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The German Journal of Sports Medicine is directed to translational science and clinical practice of Sports Medicine and its adjacent fields, which investigate the influence of physical activity, exercise, training and sports, as well as a lack of exercise affecting healthy people and patients of all age-groups. It addresses implications for prevention, diagnosis, therapy, rehabilitation and physical training as well as the entire Sports Medicine and research in sports science, physiology and biomechanics.

The Journal is the leading and most widely read German journal in the field of Sports Medicine. Readers are physicians, physiologists and sports scientists as well as physiotherapists, coaches, sport managers, and athletes. The journal offers to the scientific community online open access to its scientific content and online communication platform.

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Sportmedizin
REVIEW
THE MOLECULAR RESPONSE OF SKELETAL MUSCLETO RESISTANCE TRAINING

The Molecular Response of Skeletal Muscle to Resistance Training

Die molekulare Antwort der Skelettmuskulatur auf Krafttraining

SUMMARY

Skeletal muscle has a high degree of dynamic plasticity involving constant changes in the mix of metabolic, structural and contractile proteins which adapt this tissue to functional demands. Many mechanisms which regulate muscle adaptation are intrinsic to the muscles; i.e., relatively independent of central/ circulating regulatory factors. The aim of deliberate programs of training are the optimized activation of these intrinsic mechanisms. For example, training to improve muscle endurance targets adaptation in cellular sub-systems that regulate energy substrate selection and utilization. Training to improve muscle force targets subsystems that increase myofibrillar  protein  content.  This  latter  case  will  be  the  focus  of  the  current presentation. Cellular changes indicative of a nascent hypertrophy response can be detected within minutes to hours following a single bout resistance exercise. This  includes  changes  in  the  production  and/or  accumulation  of  myogenic messenger RNA as well as increased flux in signaling pathways with known proanabolic effects such as the regulation of protein translation. Subsequent training sessions result in the summation of these acute responses leading to functionally relevant  cellular  adaptation.  In  addition  to  the  regulation  of  myogenic  mRNA production  (transcription)  there  are  regulatory  elements  that  modulate  steps between transcription and translation. These include mRNA binding proteins and non-coding RNA (e.g., microRNA) which regulate the abundance and translational activity  of  specific  mRNAs.  An  additional  area  of  interest  in  skeletal  muscle adaptation has been the role of ancillary cell types such as satellite cells. In the specific case of skeletal muscle hypertrophy, it is clear that a number of the loading sensitive changes in myogenic gene expression are related to the mobilization of these cells. An understanding of the sensitivity and temporal responses of these anabolic regulatory mechanisms will provide practitioners with useful insights on the training stimuli necessary to optimize functional outcomes thereby improving performance.

