Cellular and Molecular Events Controlling Skeletal Muscle

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  SKELETAL MUSCLE Cellular and molecular events controlling skeletal musclemass in response to altered use François B. Favier  &  Henri Benoit  &  Damien Freyssenet Received: 7 November 2007 /Accepted: 6 December 2007 # Springer-Verlag 2007 Abstract  Gain or loss of skeletal muscle mass occurs insituations of altered use such as strength training, aging,denervation, or immobilization. This review examines our current understanding of the cellular and molecular eventsinvolved in the control of muscle mass under conditions of muscle use and disuse, with particular attention to theeffects of resistance exercise/training. The DNA content,which is a critical determinant of protein synthesis by providing the amount of DNA necessary to sustain genetranscription, can be either increased (activation of satellitecells) or decreased (apoptosis) depending on muscleactivity and ongoing physiological processes. In addition,several transcription factors are sensitive to functionaldemand and may control muscle-specific protein expressionto promote or repress myofiber enlargement. The control of skeletal muscle mass is also markedly mediated by theregulation of transduction pathways that promote thesynthesis and/or the degradation of proteins. Insulin-likegrowth factor-I plays a key role in this balance by activatingthe Akt/tuberous sclerosis complex 2/mammalian target of rapamycin pathway. Stimulation of this pathway leads tothe concomitant activation of initiation and elongationfactors resulting in the elevation of protein translation andthe downregulation of ubiquitin proteasome componentsthrough Forkhead-box O transcription factors. Keywords  Ageing.Geneexpression.Hypertrophy.IGF.Proteinmetabolism Introduction Skeletal muscle is capable of remarkable adaptations inresponse to altered activity. These adjustments to mechan-ical and metabolic demands elicit marked modifications of gene expression that could lead to gain (hypertrophy) or loss (atrophy) of muscle mass. Whereas endurance trainingleads to minor changes in skeletal muscle mass, strengthtraining induces marked hypertrophy of exercising muscles.Histochemical analyses clearly show a 10 to 30% increasein muscle fiber cross-sectional area after 10  –  12 weeks of resistance training in sedentary subjects [146]; this risereaching about 80% in weightlifting athletes [78]. On theother hand, muscle disuse (i.e., reduced muscle activity)resulting either from experimental designs (plaster cast immobilization, hindlimb suspension, denervation, bed rest,and tenotomy) or ongoing physiological (aging) and pathological processes (cancer, neuromuscular disorders,respiratory insufficiency, and sepsis) can lead to severemuscle mass loss [35, 98]. For instance, 2 to 5 weeks of  immobilization reduces fiber cross-sectional area by about 50% ranging from 10 to 70% depending on muscle fiber typeand duration of immobilization (reviewed in [152]). In somesituations associated with catabolic states, amyotrophycannot be primarily attributable to muscle disuse. Loss of muscle mass associated with these pathologies is beyond thescope of the current review and will not be discussed.Assuming that myofibrillar proteins represent about 85%of the fiber volume [70], any situation altering thesynthesis/degradation balance of myofibrillar proteins maythus contribute to muscle hypertrophy or atrophy. Consis-tently, the increase in soleus and plantaris muscle weightsto overload is directly proportional to the increase in aminoacid incorporation [53]. Similarly, animal and humanstudies showed significant increases in protein synthesis Pflugers Arch - Eur J PhysiolDOI 10.1007/s00424-007-0423-zF. B. Favier  :  H. Benoit  :  D. Freyssenet ( * )Unité Physiologie et Physiopathologie de l ’ Exercice et Handicap,IFR143, Université Jean Monnet,15 rue Ambroise Paré,42023 Saint Etienne, cedex 2, Francee-mail: damien.freyssenet@univ-st-etienne.fr   from 4.5 up to 48 h after an acute bout of resistanceexercise (RE) or after 2 weeks of resistance training [166].Elevated rates of myofibrillar or mixed muscle proteinsynthesis have