 2, 2012

Abstract To learn the mechanisms underlying resistance exercise-induced muscle hypertro-phy, recent studies on muscle protein metabolism and myogenic progenitor cells were reviewed. Numerous studies have suggested that activation of the translation process plays a major role in a resistance exercise-induced increase in muscle protein synthesis, and also in muscle hyper-trophy after a prolonged period of training. Among regulators of the translational activity, the mTORC1 signaling pathway has been shown to be important, although the relation between its upstream regulation and exercise regimen remains unclear. In addition, the muscle satellite cells play a part, even if not indispensable, in exercise-induced muscle hypertrophy, by supply-ing muscle fibers with new myonuclei. Middle to high exercise intensity has been regarded as essential for gaining muscle mass, because it causes the recruitment of large motor units with fast, type II muscle fibers, which are readily hypertrophied through activation of mTORC1 sig-naling. However, several studies have shown that low-intensity resistance exercises with either large exercise volume or prolonged contraction time effectively activate protein synthesis and induce muscle hypertrophy. These findings suggest that various strategies are possible in exer-cise regimens, and exercise intensity is not necessarily a primary factor for gaining muscular size.Keywords : mTOR signaling, FOXO, exercise intensity, muscle satellite cells, myonuclei

Introduction

Learning the mechanisms underlying resistance exer-cise-induced skeletal muscle hypertrophy is important in order to prescribe adequate exercise regimens for various subjects, each with different physical conditions. Skel-etal muscle mass is regulated by the balance between muscle protein synthesis (MPS) and breakdown (MPB). The muscle net protein balance, i.e., MPS - MPB, has been shown to become transiently positive after a bout of resistance exercise mainly due to the increase in MPS; and this process has been regarded as an important factor in muscle hypertrophy after repeated bouts of resistance exercise1). On the other hand, the size of muscle fiber may be limited by the number of myonuclei, suggesting that an increase in the size of muscle fiber beyond a certain extent requires an increase in the number of myonuclei through proliferation of the muscle satellite cells (Fig. 1). Aside from cellular and molecular mechanisms, numer-ous studies have reported the relation between resistance training protocol variables (e.g., intensity, contraction mode, and volume) and the magnitude of muscle hyper-

trophy. Based on these studies, some review articles have proposed training protocols that can be recommended for gaining muscular size2-5). Although most of these articles have indicated that the intensity of exercise is a crucial factor for gaining muscular size and strength, there are many other variables to consider. For instance, resistance exercise training with restricted muscular blood flow has been shown to cause muscle hypertrophy even at low exercise intensity6). Also, several studies have shown that low-intensity exercises with slow movement and main-tained contractile force are effective for gaining muscular size7,8). These studies provide us with an opportunity to revise the relation between training protocol variables and muscle hypertrophy. Recently, the cellular and molecular mechanisms un-derlying the regulation of muscular size are, at least par-tially, being uncovered. These mechanisms include the processes of gene transcription, signal transduction for the initiation of protein synthesis, and activation of some proteolytic enzymes. Several studies have investigated how training protocol variables affect these processes, and such studies can provide the basis for evaluating the effectiveness of a variety of training regimens used for gaining muscular size. *Correspondence: [email protected]

84 JPFSM : Ishii N, et al.

This brief review summarizes the cellular and molecu-lar events that may be related to exercise-induced muscle hypertrophy, i.e., protein metabolism, cell signaling and activation of myogenic progenitor cells, with special ref-erence to their relation to resistance training regimens. It would help us to reconsider the principles operating in the regimens of conventional resistance training, and also the effects of some novel types of training without sufficient evidence at either the cellular or molecular level.