Key words: Hypertrophy, Translation, mTOR, Satellite Cell

ZUSAMMENFASSUNG

Die  dynamische  Anpassungsfähigkeit  der  Skelettmuskulatur  umfasst  Veränderungen der metabolischen, strukturellen und kontraktilen Proteine, über die sich das Muskelgewebe an die jeweiligen funktionellen Erfordernisse anpasst.Einige Mechanismen, welche die Muskeladaptation regulieren, sind intrinsischer Art und weitgehend unabhängig von zentralen/zirkulierenden Faktoren.Das Ziel von spezifischen Trainingsprogrammen ist die optimale Aktivierung dieser intrinsischen Mechanismen. Das Training zur Verbesserung der muskulären Ausdauer zielt beispielsweise auf Anpassungen in den zellulären Subsystemen ab, welche die Verfügbarkeit und Utilisation von Energiesubstraten regulieren. Zelluläre Veränderungen, die auf eine beginnende Hypertrophie hinweisen, sind innerhalb von Minuten bis zu Stunden nach einer Krafttrainingseinheit nachweisbar.Davon  betroffen  sind  sowohl  Veränderungen  in  der  Produktion  und/oder  Akkumulation  der  myogenen  Messenger  RNA´s  als  auch  die  erhöhte  Aktivität  in Signalwegen  mit  pro-anabolen  Effekten  wie  beispielsweise  die  Regulation  der Protein- Translation. Aufeinanderfolgende Trainingseinheiten bewirken die Summation dieser Akutantworten, die wiederum zu funktionell bedeutsamen zellulären Adaptationen führen. Neben der Regulation der myogenen mRNA-Produktion (Translation) gibt es weitere regulative Elemente, welche die Schritte zwischen Transkription  und  Translation  modulieren.  Diese  umfassen  proteinbindende mRNA und nicht kodierende RNA (e.g. microRNA) welche die Menge und Translations-Aktivität der spezifischen mRNA regulieren. Wichtig für die Adaptation des Skelettmuskels sind auch die Muskelvorläuferzellen, sogenannte Satellitenzellen. Im speziellen Fall der Skelettmuskelhypertrophie ist evident, dass bestimmte belastungssensitive  Veränderungen  in  der  myogenen  Genexpression  mit  der  Aktivierung dieser Zellen verbunden sind. Ein tieferes Verständnis für die Sensitivität und die zeitliche Antwort dieser anabolen regulativen Mechanismen liefert dem Fachmann  hilfreiche  Erkenntnisse  über  die  erforderlichen  Trainingsstimuli,  die zur Optimierung funktioneller Outcomes und damit zu einer verbesserten Leistungsfähigkeit führen.

Schlüsselwörter: Hypertrophie, Translation, mTOR, Satellitenzellen

INTRODUCTION

Skeletal muscle is largest single organ system in the human body. It  functions  in  obvious  ways,  such  as  locomotion,  breathing,  and postural  maintenance.  More  recently,  less  intuitive  roles  such  as endocrine  and  possibly  immune  functions  have  been  attributed to this tissue as well (23, 30). As a result, the understanding of the totality of cellular and molecular processes within skeletal muscle has been recognized as being remarkably complex and well beyond the scope of a brief review. The literature pertaining to molecular and cellular aspects of muscle adaptation can be very difficult to decipher. In particular, human studies, due to low tissue yields, are generally focused on a very few outcome variables. Review articles can provide a broader perspective. However, the authors of reviews (including the current one) are limited by their own interests and perspectives.  The  topic  of  the  current  review  is  extensive,  easily sufficient  for  an  entire  text  book.  Accordingly,  the  current  paper will be focused, narrowly, on a limited number of adaptive cellular and molecular regulatory mechanisms related to the adaptation of mature  skeletal  muscle  in  response  to  increased  loading  such  as that encountered in a sports training setting. The mechanisms and processes were selected because, in the authors opinion, they are instructive representatives of how adaptation is regulated and are critical for hypertrophy to occur.

INTRINSIC REGULATION OF HYPERTROPHY

An  organizational  theme  for  this  brief  review  derives  from  a  key concept; that the primary mechanisms regulating the adaptation of  mature  skeletal  muscle  to  increased  loading  reside  within  the affected muscle. To illustrate this point: Experimental hypophysectomy drastically reduces, either directly or indirectly, a number of critical circulating hormones and growth factors known to regulate skeletal muscle growth. Key examples of this are thyroid hormone, growth  hormone  and  insulin-like  growth  factor-1  (IGF-I).  When the hypophysectomy procedure is performed in young adult rats it arrests all further body growth. However, when individual muscles or  muscle  groups  experience  increased  muscle  loading  in  hypophysectomized rats the relative degree of hypertrophy is the same as that seen in control animals (3).

