- An increase in ribosomal capacity is necessary for hypertrophy.
- Transcription of the ribosomal RNA (rRNA) genes precedes rRNA production and muscle hypertrophy and correlates with the magnitude of hypertrophy.
- Mechanistic target of rapamycin (mTOR) signaling regulates both ribosomal efficiency and capacity.
- mTOR localizes to the nucleus where it modulates transcription and chromatin modifications of rDNA genes.
Ribosomes are the key protein synthetic machines of every cell. Their indispensable role in this process, together with the fact that protein synthesis rates are determined by the ribosomal capacity of the muscle (1), makes ribosome production a key determinant of skeletal muscle mass. Evidence is mounting favoring ribosomal production at the onset of hypertrophy as an important mechanism of adaptation when there is a demand for growth. The regulation and importance of ribosomal production in cellular growth control have been studied extensively in a variety of cell systems and conditions (2–4). However, mechanistic insight about the regulation of muscle ribosomal capacity is presently scarce. Unlike proliferating cells, where a specific timing needs to be followed for cells to divide, postmitotic tissues like skeletal muscle need to be subjected to repeated stimuli to stimulate hypertrophic growth. Therefore, responsiveness of the skeletal muscle ribosomal production machinery likely involves a specific mode of regulation. Although it has been long established that an increase in ribosomal capacity is associated with muscle hypertrophy, recent studies from our lab and others are beginning to define the mechanisms involved in this process. Findings revealed that transcription of ribosomal DNA (rDNA) genes in response to exercise accounts for the enhanced ribosomal production seen at the onset of muscle hypertrophy. This occurs in a pulsatile fashion and seems to be different from “basal” ribosomal production, thus defining an “enhanced” response that requires upregulation of the RNA synthesizing machinery to support the increase transcriptional output of rDNA genes. Mechanistically, our laboratory determined that ribosomal RNA (rRNA) production in hypertrophying skeletal muscle is mainly regulated via transcription initiation of rDNA genes and also involves epigenetic modifications in the upstream promoter (5,6). Evidence from in vitro studies indicates that this is a fundamental mechanism of growth control necessary for the increase in ribosomal capacity of the muscle because specific inhibition of rDNA transcription blocks ribosomal production and hypertrophy. The goal of the present review is to revisit the hypothesis that ribosomal production is a key adaptive response during skeletal muscle hypertrophy and to examine recent evidence demonstrating that enhanced transcription of rDNA genes is essential for this process.
Our interest in muscle ribosomal production emerged from the strong correlation between the activation of the 70-kDa ribosomal protein S6 kinase (S6K1, formerly called p70S6k) and muscle hypertrophy (7). When compared with low-frequency electrical stimulation or running, high load contractions resulted in the specific activation of S6K1 (2), demonstrating that S6K1 activation is a resistance exercise (RE)–specific signaling event. A known role of ribosomal protein (rp)S6 phosphorylation is the regulation of ribosomal protein synthesis (8). Given that ribosome production requires the coordinated synthesis of rRNA and ribosomal proteins, we reasoned that the signaling network leading to S6K1 activation had to be linked to rRNA production. Two key studies involving the mechanistic target of rapamycin (mTOR) in muscle hypertrophy demonstrated that inhibition of mTOR signaling using Rapamycin blocked hypertrophy in vivo and in vitro (9,10). This led us to hypothesize that signaling via mTOR could regulate muscle hypertrophy by controlling muscle ribosome production and prompted us to investigate whether blocking mTOR signaling would prevent rRNA accumulation. Our initial finding that inhibition of mTOR signaling blocked rRNA accumulation and hypertrophy (11) began a line of research aimed at determining the molecular mechanisms underlying ribosome biogenesis during skeletal muscle hypertrophy. Studies that followed started to define the mechanisms involved in muscle ribosome production, the critical function of mTOR signaling in hypertrophy, and its involvement in chromatin remodeling of ribosomal genes.
