Review 905

Muscle Protein Turnover in Endurance Training: a Review

Authors Aliations

T. Seene1, P. Kaasik2, K. Alev2

1 2

Institute of Exercise Biology and Physiotherapy, University of Tartu, Estonia Department of Functional Morphology, University of Tartu, Estonia

There has been much debate about skeletal muscle capacity to adapt to long-lasting endurance exercise. Exercise in the aerobic zone of metabolism does not result in hypertrophy of skeletal muscle bres but increases their oxidative capacity. The duration and intensity of an exercise session determines the time period of depressed muscle protein synthesis and increased degradation rate during the recovery period after exercise. Protein turnover characterizes the renewal processes of muscle proteins and the functional capacity of muscle. The turnover rate of myobrillar proteins is slow in comparison with mitochondrial proteins and depends on the oxidative

Introduction
accepted after revision June 07, 2011 Bibliography DOI http://dx.doi.org/ 10.1055/s-0031-1284339 Published online: November 8, 2011 Int J Sports Med 2011; 32: 905911 Georg Thieme Verlag KG Stuttgart New York ISSN 0172-4622 Correspondence Prof. Teet Seene, PhD, DSci Institute of Exercise Biology and Physiotherapy University of Tartu likooli 18 Tartu Estonia 50090 Tel.: +372/7/375 364 Fax: +372/7/375 379 teet.seene@ut.ee

Adaptation of skeletal muscle to exercise training depends on its character, oxidative capacity, structural rearrangements of muscle bres, the turnover rate of proteins of the contractile apparatus and bre recovery from exercise-induced injury [9, 21, 40, 63, 87, 90]. Endurance training does not result in hypertrophy of skeletal muscle bres involved in the exercise response because the level of force production is relatively small compared to their maximal force-generation [10]. This type of exercise training results in the regulation of the enzyme system of the Krebs cycle, electron transport chain, capillary supply, changes in key metabolic enzymes involved in fatty acid activation, and increased oxygen uptake [40, 41, 101]. If exercise training occurs mainly in the aerobic zone of metabolism, it promotes a transition from type II to type I bres in skeletal muscle, which occurs at the expense of type II bre population [100]. This process is related to the myobrillar apparatus as myosin, the main contractile

protein, is the regulator in the conversion of chemical energy into mechanical activity. There is a clear relationship between myosin isoforms and functional properties of the skeletal muscle. Maximal shortening velocity is higher in muscle bres where myosin heavy chain (MyHC) fast isoforms dominate as the rate of actomyosin interaction is greater, because the size of the step generated by single interactions is larger [15]. It has been demonstrated that MyHC slow (I) isoform propelled actin laments at a lower speed than fast (IIb) isoforms [43]. Currently, the role of initial oxidative capacity of muscle bres in the development of endurance of athletes via the turnover rate of muscle proteins is not fully understood. There are no denite answers to the questions where the border of development of oxidative capacity of muscle bres during endurance training is and what the limiting factors are [23]. Putative mechanisms for the increase of muscle bre oxidative capacity and muscle protein turnover in parallel with endurance development prove that there is no 1:1 relationship between these indicators. On the

Seene T et al. Muscle Protein Turnover in Int J Sports Med 2011; 32: 905911

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Key words endurance training skeletal muscle oxidative capacity protein turnover

Abstract

capacity of muscle bres. The turnover rate of myobrillar proteins in the same muscle is different and is also dierent within the myosin molecule between myosin heavy and light chain isoforms. The turnover rate of muscle proteins in endurance training shows the adaptation of skeletal muscle to long-lasting exercise via remodelling of muscle structures. Adaptational coordination between myobrillar and mitochondrial compartments shows the physiological role and adaptational capacity of skeletal muscle to endurance training. It is challenging to use muscle protein turnover for the purposes of monitoring the training process of endurance athletes, optimizing training programs and preventing overtraining.