TRAINING CELLS

A second and complementary concept is that any and all exercise training is inherently targeted on the intra- and possibly inter-cellular mechanisms of cells which reside in the targeted muscle. In the context of functional hypertrophy, effective training must activate the appropriate anabolic regulatory pathways within muscle to a sufficient magnitude and with a temporal pattern that summates to produce sustained responses leading to adaptation. Leaving aside the motor learning and neural components of strength which are outside the scope of this review. Although there are some changes in myofiber phenotype , e.g., glycolytic to oxidative glycolytic shifts, these adaptations represent fine tuning of metabolic parameters and have minimal impact of force generation. Therefore, the primary cellular adaptation leading to increased strength will be an increase in contractile components along with the structure necessary to support and transmit the increased force.
To this end, training parameters such as exercise frequency, intensity and duration are scaled to provide the cellular stimuli necessary to entrain anabolic regulatory mechanisms. Using training frequency as an example, a given bout of weight lifting may elicit a robust response from an anabolic intracellular signaling mechanism (Fig. 1). Repeating that exercise bout several days later  may  elicit  the  same  level  of  response  (Fig.  2).  Repeating  the exercise bout 24-36 hours after the first might result in a different response (Fig. 3). In this hypothetical setting, the bouts depicted in  Figures  1  &  2  would  be  unlikely  to  stimulate  adaptation,  at least adaptation that would be dependent on the given cellular mechanism  depicted  here.  They  would  essentially  be  two  independent bouts of exercise. In contrast, the scenario described in Figure 3 suggests a summation of the regulatory response which, if repeated, would effect longer term alterations in the processes modulated  by  that  pathway.


This  would  be  expected  to  lead  to adaptation. Such processes are implicit in the intent of training programs. In practice, acute cellular and molecular changes indicative of a nascent hypertrophy response can be detected within very  short  time  frames  (e.g.,  minutes –hours)  following  a  single bout resistance exercise. These responses include rapid changes in the production and/or accumulation of myogenic messenger RNA as well as increased flux in signaling pathways with known pro-anabolic effects highly concentrated in the area of regulation of protein translation. Subsequent training sessions result in the temporal summation of these acute responses such that functionally relevant cellular adaptation will occur leading to increases in muscle size and strength. In a research setting, the temporal responses  of  anabolic  signaling  to  resistance  exercise  and  their summation  have  been  demonstrated  in  both  animals  and  humans (15, 7).

CRITICAL PROCESSES

This review will focus on two processes considered to be critical for a sustained hypertrophic response to increased loading. The first, protein translation and, the second, activation and incorporation of satellite cells. There is currently a strong consensus for the first, some controversy regarding the second.

REGULATION OF PROTEIN TRANSLATION

There  are  a  myriad  of  regulatory  signaling  pathways  that  havebeen  identified  as  being  relevant  to  the  development  of  loading induced  muscle  hypertrophy  (24, 28, 34, 37).  In  the  simplest  case, loading  induced  increases  in  the  contractile  protein  content  of skeletal muscle occur via increased production of protein rather than a decrease in protein degradation (25). This is an inherently logical  approach  since  the  routine  degradation  of  proteins serves  the  important  purpose  of  removing  less  functional proteins, the retention of which would be expected to negatively impact  function.  Accordingly,  pathways  that  regulate messenger ribonucleic acid (mRNA) translation, i.e., the process of protein synthesis, have received a tremendous amount of attention.
There  are  three  primary  components  of  protein  translation that are regulated during the adaptation induced by increased loading; 1. Translation initiation, 2. The availability of substrate, 3. The levels of translational capacity. A comprehensive treatment of the regulation of translation is beyond the scope of this review. However, the salient points follow.

Regulation of Translation Initiation
Several  of  the  key  regulatory  steps  for  initiation  of  translationinvolve the removal of inhibition. The initiation complex consists of a rather large number of proteins called initiation factors (IF). These initiation factors in many ways fill niches similar to those seen  for  the  regulation  of  gene  expression.  Some  dock  with specific  sites  on  the  mRNA  and  serve  to  recruit  additional initiation  factors.   Others  serve  to  promote  processes  such  as removing  structural  impediments  in  the  mRNA  which  prevent translation.  The  final  result  being  the  recruitment  of  the ribosomal machinery.
When two of these critical initiation factors, IF3 and IF4E are bound by inhibitory proteins the process of initiation is prevented (Fig. 4). Selective phosphorylation of these inhibitory proteins causes them to dissociate from their target initiation factor and allows for initiation to proceed (Fig. 5) (19). In both cases, a kinase complex which includes the protein mTOR (mammalian target of rapamycin) is responsible for the release of this inhibition (19).