RIBOSOME BIOGENESIS — MAKING THE MASTER BIOSYNTHETIC MACHINE
Ribosome biogenesis is a well-orchestrated and complex process. It starts in the nucleolus with the synthesis of rRNA and requires the coordinated presence of ribosomal proteins and hundreds of processing, export, and assembly factors (12). Ribosomes are composed of four rRNA species (18S, 5.8S, 28S, and 5S), and ~80 ribosomal proteins. Ribosome production requires the activity of all three RNA polymerases (RNA Pol I, II, and III) of which transcription of the 45S rDNA genes by RNA Pol I is rate limiting (13,14). Transcription by Pol I produces a 47/45S rRNA precursor (pre-rRNA) that is further processed into the mature 18S, 5.8S, and 28S rRNAs (15). Pol II generates messenger RNAs (mRNAs) that encode the ribosomal proteins as well as a specific set of enzymes and several small nucleolar RNA required for rRNA processing. Pol III is responsible for generating 5S rRNA and transfer RNA. The Pol I machinery is a focal control point in the production of rRNA. It includes a dedicated set of transcription factors namely upstream binding factor (UBF), the Selectivity factor-1 (SL-1) complex composed by the TATA binding protein (TBP) and at least four TBP associated factors (TAFs), transcription initiation factor-1 (TIF-1A/Rrn3), and the 14 subunit Pol I holoenzyme (16). Binding of these factors to the upstream promoter of rDNA genes determines transcription initiation rates of a fraction of the several hundred rDNA copies present in the genome (10–12). These factors constitute a “regulon” and are coordinately regulated to ensure that the core Pol I machinery is available for efficient ribosomal production (17). The rDNA genes possess a regulatory region upstream of the transcription start site with binding sites for UBF. Once UBF binds to these regions, SL-1 follows and serves as a signal for the TIF-1A-Pol I complex to recognize the promoter and activate transcription. This step is a convergence point for several signaling inputs and is partly regulated by mTOR signaling. Specifically, signaling via mTOR plays a key role in how cells adjust growth rates to internal (e.g., nutritional) and external (e.g., growth factors, mechanical loading) cues by modulating UBF and TIF-1A function via posttranslational modifications (18–20). Another regulatory aspect of rDNA transcription is the remodeling of rDNA promoter chromatin, which confers transcriptional regulation in a cell type and context-dependent manner.
RIBOSOME CONTENT REGULATES SKELETAL MUSCLE MASS
Skeletal muscle mass is mainly determined by elevations in protein synthesis (21), and this is, in turn, regulated by the ribosomal content of the muscle (1). Although a more efficient use of existing ribosomes, or “ribosomal efficiency,” accounts for the initial increase in protein synthesis after RE, overload, or growth stimulation, an increase in “ribosomal capacity” in hypertrophying muscle reflects an adaptive response to support a higher anabolic state. This increase in ribosomal capacity has been reported consistently in human (11,22–28), animal (5,11,23,29–33), and in vitro (6,11,23) models of skeletal muscle hypertrophy. Early evidence of an increase in ribosomal capacity during skeletal muscle hypertrophy was provided by Hamosch and Kaufman, who demonstrated that microsomal preparations from hypertrophying muscle contained more ribosomes than control, and hence stimulated higher protein synthesis rates (34). This was followed by Goldberg and Goodman’s work (35) showing an increase in ribosomal content in response to muscle overload in vivo. Indeed, Sobel and Kaufman (36) corroborated that the increase in rRNA content typically seen in muscle hypertrophy was associated with an increase in RNA Pol I activity, that is, more ribosomal gene transcription. Subsequent studies corroborated the elevated ribosomal content in muscles undergoing hypertrophy in various models and species, strengthening the interpretation that an increase in ribosomal capacity is an important adaptive response in muscle hypertrophy (Table).
In general, enhanced ribosomal production accompanies muscle hypertrophy; therefore, it is reasonable to conclude that ribosomal gene expression is a determining factor in the accretion of muscle mass. The quantitative relation between ribosomal mass and muscle size favors of this conclusion, which is supported by recent studies demonstrating that a higher rRNA content correlates with a greater degree of hypertrophy. Nakada et al. (37) implemented a clever incremental overload model to show that a larger accumulation of rRNA levels was associated with a higher degree of muscle hypertrophy. Human studies have reported a similar correlation between rRNA levels and the growth response to RE. After 4 wk of RE training, Stec et al. (23) found that subjects who had the highest increase in rRNA levels also displayed the largest hypertrophic response to exercise, and more recently, Mobley et al. (38) showed a similar relation between rRNA accumulation and hypertrophy. Moreover, ribosomal mass does not only correlate with the degree of exercise-induced hypertrophy but also is associated with muscle growth rates during postnatal development. Fiorotto et al. reported that ribosomal deficits consequent to inadequate nutritional intake during early life cause stunted growth throughout adulthood (22,39). Similarly in aged rodents, a diminished transcriptional ribosomal response (i.e., rDNA gene expression) seems to be responsible for anabolic resistance to mechanical loading (40,41), and in aged humans, lower rRNA levels are correlated with anabolic resistance to exercise and nutritional stimuli (24,25). In fact when ribosomal production is suppressed, muscle hypertrophy is severely impaired. Blocking transcription with actinomycin (Act) D, which inhibits DNA-dependent RNA synthesis (42), prevented synergist ablation-induced hypertrophy in rats (43). Similarly, restoration of ambulatory activity of immobilized muscle in the presence of ActD impeded muscle size recovery, which suggests that de novo ribosomal production may be necessary to amplify the growth capacity of the muscle under conditions of rapid growth (30). Overall, these studies provide a strong association between the increase in ribosomal content and skeletal muscle hypertrophy and suggest that an increase in ribosomal capacity for protein synthesis is an important determinant of muscle size.