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whole, the initial oxidative capacity of muscle bres determines the progress of endurance development in athletes but may not guarantee the nal result. The purpose of this review is to provide an overview of literature published relating to endurance training and muscle bre oxidative capacity and its relation to myobrillar protein turnover rate. This article highlights the eects of endurance training on the renewal of the myobrillar apparatus, the accompanying rearrangements in the contractile machinery and resulting skeletal muscle remodelling.

Eect of exercise intensity and duration on muscle metabolism

Both low and high intensity exercise are important components for endurance athletes training programs [53]. Endurance training programs, in a variety of forms, improve the energetic potential of muscle and result in the eective functioning of the muscle contractile apparatus for longer periods of time [35, 94, 109]. High intensity interval training supplemented into the already high training volumes elicits improvements in both short-lasting intense and prolonged exercise performance [54]. It has been shown that low volume high intensity interval training maintains an athletes endurance performance and muscle oxidative potential and increases intense exercise performance [46, 47]. Adaptation of skeletal muscle to exercise duration and intensity changes muscle glycogen level [22] and protein synthesis rate [72] within several hours after exercise. The post exercise response is fundamentally more important to the state of protein metabolism changes that occur during exercise [102]. On the other hand, the duration and intensity of an exercise session determines the time period of depressed protein synthesis rate and the rate of degradation of muscle protein after exercise training, i. e. during the recovery period [49, 83, 87, 90]. It is well known that protein synthesis is an energy consuming process and as depicted in the context of sports performance and energy metabolism, it is strongly related to implication recovery period. Low cellular energy level induces in response to sustained contractile process activation of the 5adenosine monophosphateactivated protein kinase (AMPK). AMPK reduces translational processes and a low energy status is associated with a high rate of protein turnover, which limits the increase of bre size [105]. Lack of recovery also leads to changes in the skeletal muscle myobrillar apparatus, particularly the destruction of contractile proteins and decreased exercise performance [82, 83, 90]. Several studies have shown that in addition to type I bres, type II bres, particularly IIA bres, are also recruited during endurance training [45, 82, 83, 85, 87, 88]. Due to the diversity of molecular mechanisms in dierent bre types, muscle functions uniformly during intervention to exercise [5, 9, 31]. Changes in myosin isoform composition during endurance training may be qualied as qualitative remodelling of skeletal muscle by replacing isoforms, which better suit the energetic adaptation to prolonged force-generation activity [9].

Protein synthesis and degradation in muscle bres

It seems paradoxical that high oxidative bres are relatively small, but have a larger capacity for protein synthesis compared to low oxidative bres [105]. These bres contain higher quantities of satellite cells, myonuclei, mitochondria, mRNA, and total ribosomal RNA content (i. e., components of the transcription machinery). IGF-1 expression, a stimulator of myobrillar protein synthesis, is also higher in type I bres [14, 96]. Myostatin, expression inhibitor of muscle hypertrophy, is higher in type II bres [55, 110]. At the same time, the components of the degradation machinery of muscle proteins, such as ubiquitin ligases MAFbx and MuRF, are about 2-fold higher in bres with higher oxidative capacity [105]. The higher rate of protein degradation in muscle bres with higher oxidative capacity is balanced by a high rate of synthesis. This may be an important factor limiting the size of these bres [105]. As a result of that steady state, protein turnover rate is faster in muscle bres with higher oxidative capacity. In these bres, the half-life of mitochondrial protein is the shortest although the turnover of cytochrome C is higher in the low oxidative bres [39]. The concept of protein turnover was described about 7 decades ago [80]. All proteins are in a continous process of synthesis and degradation and characterize renewal processes in the subse quent tissue ( Fig. 1). Amino acids that are released during intracellular degradation of proteins are extensively reutilized for protein synthesis within the cell or transported to other organs where they enter intercellular recycling. The continuous