Resistance exercise training and muscle protein me-tabolism

1. Muscle protein metabolism1-1. Cell signaling in muscle protein synthesis Theoretically, MPS can be regulated in three processes: the number of myonuclei (DNA content), the transcription of DNA, and the translation of mRNA (Fig. 1). Among these processes, the translation of mRNA has been shown to play a crucial role in an exercise-induced increase in MPS9-11). The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway is considered as a key reg-ulator of translation initiation and has been shown to be important in muscle hypertrophy12,13). Resistance exercise has been shown to activate mTORC1 signaling, although its upstream regulation has not been fully understood14-16) [Fig. 2; for more detail, see recent reviews14,16-18)]. Acti-vation (phosphorylation) of mTORC1 stimulates MPS through phosphorylation of its downstream targets, eu-karyotic initiation factor 4E binding protein (4E-BP1) and p70 ribosomal protein S6 kinase (p70S6K). Multisite phosphorylation of the translational repressor 4E-BP1 results in its dissociation from eukaryotic initiation factor 4E (eIF4E), thereby allowing eIF4E to assemble with eI-F4G, and facilitate the recruitment of other translation ini-tiation factors to form the eIF4F complex19). On the other hand, activation of p70S6K by mTORC1-mediated phos-phorylation promotes the translation of mRNA through several substrates, such as SKAR, eEF2K, eEF4B, PDCD4, CCTβ, CBP80, and rpS6, a component of the

40S ribosome20). Increases in the phosphorylated forms of 4E-BP1 and p70S6K after a bout of resistance exercise have been shown to positively correlate with MPS21-23), and also with the magnitude of muscle hypertrophy after repeated bouts of exercise13,24,25). Resistance exercise also activates extracellular signal-regulated kinase (ERK) 1/2 and its downstream substrate, p90 ribosomal S6 kinase (p90RSK)22,26-29). The ERK1/2 signaling pathway is also known to play a regulatory role in translation initiation, either dependently or indepen-dently of the mTORC1 signaling pathway12,30). Therefore, quantifying several signal transduction substrates in both mTORC1 and ERK1/2 signaling pathways is thought to be an effective way to predict protein synthesis activity.

1-2. Cell signaling in muscle protein breakdown Currently, three proteolytic systems are known to be involved in the skeletal muscle protein breakdown: ly-sosomal proteases (cathepsins), the cytosolic calcium-dependent calpain system, and the ATP-dependent ubiq-uitin-proteasome system (UPS). Among these systems, UPS plays an important role in MPB and is thought to be regulated by the muscle-specific ubiquitin ligases (E3): muscle atrophy F-box (MAFbx/Atrogin-1) and muscle-specific RING finger-1 (MuRF1)31,32). Either unloading or aging causes muscle atrophy through activation of MPB by elevated expressions of Atrogin-1 and MuRF133,34). In addition, elevated expressions of Atrogin-1 and MuRF1 mRNA are associated with several diseases, e.g., sepsis35), cancer36), AIDS37), diabetes38), and renal failure39), which eventually cause the loss of muscle mass. The expression of ubiquitin ligases is regulated by the Forkhead transcription factor (FOXO). When protein syn-thesis is activated, FOXO is simultaneously phosphory-lated through protein kinase B (Akt/PKB) pathway and is kept localized in the cytosolic compartment (Fig. 3). On the contrary, the dephosphorylated form of FOXO moves from the cytosol into the nucleus, and upregulates the transcription of ubiquitin ligase genes40). A pro-inflamma-tory cytokine, tumor necrosis factor-α (TNF-α) induces

Satellite cell activation

Myonulear number / DNA content

DNA transcription

mRNA translation

Muscle protein synthesis

Muscle protein breakdown

Satellite cell proliferation

Net protein balance

Muscle fiber size

Fig. 1 Major events involved in the regulation of skeletal muscle size.

85JPFSM : Muscle hypertrophy and training regimens

2. Resistance training protocol variables and muscle pro-tein metabolism2-1. High intensity is not essential for muscle protein syn-thesis It has been widely accepted that resistance training at an intensity ranging from 70 to 90% of 1-repetition maxi-mum (1RM) or from 6 to 12 RM is optimal for gaining

muscle atrophy through the upregulation of protein deg-radation. This process is possibly mediated with the phos-phorylation of nuclear factor kappa B (NFκB) inhibitor (IκB), which allows NFκB to separate from IκB and initi-ate the transcription of MuRF1 gene41). Also, TNF-α may stimulate phosphorylation of p38, which then promotes the expression of Atrogin-141).

mTORC1

Resistance exercise

Mechanical stress Growth factor Nutrient sensing

4E-BP1 p70S6K

mRNA translationMPS

FOXO

MPB

Atrogin-1 MuRF1

Fig. 2 A simplified schematic representation of how resistance exercise increases muscle protein synthesis (MPS) and breakdown (MPB). Resistance exercise increases both MPS and MPB through mTORC1 and FOXO signaling pathway, respectively. We depicted rough outline to help the reader to understand the whole context. For more details, please refer to the recent review articles14,16-18).