Substrate for Translation
Two classes of substrate are required for translation to proceed; 1 Amino Acids. 2 mRNA. In healthy individuals, availability of amino acids  is  largely  a  function  of  nutrition.  The  availability  of  specific mRNA is regulated at two levels; 1 Transcription (and processing). 2  Degradation.  There  are  a  number  of  non-  and  muscle-specific transcription  factors  that  regulate  the  production  of  myogenic mRNAs. The family of myogenic regulatory factors such as MyoD and myogenin are some of the most commonly cited muscle specific transcription factors and have powerful effects on muscle gene expression (6).
The regulation of mRNA stability can be accomplished via the binding of proteins to internal AU rich regions of mRNA (12). The expression and activity of these regulatory proteins has recently begun to be explored in skeletal muscle (13, 40, 24). In pilot studies we have found the levels of mRNA for AU binding proteins such as HuR (Human antigen R ) and Tis11B (tristetraprolin family protein) be very sensitive to increased or decreased loading in rodent muscles (unpublished).
Recent  discoveries  have  shown  that,  in  addition  to  proteins, there is a class of small non-protein coding RNAs called microRNA (miRNA) can alter the stability of mRNA via binding to complementary  sequences  in  the  mRNA  (41).  In  addition  to  altering stability, miRNA binding can prevent mRNA from completing the translation process.

Regulation of Translational Capacity
Translational capacity is determined by the number of functional ribosomes present in cells. Ribosomes consist primarily of ribosomal RNA (rRNA) and accessory proteins. The most critical step required to increase ribosomal capacity involves up-regulation of the activity of RNA Polymerases (POL) leading to the transcription of ribosomal DNA (rDNA) and ribosomal proteins (27). In this context, mTOR, a key regulator of translation initiation, is also known to play an important role in significantly up regulating RNA Polymerase activity leading to increased production of ribosomal RNA and proteins (27).
While translational efficiency, i.e., protein produced per unit of ribosome, can increase to some extent (8), sustained increased in ribosomal capacity are necessary for a successful, sustained, hypertrophic responses to increased loading (2). Ribosomal RNA (rRNA) makes up the preponderance of total RNA. As a result, changes in total RNA and, presumably, translational capacity can be inferred via the relatively simple process of measuring total RNA content in muscles or muscle samples. Such measurements demonstrate that this response is very sensitive to increased loading. In both rodents and humans we have found that total RNA increases significantly following just two consecutive bouts of resistance exercise (7, 16).

mTOR a Critical Regulator of Hypertrophy
These  foregoing  vignettes  have  touched  upon  the  critical  role  of mTOR  in  the  regulation  of  translation.  More  globally,  mTOR  is recognized as a powerful regulator of cell size in many cell types (27). One of the primary roles of mTOR is thought to be sensing whether conditions favor growth (18). In this role, mTOR receives input from a number of signaling cascades that respond to growth factors and hormones, most notably, Insulin and IGF-I (38). Recent data  suggests  that  mechanisms  responsive  to  mechanical  loading of muscle cells can also regulate mTOR activity independent growth factor input (17).
In addition to growth factors and mechanical loading, mTOR activity is sensitive to nutritional status, in particular, amino acid availability  (21).  This  role,  as  a  sensor  of  amino  acid  availability, may be of particular interest in the context of sport. Published attempts at regulating the availability and timing of nutritional support relative to training bouts may be directly manipulating mTOR activity (21).
Clearly,  common  sense  would  suggest  that  the  presence  of inflammation  would  be  expected  to  be  detrimental  to  anabolic processes. Components of the inflammatory response are known to negatively impact mTOR activity (26). This response has had adaptive value in that it conserves both energy and amino acid pools to promote an effective response to injury and infection at time when an organism would generally experience a decrease in its ability to gather or hunt food. In modern humans, assuming the  availability  of  adequate  nutrition,  this  response  has  lost  its adaptive value.
Of  particular  interest  in  the  setting  of  sports  training  are recent reports that endurance mode exercise may also directly, if transiently, regulate mTOR activity. There are reports that the protein AMPK (5' adenosine monophosphate-activated protein kinase) when activated, can down regulate mTOR activity (36). In this context it is important to appreciate that the process of translation  is  costly  in  terms  of  energy.  For  example,  for  each amino acid added to the nascent polypeptide approximately four high energy bonds are consumed (9). AMPK activity is sensitive to  the  energy  charge  in  cells  and  is  activated  at  times  of  high energy usage (22). Acutely, the primary role of AMPK appears to be the up regulation of processes that increase energy supply. In light of the high energy cost of protein synthesis, AMPK signaling that leads to decreased mTOR activity appears to be quite logical, deferring the less immediate need for protein production in favor of the need for energy conservation to support contractile activity.
In  sum,  the  regulation  of  mTOR  is  critical  to  processes  that contribute to the hypertrophic response and it in turn integrates stimuli from many sources to modulate this response (38) (Fig. 6).