Muscle bre oxidative capacity

The maximum rate of oxygen consumption (VO2max) per volume unit and the cross-sectional areas of striated myocytes from dierent vertebrates vary across a 100-fold range [105]. Muscle bres with high oxidative capacity are relatively small compared to bres with low oxidative capacity pointing to an increase in relationships between bre cross-sectional area and VO2max [105]. It is necessary to mention that among striated
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muscle cells, only cardiocytes have high oxidative capacity, while skeletal muscle bres have low (type IIB/X) and higher oxidative capacity (type I and IIA) [76, 82, 87, 91]. VO2max is proportional to succinate dehydrogenase (SDH) activity [12] or oxoglutarate dehydrogenase activity [13] and consequently to the number of mitochondria [44, 71]. Muscle bres with a relatively large cross-sectional area had low SDH activities and vice versa [50, 73]. It has been shown that muscle bre can hypertrophy and increase strength potential at the expense of endurance capacity [105]. Type I and IIA muscle bres have a relatively large oxidative capacity and small bre size compared to type IIB/IIX bres. Muscle bre size, not necessarily the bre type, is related to its oxidative capacity [105]. The same authors raised the question why high oxidative muscle bres remain relatively small compared to low oxidative muscle bres. It is well known that physiological function of muscle bre type is an outcome of MyHC isoform expressed within bre. Some bres, the so-called hybrid bres express a combination of 2 or more MyHC isoforms [17, 93]. Laboratory animal experiments have shown that the relative proportions of hybrid bres vary signicantly from muscle to muscle [17]. In human skeletal muscle, hybrid bre types represent a signicant population of bres, but the stability of this bre phenotype is currently unclear. For example, electrical stimulation increases the proportion of hybrid bres [68] and mechanical load and thyroid hormone changes the proportion of hybrid bres in skeletal muscle [18]. It has been shown that running exercise declines the hybrid bres in human skeletal muscle [51], whereas muscle hybrid bres are relatively refractory to the eect of exercise in mice [32]. It is not clear yet what role hybrid bres play in endurance training of athletes, particularly the role of these bres in changes of skeletal muscle oxidative capacity.

Review 907

turnover of muscle proteins determines how the myobrillar or mitochondrial fractions balance change, and accordingly change muscle functional capacity [64]. Muscle bres with higher oxidative capacity contain a higher level of cathepsin suggesting that there is a higher potential for protein degradation in muscles with high protein turnover [11]. The protein turnover rate in skeletal muscle bres is very slow. After an acute lesion or in chronic pathological conditions, satellite cells are induced to proliferate and may change the protein turnover [33]. Vertebrate skeletal muscle bres are multinucleate cells [57] with hundreds of thousands of myonuclei [34, 78]. Each myonucleus regulates gene products within a nite volume called the myonuclear domain [3] or DNA unit [20] and has been dened as the theoretical volume of cytoplasm associated with a single myonucleus [3, 4]. Cytoplasmic volume per myonucleus is smaller in bres expressing slow as compared to fast MyHC [73, 103] or in bres highly active in protein synthesis [29]. The greater concentration of myonuclei in slow-twitch (ST) bres has been shown to be related to a higher rate of protein turnover [103]. RNA and protein ratio called the RNA unit [58] and the protein synthesis per RNA unit has been dened as the activity of RNA [58] and shown as a stable indicator of protein synthesis or eectiveness of the translation process in cell in physiological conditions [61, 108]. About 4 decades ago, it was shown that the protein turnover rate depends on the type of muscle [28] and even functionally related proteins such as myobrillar proteins have dierent speed of renewal [79]. It was shown that a relationship exists between the turnover rate of myobrillar protein and quantity of mitochondria in muscle [28, 98]. The concept of plasticity of skeletal muscle [30, 65] enables bres to adapt themselves to dierent genetic and environmental inuences on the cellular and molecular level, which in turn lead to the changes in metabolic functions [31]. According to contemporary understanding, muscle protein turnover rate may be used for diagnostic purposes of muscle diseases and training monitoring. Changes in the turnover rate of myobrillar proteins characterize the renewal processes in the contractile apparatus during adaptation to increased functional activity [66, 67]. As muscle bres have limited capacity for hypertrophy and increase oxida-