Moderate intensity Higher intensity

Myostatin

Satellite cellproliferation

Myonuclearnumber

IGF-1

PI3K PI3K-P

Akt Akt-P

mTORC1 mTORC1-P

p70S6K p70S6K-P

Muscle proteinsynthesis

FOXO-P FOXO

Atrogin-1MuRF1


Muscle fiber damages

Fig. 3 Intensity-dependent changes in muscle protein synthesis and breakdown in eccentric exercise. IGF-1, insulin-like growth factor-1; PI3K and PI3K-P, phosphoinositide 3-kinase and its phosphorylated form; Akt and Akt-P, protein kinase B and its phosphorylated form. Based on Ochi et al.83).


matched22). More recently, they also reported that low-intensity (30% 1RM) resistance exercise with slow lifting movements (6-s concentric and 6-s eccentric actions with-out pause, 3 sets) effectively caused an increase in MPS, when the exercise was performed until failure. The effect was much greater than that of exercise with the same intensity and volume (number of repetitions) but shorter movement duration (1-s concentric and 1-s eccentric actions)8). These studies suggest that either mechanical impulse (contractile force x time) or muscle fatigue is an important factor in the activation of MPS. It has been shown that both resistance exercise-induced phosphorylation of signal transduction substrates and muscle fiber hypertrophy occur mainly in type II fi-bers61-63). Therefore, recruiting type II muscle fibers ap-pears to be an indispensable factor in resistance exercise regimens for gaining muscular size. Henneman’s “size principle” states that smaller motor units are predomi-nantly recruited and the larger motor units are addition-ally recruited with increasing force production64). Because type II fibers are mainly involved in large motor units with a high recruitment threshold, they are not readily recruited by low-intensity resistance exercise. However, fatiguing exercise at low intensity has also been shown to eventually cause the recruitment of large motor units as the ability of muscle to generate force progressively de-clines and approaches the given exercise intensity65-68). According to the above arguments, it is suggested that repeated bouts of low-intensity resistance exercise ef-fectively causes muscle hypertrophy if each exercise is performed until failure. In fact, Tanimoto & Ishii reported that low-intensity (~50% 1RM) resistance exercise with slow lifting movement and maintained force generation (3-s concentric and 3-s eccentric actions) performed until volitional fatigue induced muscle hypertrophy compa-rable in magnitude to that induced by high-intensity (~80% 1RM) exercise with conventional movement speed (1-s concentric and 1-s eccentric actions). In addition, low-intensity resistance exercise with conventional movement speed (same exercise intensity and volume as those for the exercise with slow movement) did not cause muscle hypertrophy7). As already mentioned, both low-intensity exercise with large exercise volume and that with slow movement and long contraction time cause acute increases in MPS. This suggests that a low-intensity exercise regimen with con-ventional movement speed is also effective for gaining muscular mass if it eventually causes strong muscular fatigue. To test this, we recently examined the long-term effect of low-intensity, exhaustive exercise (30% 1RM, 4 sets, repetition until failure in each set) on muscular size. This exercise regimen caused muscle hypertrophy, the magnitude of which was similar to that caused by a typi-cal, high-intensity regimen (75% 1RM, 10 reps × 3 sets) (Ogasawara et al. in preparation). These results indicate thatl exercise intensity is not necessarily a primary vari-