Muscle Satellite Cells and Hypertrophy
In addition to the more obvious need to increase muscle protein, a robust and sustained hypertrophic response appears to require the activation, proliferation, differentiation and fusion of satellite cells. The context for this theoretical framework is rooted in the myonuclear domain- (4) or DNA unit-hypothesis (10). This hypothesis holds that there is a finite relationship between the number of myonuclei and the size of myofibers and that, above some threshold of expansion, the addition of myonuclei is necessary to maintain  ongoing  hypertrophic  processes  (4, 32).  Some  investigators have speculated that, under some circumstances, the incorporation of myonuclei into myofibers may precede and drive subsequent hypertrophy (5).
However,  some  experimental  results  have  been  interpreted to indicate that satellite cells are not required to support the hypertrophic response. For example, Kadi et al. observed, in human studies,  that  moderate  levels  of  muscle  hypertrophy  can  occur in  the  absence  of  significant  levels  of  myonuclear  incorporation (20). However, the question which must be asked is what degree of muscle hypertrophy is attained across the myofibers in a given study. It is to be expected that the relationship between myofiber size and myonuclear number would have a fairly wide range. Such a design seems logical in that there would be an appreciable metabolic and resource expense associated with the constant activation of satellite cell proliferation in response to moderate fluctuations in muscle loading.
It also seems reasonable to expect that, after a period of rapid satellite cell or myoblast activity (i.e., proliferation, differentiation and fusion) there would be a period during which new myonuclei become operational and contribute to the process of protein synthesis leading to a reestablishment of the myonuclear number to myofiber size ratio and that this would take place in the absence of further cell replication events (29, 33).

Are Satellite Cells Required for Hypertrophy?
In  rodent  muscles  we  found  that  incapacitation  of  satellite  cell proliferative activity severely limits the hypertrophic response to a  powerful  loading  stimulus  (2).  More  recently,  Petrella  et  al.  reported that, in a large cohort of subjects who participated in a 16 week  resistance  training  study,  a  sizable  proportion  of  subjects experienced a negligible amount of hypertrophy (non-responders) while  responders  had  increases  in  myofiber  size  of  ~40%  (31). One of the primary characteristics which distinguished these two groups was the ability to add myonuclei to myofibers. This same research group went on to demonstrate that the relative ability to mobilize satellite cells and add myonuclei corresponded to the degree of hypertrophy seen in human subjects (32). Taken together, these results indicate that, above some threshold of myofiber to myonucleus ratio, the ability to add myonuclei via the mobilization of satellite cells is an important contributor to the hypertrophic response.