been recorded in both fast- and slow-typemuscles with eccentric, concentric, or isometric contrac-tions [87, 97, 107, 118]. However, a single bout of RE also increases protein degradation, but to a lesser extent than protein synthesis, so that the net protein balance isincreased [118]. One week of passive stretch, which isknown to promote muscle growth, induces a similar pattern,i.e., a concomitant increase in both protein synthesis anddegradation with the rise in synthesis being more pro-nounced than the one in degradation [55]. Nevertheless, adecrease in protein degradation may transiently occur at theearly stages of hypertrophying process [55, 155]. Inactivity has opposite effects. Protein synthesis in skeletal muscle isreduced after 6 h of plaster-induced immobilization [23],after 14 days of bed rest [43], or in elderly [166]. Hindlimb suspension also decreases protein synthesis in gastrocne-mius and soleus muscles and elevates protein degradationleading to protein loss [56, 152]. Similarly, muscle  breakdown occurs after sciatic nerve section in rat soleusand EDL muscles [54]. In summary, conditions associatedwith skeletal muscle hypertrophy are characterized by astrong increase in protein synthesis leading to positivenitrogen balance, whereas muscle disuse is accompanied bya rapid and transient decrease in protein synthesis together with a marked increase in protein degradation.While these adaptations are now well described, themolecular and cellular mechanisms responsible for skeletalmuscle mass gain or loss in response to use and disuse begin to be understood. Theoretically, skeletal muscle geneexpression can be controlled by regulating the number of myonuclei (DNA content), muscle gene transcription,translation, and/or muscle protein degradation (Fig. 1), eachone of these events being susceptible to be the target of regulatory influences triggered by altered use. The purposeof the present review is to depict our recent knowledgeabout the mechanisms regulating muscle mass in situationsof altered use. Particular interest will be accorded to theinfluence of RE because of its potential role for compen-sating disuse-related atrophy of skeletal muscle [4, 41, 63]. DNA content From a theoretical point of view, the number of myonucleiis a critical determinant of protein synthesis capacity by providing the amount of DNA necessary to sustain genetranscription. The relation between myofiber size andmyonuclei number gave rise to the concept of myonuclear domain, which is the amount of cytoplasm supported by asingle myonucleus. Although the myonuclear domain shouldnormally be expressed as a volume ( μ  m 3 /myonucleus, [24]),most of studies present the fiber cross-sectional area per nucleus (myonuclear domain area). Particularly, Kadi et al.[80] and Petrella et al. [117] have suggested in human that  there may be a ceiling size of the myonuclear domain areaof about 2,000  μ  m 2  beyond which a fiber will not be able tohypertrophy unless it can add more myonuclei. Althoughcaricatural, this ceiling size may explain why some studiesreported an increase in myonuclear number (pre-trainingmyonuclear domain  ≈ 2,000  μ  m 2 ) [80] in response to strengthtrainingwhileothersdidnot(pre-trainingmyonuclear domain <2,000  μ  m 2 ) [79, 117]. During unloading-induced muscle atrophy, a reduction in the myonuclear domainarea has been reported [4, 5]. This may result from a greater  (or faster) decrease in fiber cross-sectional area than in Fig. 1  How muscle useand disuse may control skeletalmuscle mass? Musclecontractions can cause therelease of factors from non-muscular srcin (hormones)and muscular srcin (autocrine/  paracrine and intracellular factors). These factors may inturn modulate muscle mass by altering the number of myonuclei, transcriptional andtranslational capacity, and therate of protein degradationPflugers Arch - Eur J Physiol  myonuclei number (Fig. 2a) as observed during denervation[136]. Aging-related atrophy seems to involve a different sequence of events. Brack et al. proposed that the decrease inmyonuclei number with aging does not follow fiber sizereduction, but rather drives it [24]. In this situation,myonuclear death will result