muscular size2,42,43). Therefore, most studies on the effect of resistance exercise on MPS have used this range of in-tensity, and have reported increases in the phosphorylated forms of signal transduction substrates and activation of MPS12,44-54). In agreement with previous studies showing that low-intensity (e.g., <50% 1RM) resistance training is not sufficient to cause muscle hypertrophy2,42,43), several studies have reported that low-intensity exercise is sub-stantially ineffective to activate MPS23,55,56). However, Kumar et al. recently reported that MPS increased with exercise intensity of up to 60% 1RM, whereas no further increase in MPS occurred at higher intensity (75 and 90% 1RM), even when the exercise volume was matched23). This study implies that repeated bouts of resistance exercise at 60% 1RM can cause mus-cle hypertrophy comparable in magnitude to that induced by resistance training at higher intensity (70-85% 1RM), because acute changes in muscle protein synthesis have been shown to correlate with changes in muscle size after a period of training57). Low-intensity (30-50% 1RM) resistance exercise with restricted muscular blood flow has been shown to readily fatigue the working muscle58,59), and cause muscle hy-pertrophy and strength gain after a period of training6,60). Fujita et al. reported that this type of exercise effectively stimulated mTORC1 signaling pathway and MPS, while a normal exercise (without blood flow restriction) of the same intensity and volume did not55). These studies imply that high-intensity is not prerequisite to stimulate MPS and to gain muscular size.

2-2. Low-intensity exhaustive training stimulates muscle protein synthesis Exercise volume (e.g., weight × repetitions × sets) is also an important variable in resistance training regimens. Generally, using multiple sets has been believed to be superior to a single set for muscle hypertrophy. Burd et al. reported that the increase in MPS was much larger and lasted longer after an exercise session with multiple sets (3 sets) than after that with a single set21). Furthermore, Terzis et al. reported that phosphorylated forms of both p70S6K and its downstream target rpS6 increased with exercise volume (1 set < 3 sets < 5 sets), though MPS was not measured24). On the other hand, phosphorylation of extracellular signal-regulated kinase (ERK1/2) and its downstream substrate p90RSK was not affected by the increase in exercise volume in both studies. These stud-ies suggest that the mTORC1 signaling pathway is more responsive to exercise volume than the ERK1/2 signaling pathway. Burd et al. recently reported that low-intensity (30% 1RM) resistance exercise caused an increase in MPS similar to high-intensity (90% 1RM) exercise, when the exercise was performed until repetition failure22). How-ever, the low-intensity exercise was far less effective than the high-intensity exercise when the exercise volume was


able in exercise regimens for gaining muscular size.

2-3. Mode of muscle contraction may not be a primary determinant for muscle protein synthesis Resistance training protocol variables include the mode of muscle contraction, i.e., isotonic, isometric, isokinetic, concentric, eccentric, etc. However, contraction mode-specific effects on MPS and muscular size are unknown. Up to present, a limited number of studies have separately investigated the effects of concentric and eccentric ac-tions under nominally isotonic conditions. Generally, eccentric training performed at high intensities has been shown to be more effective for gaining muscle mass than concentric training69), but no difference in muscle-hypertrophic effect has been reported between these two types of training with the same exercise volume (weight x repetitions)70). Moore et al. reported that MPS increased more rapidly after eccentric exercise than after concen-tric exercise, but no substantial difference in the magni-tude of MPS was observed between these two types of contraction mode71). Cuthbertson et al. also reported no significant difference in MPS between concentric and ec-centric contractions72). However, it should also be noted that high-intensity eccentric exercise gives rise to strong mechanical stress, which may cause some additional ef-fects specific to eccentric actions69). Thus, high-intensity eccentric exercise may be useful as a part of periodized training regimens, because performing the same regimen of resistance training is known to cause a gradual decline in the acute changes in signal transduction substrates and MPS after a bout of exercise51,73,74), and also in the rate of muscle growth75,76).