Activation of Muscle Satellite Cells
Satellite cell participation in the hypertrophic process has been the focus of intense study for a number of years. In that time much has  been  learned  about  the  regulatory  mechanisms  within satellite  cells  (39).  Recently,  results  have  been  published  whichsuggest a, much sought after, direct link between the mechanical loading  of  myofibers  and  the  initiating  events  leading  to  the activation  of  satellite  cells.  For  example,  Kosek  and  Bamman reported  that  resistance  training  results  in  changes  in  the dystrophin-associated  protein  complex  which  may  provide  a regulatory link (24). It is suggested that loading induced changes in  nitric  oxide  synthase  (NOS)  activity,  associated  with  the dystrophin-associated  protein  complex,  could  result  in  the release of hepatocyte growth factor (HGF) from the extracellular matrix  of  myofibers  allowing  it  to  interact  with  receptors  on satellite cells. HGF has been shown to be critical for the transition from quiescence to activation in satellite cells (35).

SYNTHESIS

This brief review has touched on but a small percentage of the information available regarding cellular and molecular regulation of muscle adaptation. However, it is hoped that the approach used in this review can be used to synthesize new, testable hypotheses. For example, in the study by Petrella at al., discussed above, the non-responders who failed to incorporate new myonuclei did experience  a  robust  level  of  satellite  cell  proliferation  (31).  This suggests that the activation steps such as the production of NO and  release  of  HGF  via  alterations  in  the  dystrophin-associated protein complex were probably intact in these subjects. The defect would seem to be related to either the differentiation of satellite cell progeny or their incorporation into myofibers. In the cited work by Kosek and Bamman, older subjects experienced similar changes in dystrophin-associated protein complex following resistance training but also failed to demonstrate similar levels of hypertrophy relative to young subjects (24). One of the features that distinguished the old from the young in that study was enhanced  activation  of  stress  related  kinase  p38.  This  kinase  has been associated with muscle atrophy, in part, via the activation of muscle specific ubiquitin-ligases such as MuRF1 (11, 14). One of the key processes down stream of IGF-I signaling is known to be the suppression of muscle specific ubiquitin-ligase expression. This suggests a point of potential interaction between IGF-I and p38  related  signaling.  More  generally,  IGF-I  has  been  shown  to stimulate the differentiation of satellite cells and promote their subsequent incorporation into existing myofibers (1)

SUMMARY

Skeletal muscle hypertrophy is often quantified by as an increase in myofiber cross sectional area. Functionally significant increases in myofiber cross sectional area are a result, primarily, of an increase the amount of contractile protein present in myofibers. This occurs via the process of protein synthesis, that is, mRNA translation.
In this context it is important to remember that the mechanisms which sense changes in loading state and those which generate adaptive responses reside within the cells of the targeted muscles.  From  this  awareness  proceeds  the  understanding  that training programs which seek to increase muscle size are manipulating cellular and molecular mechanisms. With regard to understanding specific regulatory mechanisms, an appreciation of the various stimuli and signaling pathways that alter the activity of mTOR can be a very fruitful approach to learning about regulatory mechanisms in general and a useful starting point for understanding muscle specific regulation. The second critical process presented  in  this  review  is  a  subject  of  ongoing  debate.  When following this debate, the various models used to derive results should be carefully and critically evaluated. As an intellectual approach to understanding muscle hypertrophy, the literature that contributes to the debate regarding satellite cell participation will provide  many  useful  insights  regardless  of  bias  or  the  eventual outcome of the debate.

Acknowledgments:  The  author  wishes  to  thank  Prof.  Dr.  Juergen Steinacker  for  providing  the  opportunity  to  present  this  work  at German  Congress  of  Sports  Medicine  in  2009.  The  authors  research  is  supported  by:  U.S.  National  Institutes  of  Health  grant# P01HD048721-Project 1 and U.S. National Space Biology Research Institute Project #MA01601.

Competing interests: None

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Corresponding Author:
Gregory Adams
University of California, Irvine
Department of Physiology and Biophysics
Medical Sciences 1
Irvine, CA 92697-4560
USA
E-Mail: GRAdams@uci.edu
 
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