tive capacity at the same time, it shows that a competition exists between the turnover rate of myobrillar and mitochondrial proteins [105]. It has been demonstrated that the turnover rate of MyHC isoforms does not only show dierences between the muscles of dierent twitch characteristics, but also between fast-twitch (FT) muscles, and the turnover rate is faster in FT muscles with a higher oxidative potential [82]. Faster myosin turnover rate supports qualitative remodelling FT muscle with higher oxidative capacity so that the former pattern of MyHC and myosin light chain (MyLC) isoforms changes. This process shows that muscles with higher oxidative capacity adapt faster to the new condition [30]. In the light of recent ndings, the expression of specic contractile, regulatory and minor protein isoforms is a relevant, though not the only mechanism of regulation of heterogeneity and plasticity of skeletal muscle. The pattern of MyHC isoforms in skeletal muscle might change for several reasons.

Eect of endurance training on interaction between mitochondria and sarcomeres

Skeletal muscle oxidative capacity increases with endurance training and the decline in oxidative capacity is related to the reduction in tness [74]. Endurance training stimulates mitochondrial biogenesis and improves their functional parameters [42, 56]. Exhaustive endurance exercise produces undesired eects and results in a marked decrease in cytochrome c/aa3 ratio by about 37 % in striated muscles with high oxidative capacity (heart muscle), and the reason for the decit of cytochrome C is the disruption of the outer membrane [48]. Studies in skeletal muscle have shown a potential role of mitochondrial impairment during exhaustive exercise and subsequent muscle bre damage [87, 89]. It has been shown in striated muscles with high oxidative potential that intracellular phosphotransfer systems constitute a major mechanism linking mitochondria and ATPases within specic structures intracellular energetic units [76, 92]. Mitochondria are precisely positioned between the myolaments throughout the whole muscle due to the xed juxtaposition of mitochondria with sarcomeres [104]. The eectiveness of metabolic signalling strongly depends on structural-functional relationships of the interaction between mitochondria and sarcomeres [91]. Under conditions of hypoxia, the connections between mitochondria and sarcomeres are disturbed as sarcomFig. 1 Protein turnover in muscle bre. Protein turnover is a continuous process determined by the ratio between protein synthesis and degradation rate. Protein turnover rate is faster in muscle bres with higher oxidative capacity. Protein turnover characterizes renewal processes in muscle bres and, accordingly, changes in muscle functional capacity. Faster turnover of muscle proteins also provides faster regeneration of bres and their readiness for the next endurance training load.

Increase in DNA Unit Number Hypertrophy Increase in Protein Synthesis Rate Ratio between Protein Synthesis Rate and Protein Degradation Rate

Muscle Fibre Oxidative Capacity Nucleus RNA Protein

Protein Turnover Rate

Increase in Protein Degradation Rate Atrophy Decrease of DNA Unit Numbers

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Exhaustive exercise and ROS

Exhaustive exercise stimulates the generation of reactive oxygen species (ROS), which damage muscle cells, being side products of oxidative phosphorylation, due to univalent reduction of molecular oxygen by electrons leaking from the respiratory chain [26, 69] and induce damage of this chain [59]. Mitochondria are the source and target of ROS because complexes I and III of the electron transport chain are the main sites of mitochondrial superoxide production [38, 60]. The magnitude of changes in exercise induced ROS depends on the type of muscle bre [7] as cellular Ca2+ overload activates the degradation of muscle proteins and membrane phospholipids via Ca2+ dependent proteolytic and phospholipolytic pathways [6]. Ca2+ overload results in the uptake of Ca2+ into mitochondria [99], reduces mitochondrial capacity to synthesize ATP and causes damage of mitochondrial membranes.