3. Resistance exercise and muscle protein breakdown So far, most studies on changes in protein metabolism after resistance exercise have mainly investigated MPS and MPS-related signal transduction, because it has been shown that MPB does not change considerably after exer-cise. Phillips et al. reported that the rate of MPB increased after a bout of resistance exercise in sedentary subjects51). Yang et al. and Louis et al. also showed that the expres-sion of MuRF1 mRNA increased after one bout of high-intensity (65~70% 1RM) resistance exercise in sedentary men52,118). Leger et al. showed that an 8-wk resistance training period caused increases in FOXO1, Atrogin-1 and MuRF177). These studies indicate that resistance exer-cise causes both acute and chronic increases in MPB. On the other hand, Phillips et al. showed that the rate of MPB did not change after a bout of resistance exercise in trained subjects51). Mascher et al. showed that the expres-sion of Atrogin-1 mRNA was reduced by 32% after the second session of training when compared to that after the initial session of training78). Karagounis et al. investi-gated the effects of three bouts of resistance exercise on TNF-α and IKK using a rat training model, and showed

that the expression of these proteins markedly increased in response to the initial bout, whereas the responses to subsequent bouts of exercise declined gradually79). Zanchi et al. also showed that a 12-wk resistance training period caused decreases in atrogin-1 and MuRF1 in rats80). These studies suggest that repeated bouts of resistance exercise diminish the acute increase in MPB after exercise. High-intensity eccentric exercise is known to cause structural damage in muscle fibers (Z-line streaming and sarcomere disruption), inflammatory reactions and MPB81). Willoughby et al. investigated changes in the expression of atrogin-1 protein after two successive bouts of 150% 1RM eccentric training, and showed that the increase in atrogin-1 protein after the 2nd bout was dimin-ished as compared to that after the 1st bout of training82). These studies suggest that eccentric exercise promotes MPB within muscle fibers subjected to intense mechani-cal stress, but some adaptation takes place gradually with the succession of training. On the other hand, our recent study with the rat eccentric training model has shown that changes in both MPS and MPB are strongly dependent on exercise intensity (Fig. 3). Eccentric contractions with slow stretch and moderate contractile force activated the signal transduction towards MPS; whereas those with rapid stretch and large contractile force worked oppositely to activate the signal transduction towards MPB83). There-fore, the speed of eccentric actions would be an important factor even in conventional resistance training regimens for optimizing protein metabolism.

Myogenic cells and their contribution to muscle hy-pertrophy

1. Satellite cells are major myogenic progenitor cells in the adult skeletal muscle Skeletal muscle adapts to the environment with dy-namic changes in its architecture. In response to anabolic stimulus or damage, myogenic cells within muscle are activated and play a role to form a new architecture. It has been reported that several types of myogenic progenitor cells exist, such as muscle satellite cells, bone marrow stem cells, skeletal muscle side population cells, and me-soangioblasts84). The satellite cells, especially, are major myogenic progenitor cells in adult muscle. Satellite cells are quiescent cells located between the sarcolemma and the basal lamina85). When muscle is in-jured or subjected to mechanical stress, satellite cells are activated to enter the cell proliferation cycle, differenti-ate, and finally fuse with muscle fiber86). This process has been regarded as a key event in muscle regeneration and hypertrophy. Up to present, two strategies have been taken to examine relationships between resistance exer-cise training and satellite cell activation/proliferation. One is immunohistochemical observation to identify satellite cells and myonuclei. The other is to measure expressions of “myogenic” mRNAs in exercised muscle specimens


(Fig. 4). Although both are definitely effective strategies, this review will mainly focus on immunohistochemical studies with human subjects.

2. Effect of resistance training on satellite cell number Satellite cells provide muscle fibers with additional nuclei so as to increase the capacity of muscle fibers for hypertrophy. Acute effects of resistance exercise on the number of satellite cells have been examined in young and old subjects. A single bout of strenuous eccentric ex-ercise increased N-CAM positive satellite cells in young (20-35 years) and older (60-75 years) subjects87-89). The magnitude of increase in young men (3.2±1.3 fold) was higher than in older participants (1.3±0.6 fold) when expressed relative to pre-exercise numbers88). Electrical stimulation of the gastrocnemius muscle also increased the number of activated satellite cells (+CD56+Ki67) within 48 hours in young (20±5 years) subjects90). Com-bined exercise with cycle ergometer ( < 62% of workload capacity) and leg press machine (55-70% 1RM) activated satellite cells (+DLK1+CD56) within 9 hours in young subjects91). Taken together, one bout of resistance exercise induces the activation and proliferation of satellite cells, especially in younger subjects. Interestingly, several stud-ies reported that satellite cell proliferation after resistance training was attenuated by anti-inflammatory medica-tion92,93), suggesting that inflammatory reaction plays a part in the activation of satellite cells.