TRANSCRIPTION OF RIBOSOMAL RNA GENES DETERMINES MUSCLE’S ANABOLIC CAPACITY
Despite the strong association between the accumulation of ribosomal mass and muscle hypertrophy, little was known until recently about the molecular mechanisms responsible for muscle rRNA production during hypertrophy. Studies from our laboratory revealed that enhanced rDNA transcription is responsible for rRNA production and precedes muscle hypertrophy. At the onset of hypertrophy, transcription of rDNA genes is pulsatile and promotes rRNA accumulation. We identified this early transcriptional response in vivo employing the synergist ablation model in rodents (5), an acute bout of RE in humans (22), and in vitro serum-stimulated myotubes (6,11) (Fig. 1). Mice subjected to overload display a robust and transient increase in rDNA transcription peaking at 3 d and returning to basal levels by 7 d postoverload (5). Stimulation of myotubes in vitro also induces a transient response in rDNA transcription (6), which precedes rRNA accumulation, the augmentation of protein synthesis, and hypertrophy. In humans, an acute bout of RE induces a rapid increase in 45S pre-rRNA levels detectable within 4 h postexercise (22). The latency of the increase in 45S pre-rRNA in humans is at least 48 h, which precedes the earliest reported observation of hypertrophy after the initiation of RE training (45). The striking concordance across such different models of hypertrophy indicates that transcription of rDNA genes is a well-conserved response preceding rRNA accumulation and muscle hypertrophy. However, despite these strong associations, rigorous research testing the necessity of rRNA production for muscle hypertrophy was lacking until recently. As mentioned previously, inhibition of DNA-dependent RNA synthesis using ActD prevented hypertrophy in vivo. Although it is tempting to speculate that this effect was due to the inhibition of rRNA synthesis, one should consider the fact that ActD, at high doses, also inhibits Pol II and III. Thus, the inhibitory effects reported using ActD could have also been due to the inhibition of ribosomal protein and 5S rRNA synthesis and the accessory factors necessary for Pol I transcription. Furthermore, because of the potential involvement of nonmuscle cells in the hypertrophic process in vivo (i.e., satellite cells, fibroblasts, macrophages), systemic treatments to block rRNA production may have prevented hypertrophy by inhibiting the action of nonmuscle cells. To circumvent the previously mentioned limitations, we used an in vitro model to test whether inhibition of Pol I transcription using the specific inhibitor CX-5461 was sufficient to prevent muscle hypertrophy. CX-5461 precludes the interaction between SL-1 and the rDNA promoter, thereby preventing the formation of the Pol I pre-initiation complex assembly (46). Inhibition of Pol I activity effectively blocked 45S pre-rRNA accumulation and myotube hypertrophy, indicating that in this system, rDNA transcription is necessary for rRNA production and myotube hypertrophy (6). This finding also corroborated our in vivo results showing that an increase in ribosomal production during hypertrophy is regulated at the transcription initiation step. Consistent with the peak in 45S pre-rRNA levels detected after the imposition of overload, we observed an increased association of the Pol I factors UBF, c-MYC, and WSTF at the rDNA promoter, an indication that transcription initiation modulated rRNA production (5). Moreover, these studies are in line with our earlier finding that preventing the action of UBF by blocking mTOR signaling halts rRNA accumulation and prevents myotube hypertrophy (11). Another nuclear event important for rDNA transcription initiation at the onset of hypertrophy is the localization of mTOR in the cell nucleus. We recently identified mTOR bound to the rDNA gene promoter, where it appears to modulate chromatin rearrangements permissive for rDNA transcription. After rapamycin treatment, a reduction in histone 3 lysine 56 acetylation and an increase in linker histone H1 take place, indicating that signaling via mTOR has chromatin remodeling functions necessary for hypertrophy (6). Altogether, these studies suggest that promoter enrichment of Pol I factors and nuclear mTOR signaling may be responsible for priming or maintaining transcription initiation and the competent state of rDNA genes. These mechanisms provide evidence that ribosomal gene transcription initiation regulates rRNA accumulation at the onset of skeletal muscle hypertrophy.