Role of MyHC and MyLC Isoforms in endurance training

During the last 2 decades, it has been shown that among multiple isoforms of muscle proteins MyHC and MyLC isoforms play an important role in muscle function. These 2 isoforms of the myosin molecule have a dierent turnover rate. MyLC isoforms turnover is faster than MyHC and their recovery dynamics from endurance exercise are also dierent [84]. Simultaneously with increased contractile protein degradation, endurance training also increased the degradation rate of MyHC isoforms [83, 87]. The degradation rate of MyHC isoforms increases in spite of the increase of oxidative potential of FT skeletal muscle. The decrease of expression of MyHC IIb isoform in FT muscles is caused by the intensive degradation of the isoform during endurance training, which is probably the main reason for unchanged turnover rate of MyHC IIb isoform in endurance trained rats [77]. During the adaptation to long-lasting endurance exercise, a decrease of MyHC IIb isoform in FT skeletal muscle shows the transformation of muscle contractile apparatus in accordance with the increase in muscle oxidative capacity and does not necessarily show the decrease of muscle contraction speed. It has been claimed that in order to better understand the role of MyLC in skeletal muscle, it is necessary to study changes in MyLC in parallel with the quantication of MyHC under the same conditions [107]. During muscle atrophy of dierent genesis, it has been shown that MyLC 1fast and 2fast isoforms increase in parallel with the increase in the relative content of MyHC IIb isoforms [25]. A decrease in the relative content of MyLC 1fast isoform is an indicator of the slowing of muscle contraction [37]. This standpoint has been supported in rat skeletal muscle by decreasing MyLC 1fast isoform in the following direction EDLPla diaphragm (Dia) soleus (Sol) muscle [2].

Eect of endurance training on contractile protein turnover

Changes in muscle protein turnover rate during endurance training may be regarded as an adaptation of a tissue or cells to long-lasting low intensity functional activity. This adaptation provides a rapid means for the redistribution of amino acids into new proteins as they are required because amino acids are derived from protein breakdown and incorporated into the newly synthesized protein. Aerobic exercise stimulates protein turnover by increasing muscle protein degradation and synthesis in the recovery phase after exercise [19]. The turnover rate of MyHC and MyLC isoforms provides a mechanism by which the type and amount of protein can be changed in accordance with the needs of the contractile machinery during adaptation to endurance training [2, 82]. Activity patterns of muscle bres where MyHC I and IIa isoforms are dominant have relatively high oxidative capacity and are recruited during endurance exercise [85]. It has been shown that in rat FT plantaris (Pla) and extensor digitorum longus (EDL) muscles, the dierence in oxidative capacity is about 10 % [82].
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eric components disintegrate the muscle cell structure and cause cell injury and death [91]. The activation of apoptosis may be partly responsible for the initiation of protein degradation and loss of muscle nuclei associated with local atrophy [27]. For example, the disruption of desmin impairs the linking of mitochondria to Z-disc and skeletal muscle exhibits impaired oxidative phosphorylation [75]. AMPK becomes activated in skeletal muscle during acute bouts of exercise [8]. AMPKs main function is to monitor the energy status of muscle bres and maintain muscle energy homeostasis [62]. Long-lasting endurance exercise may lead to the depletion of the energy system, neuromuscular fatigue and muscle damage [1]. Children have less muscle mass than adults and generate lower absolute power during high-intensity exercise. Childrens muscles are better equipped for oxidative than glycolytic pathways during exercise and have a lower ability to activate their type II muscle bres [70]. Skeletal muscle oxidative capacity increases with endurance training and an age-associated decline in oxidative capacity is related to the reduction in tness [74]. Aerobic endurance training can positively inuence structural changes in capillarity [36]. Type IIB muscles exhibit increased ADP concentrations in response to an increased workload, which conforms to the respiratory control theory in skeletal muscle [75].