Repeated bouts of resistance training also cause chronic increases in the number of satellite cells. The phenome-non, unlike the acute response, appears to be independent of age and gender. Kadi and Thornell showed that a 12-wk strength training (shoulder press, rowing, triceps and latissimus pulldown; 10-12 RM) induced concomitant increases in muscle fiber cross sectional area (36%), myo-nuclear number (70%), and satellite cells (+CD56) (46%) in female trapezius muscle94). Several studies demonstrat-ed that more than 9 weeks of resistance training increased the number of satellite cells (electron microscopy or +Pax7) in both younger and older subjects, regardless of gender difference95-98). Notably, Verdijk et al. showed that, in elderly adults (72±2 years), a 12-wk resistance training period increased type II muscle fiber cross-sectional area and the number of adjacent satellite cells (+CD56)99). This might be related to the aging-specific atrophy of type II muscle fibers and the decrease of subsidiary satellite cells in the elderly88,100).

3. Effect of endurance training on satellite cell number In comparison to resistance training, responses of satel-lite cells to endurance exercise training have not been well documented. Charifi et al. showed that a 12-wk endurance training period (cycle ergometer; 65-95% of peak oxygen consumption) elicited an increase in satellite cell (+CD56) number in vastus lateralis in elderly subjects (73±3 years). Their research also showed no significant increases in

activate

+SCM cell

+SCM +MGM +nCCM cell

commited

addition of myonuclei

muscle fiber

SCM

satellite cell markerMGM

myogenic marker

Pax7

Myf5

CD34

c-Met

NCAM

self renew

+SCM +pCCM cell

MyoD

myogenin

MRF4

Myf5

pCCM

positive-regulating

cell cycle marker

nCCM

negative-regulating

cell cycle marker

Cyclin

cdk

p21

p27

p57

+MGM +nCCM cell

Fig. 4 Myogenic markers for myogenesisFrequently used markers for proliferation and differentiation of myogenic cells are shown. Please refer to articles by others for detailed information.


the number of myonuclei and the muscle cross sectional area101). Verney et al. examined the effects of a combina-tion of resistance training for the upper limb muscles (20-10 RM) and endurance training with the lower limb (cycle ergometer; 75-95 HRmax). After a 14-wk training period, the numbers of NCAM-positive satellite cells increased in both upper and lower limb muscles, whereas the numbers of myonuclei were unchanged102). Recently, Snijders et al. reported that a 6-month endurance-type exercise did not alter the number of satellite cells in muscles of type 2 dia-betes patients103). Although further studies are needed, en-durance exercise appears to stimulate, to some extent, the proliferation of satellite cells in healthy subjects. It should also be noted that endurance exercise does not increase the number of myonuclei.

4. Roles played by satellite cells and myonuclei in muscle hypertrophy Although the “myonuclear domain”, i.e., cytoplasmic volume per myonucleus, has been regarded as important in the regulation of myonuclear number, numerous stud-ies have shown that the size of myonuclear domain is variable, depending on muscle fiber type, age, and muscle usage104,105). In addition, there have been several papers describing that satellite cells are not indispensable for muscle hypertrophy106,107). For example, satellite cell-de-pleted mice showed a double increase in muscle size after a 2-wk functional overload107). Hypertrophy caused by Akt-activation in mouse skeletal muscle was associated with neither satellite cell activation nor newly myonuclear incorporation108). For humans, Petrella et al. showed a significantly larger myofiber area per myonucleus in “ex-treme responders”, i.e., individuals who showed marked muscle hypertrophy after resistance training109). Thus, the size of the myonuclear domain may not be defined initial-ly, so that it may not be a major reason why the activation of satellite cells occurs along with muscle hypertrophy. However, muscle hypertrophy is actually accompanied by a proliferation of satellite cells94). Kosek et al. showed that resistance training-induced muscle fiber hypertrophy was superior in young men than in young women and older adults110). Petrella et al. found that the number of satellite cells (+NCAM) and myonuclei increased only in young men. These studies suggest that the ability of myofiber to incorporate new myonuclei is important to achieve potent hypertrophy111). Petrella et al. also showed that “extreme responders” had more satellite cells before resistance exercise. After resistance exercise, the extreme responders exhibited significant increases in the numbers of myonuclei and satellite cells along with an increase in the fiber area per myonucleus109). Based on these results, the authors argued that individuals with a greater basal number of satellite cells achieved potent muscle growth after a period of training, because they had a higher abil-ity to expand the satellite cell pool109). Thus, the activation of satellite cells possibly enhances the growth of muscle