in a transient increase in themyonuclear domain, leading to a cytoplasmic loss andultimately to the restoration of myonuclear domain size(Fig. 2a).Even if terminally differentiated myotubes have beenshown to dedifferentiate and proliferate when stimulatedwith msx1 expression [112], these events are rare andmyonuclei of mature myofibers are generally considered to be post-mitotic. In this context, supplemental geneticmaterial can be only brought by satellite cells. Satellitecells can be activated in response to traumatic lesionsrequiring muscle regeneration [37]. Once activated, satellitecells proliferate and fuse together and/or with preexistingfibers to regenerate muscle tissue. Satellite cells can be alsoactivated when the load placed upon the muscle increases.Indeed, some markers of satellite cell activation (cyclin D1)and differentiation (p21) are increased after acute RE [19,84] or strength training in humans [80]. In accordance with these findings, studies on strength-trained athletes or onsubjects performing resistance training evidenced signifi-cant increase in satellite cell number [79, 80, 130]. What is the physiological significance of such an activation after RE? Are the satellite cells activated to repair muscledamage after strength exercise, and/or the incorporation of additional nuclei is required to enhance the synthesiscapacity of the fiber and promote hypertrophy? Irradiationexperiments (aimed at inhibiting satellite cell activation)strongly suggest that supplemental nuclei addition from thesatellite cell pool is necessary for marked hypertrophy.Indeed, irradiated fibers, which do not hypertrophy after surgical overloading, do not exhibit increase in DNAcontent nor in myofibrillar proteins [1]. Nevertheless,synergistic ablation is an extreme model of muscle over-loading and may likely induce damage and subsequent satellite cell activation [75]. This raises the question of whether satellite cells can be involved in skeletal musclehypertrophy independently of any ongoing reparation/ regeneration processes. Although provocative, the idea that one may need to break muscle to activate satellite cell and build more muscle should be reasonably questioned. Thedevelopment of new methods to directly assess thecontribution of satellite cells in skeletal muscle hypertrophywould thus be helpful. In addition, the contribution of satellite cells in muscle hypertrophy needs to be assessed ina more physiological condition such as resistance trainingin human.The number of myonuclei in single muscle fiber decreases in response to reduced load such as spaceflight [5, 34], hindlimb suspension [4, 91], immobilization [143], or denervation [136]. Aging may be also associated with adecline in the number of satellite cells and nuclei per fiber [24, 79]. The loss of myonuclei with disuse results from an increase in myonuclear death by apoptosis. Consistently,elevated levels of DNA fragmentation and expression of  pro-apoptotic gene such as Bax or caspase-3, caspase-6,caspase-9, or caspase-12 have been recorded after unload-ing [18, 91, 139, 142] or with aging [142].  Numerous growth factors are known to regulate satellitecell activity, among which insulin-like growth factor (IGF)-I[6] and myostatin [100] are of particular interest. Messenger  RNA (mRNA) and protein content of IGF-I correlate withand preceded the increase in whole muscle DNA content inresponse to muscle overload [2]. Mechano-growth factor (MGF; a variant of IGF-I, see below) and hepatocyte growthfactor also promote satellite activation [7, 164]. As mechan- ical stress induces HGF release and increases MGF mRNA,these factors may contribute to the regulation of myonucleiaccretion when muscle load is increased. In addition,administration of testosterone, a strong anabolic agent whoseserum concentration is increased after strength training [86],results in an increase in both satellite cell and myonucleinumbers [78, 141]. On the contrary, satellite cell activation Fig. 2  Hypothetical mechanisms of myonuclear loss associated withmuscle fiber atrophy.  a  Reduction in protein content without myonuclear loss (decrease in myonuclear domain area) and  b subsequent loss of myonuclei.  