As noted previously, the transcriptional response of rDNA genes is associated with an increase in the Pol I machinery. Compared with basal levels, such dynamic range in rRNA production requires an increase in the factors modulating Pol I transcription. We observed an increase in the Pol I regulon in vivo in rodents subjected to synergist ablation (5), humans after an acute bout of RE (Fig. 2), and in vitro myotube hypertrophy (6). Expression of the Pol I regulon necessary for hypertrophy as inhibition of Pol II transcription or protein synthesis abrogates the accumulation of Pol I factors and prevents hypertrophy. The need to synthesize the regulon to support enhanced Pol I transcription clearly distinguishes an enhanced mode of rRNA production in hypertrophy that is different from basal ribosomal production. Expression of the Pol I regulon is coordinately regulated by at least the transcription factor c-Myc (17). After overload in mice, c-Myc levels are rapidly induced, suggesting that in skeletal muscle, the Pol I regulon may be modulated by c-Myc levels. Interestingly, data from other systems demonstrated the c-Myc also is a transcriptional activator of rDNA genes (48,49); therefore, c-Myc may coordinate transcription of rDNA genes and the factors needed for enhanced ribosomal production. The response of c-Myc to acute RE is conserved in humans; however, it is notable that its expression is attenuated in the trained state. This is an intriguing aspect of muscle rRNA production; when a bout of RE that induces rDNA transcription in the untrained state is performed at the same relative intensity in the trained state, the response of 45S pre-rRNA is attenuated (22). Although this explains previous data demonstrating that during a training period, changes in 45S pre-rRNA are typically seen in the early stages of muscle hypertrophy, it raises the question of how ribosomal mass is stimulated and maintained in the trained state, where elevated rRNA levels are consistently reported and correlate with muscle hypertrophy (Table).
SUMMARY AND FUTURE PERSPECTIVES
In the present review, we summarized the key mechanisms supporting the hypothesis that enhanced rDNA transcription leads to an increase in ribosomal capacity and is critical for muscle hypertrophy (Fig. 3). Despite recent advances in our understanding of this process, a number of outstanding questions remain unanswered. For example, what is the latency of rDNA transcription in humans after an acute bout of RE? When does rDNA transcription becomes attenuated by training? Is this response modified by nutritional status? Why is the response in the trained state apparently attenuated, and how do trained muscles maintain their ribosomal capacity? Could this be a consequence of reduced ribosome degradation via ribophagy? What is the signal(s) that attenuates rDNA transcription in the trained state? Although it is tempting to speculate that a negative feedback mechanism is responsible for the observed attenuated response trained muscle, it remains unclear what factor(s) may exert such feedback. One exciting possibility is that ribosomal proteins may play a role in this process because 1) a number of them are believed to have extraribosomal functions and 2) they are not made in stoichiometry across tissues. In skeletal muscle specifically, rpL3L, rpl37a, rpl38, rpl41, rpl44, rpS13, rpS17, rpS24, and rpS26 are overexpressed compared with other tissues (52–54), suggesting tissue-specific extraribosomal function(s). Another interesting possibility is that changes in the free ribosome-to-polysome ratios may negatively feedback to rRNA synthesis (55). In trained muscle, a higher content of ribosomes not engaged in protein synthesis may signal back to the rDNA genes that enough ribosomes are available, and thereby repress transcriptional activation. This would suggest that ribosomal efficiency could play a role in maintaining anabolism when sufficient ribosomal capacity for protein synthesis is available. A recent study may support this hypothesis. Crossland et al. (47) reported that inhibition of Pol I activity by CX-5461, although it prevented ribosomal production, did not block IGF-1-induced hypertrophy, suggesting that under certain circumstances, enough ribosomal machinery is available to cope with the growth demands of the cell.
In summary, although the majority of studies consistently demonstrated a very strong association between changes in ribosomal capacity and muscle hypertrophy, and that preventing the increase in ribosomal capacity impairs muscle hypertrophy (6,11,23,30), future studies examining the mechanistic underpinnings of how this process is regulated in response to diverse hypertrophic stimuli will further our understanding of this important aspect for the regulation of skeletal muscle mass.
Support: The Pennsylvania State University.
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