fibers, and is important especially in the later phase of muscle hypertrophy112,113). Satellite cells definitely play an indispensable role in the muscle regeneration process. They are able to regen-erate damaged muscle fibers and have been the target for cell grafting therapy114,115). Muscles lacking satellite cells could not regenerate normal muscle fibers seven days after 1.2 % BaCl2 induced injury107). Since strenuous ex-ercise is considered to cause micro traumas in muscle fi-bers, satellite cells might be essential especially in heavy resistance training to induce potent hypertrophy. Apart from the notion of myonuclear domain, the num-ber of myonuclei may be directly related to the activation of protein synthesis. By using C2C12 cells, Nader et al116) showed that serum-stimulated muscle growth was associ-ated with significant increases in retinoblastoma protein (Rb) phosphorylation and cyclin D1 protein. Cyclin D1 was detected in the nuclei of myotubes. These cell cycle regulating proteins increased ribosomal RNA through its upstream binding factor (UBF), and eventually acti-vated the translation process. Interestingly, these events occurring in the growth of myotube were blocked with rapamycin, suggesting that mTORC1 signaling regulates the expression of cell cycle regulating proteins within myonuclei. Another study showed that cell cycle regula-tors such as p21 and Rb, were detected in the myonuclei of mature muscle fibers in vivo 117). A similar association of increased cell cycle regulators with hypertrophy has previously been shown in heart muscles118). Therefore, an increased number of myonuclei could enhance translation activity through increased expression of cell cycle regula-tors, when mTORC1 signaling is activated by resistance exercise.

Summary and conclusion

To summarize the present review, Fig. 5 illustrates an overview of the relation between some variables in a re-sistance exercise regimen and protein metabolism. Up to the present, numerous studies have suggested that activa-tion of the translation process plays a major role in a re-sistance exercise-induced increase in muscle protein syn-thesis, and also in muscle hypertrophy after a prolonged period of training. Among regulators of the translational activity, the mTORC1 signaling pathway has been shown to be important in exercise-induced muscle hypertrophy, although the relation between its upstream regulation and exercise regimen remains unclear. Compared to muscle protein synthesis, muscle protein breakdown may play a minor role, because it does not show considerable changes after exercise. However, strenuous resistance ex-ercise such as heavy eccentric exercise has been shown to stimulate protein degradation, due possibly to structural damage to the working muscle fibers. On the other hand, it has also been shown that eccentric exercise with mod-erate intensity suppresses protein degradation through


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Variables inexercise regimen

Upstream factors

Cell signaling

Protein metabolism

IntensityContraction mode(concentric/eccentric)

Volume Mechanical impulse(force x time)

Fiber damages

Type II fiber recruitment

Muscle fatigue

Satellite cell activation

Increased myonuclei

FOXO signaling

Ubiquitinligases

mTORC1 signaling

Cell cycle regulatorsTranslation of mRNA


Muscle protein synthesis

<

Muscle fiber hypertrophy

Fig. 5 Schematic presentation of the relations between variables in resistance exercise regimens and muscle protein metabolism.

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Roles played by protein metabolism and myogenic progenitor … · 2019-10-26 · signaling pathway is also known to play a regulatory role in translation initiation, either dependently