c  Loss of myonuclei with constant  protein content (increase in myonuclear domain area) and  d  subsequent decrease in protein content. Note that cross-sectional areawithin each of the  triangles  on  a  and  d   is similar Pflugers Arch - Eur J Physiol  and self renewal is repressed by myostatin, a master negativeregulator of skeletal muscle mass [100]. Other growth factorsare also well known to regulate satellite cell activation and proliferation both in vitro and in vivo [67]. The physiologicalrelevance of these factors during muscle atrophy andhypertrophy is potentially valuable but is still poorlyinvestigated. Transcription The expression of muscle-specific proteins can be enhancedor repressed by numerous transcription factors. They maythus be critical in coordinating the response of skeletalmuscle to altered use. Myogenic regulatory factors (MRFs),including MyoD, myogenin, Myf5, and MRF4, have beensrcinally described to play major role in myogenesis [113].Although sometimes controversial, increased muscle loadappears to up-regulate myoD, myogenin, and MRF4expression (Table 1) with differences between muscle fiber types, experimental design, and protocol duration. It remains to determine whether this is directly linked tochanges in muscle-specific gene expression. Data regardingMRF expression during disuse are less consensual sincesome studies report a decrease [94] or no change [69] in MRF expression, while others show an increase [64, 147]. The significance of such variations is not clearly defined but may be related to the shift in fiber phenotype occurringwith reduced activity. Novel advances have been brought  by the use of transgenic models. For example, soleusmuscle weight did not differ after 2 weeks of unloading between wild-type and MyoD  − /  −  mice [140]. However,myosin heavy chain IIB expression was reduced in the KOanimals, suggesting that MyoD rather drives fiber pheno-type in this situation. Taken together, these data indicatethat the role of MRFs in controlling muscle mass would bemore effective under conditions of increased muscle load.Another level of regulation is provided by the inhibitors of differentiation (Id), a family of proteins that prevent MRFs binding to DNA, whose expression is enhanced duringdenervation, unloading, and aging [8, 59]. A number of  molecular partners have also been demonstrated to interact with and modulate the activity of MRFs, such as pCAF, p300 [120], and Sirt1 [46]. Most of these studies have been done during in vitro myogenesis and the relevance of theseobservations in adult skeletal muscle during altered useneeds to be established.Several transcription factors involved in skeletal muscleremodelingarecontrolledinaCa 2+ -dependent manner, notably by the Ca 2+ -sensitive phosphatase, calcineurin. Nuclear factor of activated T cells has been well implicated in skeletalmuscle-specific gene expression and cardiomyocyte growth[106]. However, its influence on skeletal muscle hypertro- phy is controversial. Indeed, some studies reported that calcineurin inhibition by cyclosporin A prevented musclegrowth/hypertrophy both in vitro [109, 137] and in vivo Table 1  Myogenic regulatory factors mRNA level in response to increased muscle useModel Muscle Species Myf5 MyoD Myogenin MRF4 ReferenceAcuteHFES VL Human  ↑ ↑  [19]HFES MG Rat   ↑  [62]RE VL Human ns  ↑ ↑ ↑  [165]RE VL Human ns  ↑  ns  ↑  [122]RE VL Human ns [66]ChronicRT (16 weeks) VL Human  ↑ ↑  [14]RT (10 weeks) VL Human ns ns  ↑  ns [69] a  RT (8 weeks) rest VL Human ns ns [88] post-ex ns  ↑ Compensatory overloading(3 months)Pla Rat   ↑  1 st  to 3 rd day [1]Stretch overload (6  –  72 h) ALD Quail  ↑ ↑ ↑  [95]Pat   ↑ ↑ Compensatory overloading (3 days) Sol Rat   ↑  (1 st  day) [114]PlaStretch (2  –  3 weeks) ALD Chicken ns  ↑  [28]Stretch (2 days) Sol Rat ns  ↑  [94]Pla  ↑  ns  HFES   High frequency electrical stimulations,  RE   resistance exercise,  RT   resistance training,  VL  vastus lateralis,  MG   medial gastrocnemius,  Pla  plantaris,  ALD  anterior latissimus dorsi,  Pat   patagialis,  Sol   soleus,  ns  no significant change a  Protein levelPflugers Arch - Eur J Physiol
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