Endurance exercise training increased the oxidative capacity in Pla muscle by 16 % and in EDL muscle by 12 % [82]. How much of gene expression of MyHC isoforms is due to genetic predisposition and how much to the specicity of training is unresolved [9]. Dierences in MyHC isoforms turnover rate between FT muscles show that the turnover rate is faster in muscles where oxidative capacity is higher [82]. Changes in MyHC isoforms turnover rate in FT muscles during endurance training also characterize changes in myobrillar apparatus through protein metabolism. The latitude of changes (increase, decrease) in myosin isoforms turnover rate also shows the signicance of MyHC isoforms in the process of adaptation to endurance training. Although the exact role of MyLC isoforms in FT muscles during endurance training is not fully known, changes in MyLC isoforms relative content and their relation to the character of training show that they play an important role in the process of modulation of the contractile machinery during the increase of oxidative capacity and degradation rate of contractile proteins [2]. There is still no answer to the question whether other myobrillar proteins can modulate the functional properties of myosin during endurance training and if it is dependent on the training volume. C-protein, which binds either myosin and actin or aects the mechanical properties of myosin cross-bridges by linking the S2 segment of myosin to the backbone of the thick lament [37], has shown to be very sensitive to high training volume [83]. C-protein together with MyHC isoforms plays the key role in changes of functional properties of the contractile machinery during excessive increase in endurance training volume [83].

Review 909 Conclusion

Recent evidence suggests that a constant increase of endurance training volume is not the only way to improve athletes competitive results, but it is reasonable to assume that an increase of muscle strength capacity is possible at the expense of endurance capacity. Endurance training stimulates mitochondrial biogenesis and an increase of skeletal muscle oxidative capacity. Exhaustive endurance exercise results in a marked decrease in cytochrome C/aa3 ratio in skeletal muscle with higher oxidative capacity. Disruption of minor muscle protein desmin impairs the linking between mitochondria and myobrils and muscle exhibits impaired oxidative phosphorylation. Muscle protein turnover demonstrates the continuous process of protein synthesis and degradation, characterizing renewal processes, and functional capacity of muscle. The turnover of contractile proteins provides a mechanism by which the type and amount of protein can be changed in accordance with the needs of the contractile machinery during adaptation to endurance training. Aerobic exercise stimulates protein turnover by increasing muscle protein degradation and synthesis in the recovery phase after exercise, while exhaustive exercise conversely elicits slower turnover rate of contractile proteins. The turnover rate of contractile proteins depends on the oxidative capacity of muscle bre. Changes in myobrillar protein turnover rate may be regarded as the remodelling of contractile machinery during endurance training supporting the energetic adaptation of muscle. Muscle proteins turnover rate is applicable in monitoring the training process of endurance athletes and enables to optimize training programs and prevent overtraining.

Acknowledgements
This study was supported by the funds of the Ministry of Education and Research of the Republic of Estonia, research project number SKKSB1787.

Eect of excessive volume of endurance training

Excessive volume of endurance training leads to exercise intolerance. In skeletal muscle, decreased capillarization may impair the exchange of oxygen between capillaries and muscle tissue and this contributes to exercise intolerance [24] and explains the changes in MyHC pattern in FT muscle during an excessive increase of endurance training volume [85]. Chronic exhaustive endurance exercise leads to the decrease of both DNA and RNA units in FT skeletal muscle [85]. Excessive volume of endurance training and lack of recovery lead to the decrease of physical work capacity [85]. There are several reasons for the decrease of physical work capacity: training stimulus lasts too long in each exercise session and is too frequent, which interrupts the recovery phase and the necessary adaptation does not occur [90]. The decrease of the DNA content, DNA units and RNA units in skeletal muscle are typical for exercise caused or glucocorticoid caused myopathic muscles [86, 90]. The decreased myobrillar protein synthesis rate, increased degradation rate, and slower turnover rate are indicators that refer to excessive volume of endurance training and development of myopathy [86, 87, 90]. In contrast, in myopathic muscles heat shock protein synthesis rate increases, which shows the increased stress tolerance of aected muscle bres and cellular repair process [77, 90].

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