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POINT-COUNTERPOINT COMMENTS
Research Institute for the Biology of Farm Animals
Dummerstorf, Germany
The following letters are in response to Point:Counterpoint: "Satellite cell addition is/is not obligatory for skeletal muscle hypertrophy" that appears in this issue.
To the Editor: Our data suggest that satellite cell incorporation into myofibers is not an obligatory event in each case of skeletal myofiber hypertrophy. Responses of skeletal muscle to any factors are often examined during postnatal growth. Therefore, net fiber hypertrophy at the end of a specified period will mostly include satellite cell addition, although a hypertrophic stimulus does not necessarily activate satellite cells. In our opinion, it depends on the kind of stimulus whether satellite cells are activated. By sequential muscle biopsy of the same individual pigs during postnatal growth we have seen that myofiber hypertrophy was accompanied by a continuous increase in myonuclei following a typical growth curve (1). The number of nuclei per fiber increased and the size of the nuclear domain decreased with age until a plateau was reached. Treatment with growth hormone (GH) over 10 wk stimulated myofiber hypertrophy significantly but did not increase the nuclear number per fiber, resulting in a lowered nuclear cytoplasm ratio compared with the untreated controls. After withdrawal from GH these differences rapidly disappeared. Consistently, our results on treatment with the 
2-adrenergic agonist clenbuterol obtained with rats (3, 4) and chickens (2) showed that addition of satellite cells was not necessary for the hypertrophic response of the fibers after 12 days or 3 wk, respectively. Both in rats and chickens, muscular protein degradation was reduced and protein synthesis was stimulated at the pretranslational level. In all studies mentioned, only myofiber nuclei within the sarcolemma have been considered.
REFERENCES
Department of Physiology and Biomedical Engineering
Mayo Clinic College of Medicine
To the Editor: Skeletal muscles fibers are multinucleated, with each nucleus affecting gene products in a finite volume [myonuclear domain (MND)]. A key question addressed in this Point:Counterpoint (3, 4) is whether MND size is regulated during fiber hypertrophy by fusion of activated satellite cells. In type-identified rat diaphragm muscle (DIAm) fibers, MND size is not maintained during conditions associated with changing fiber size (1, 5). In adult DIAm, MND size varies across fiber types (
80% larger in type IIx and IIb fibers vs. type I and IIa fibers), but there is no relationship between fiber size and myonuclear number (r2 0.5). With normal fiber growth, MND size increases proportionately (5). Thus MND size does not appear to be regulated as fiber size increases. After DIAm denervation, significant satellite cell activation occurs after 1–3 days (2). By 7–14 days after DNV, type I fibers hypertrophy while type IIx and IIb fibers atrophy, and MND size changes proportionately (1). Thus, under this condition in which satellite cell activation occurs, MND size is not regulated. It is possible that fusion of activated satellite cells may be delayed (4), but it is unlikely this delay would be >14 days. It is possible that a "ceiling" may exist beyond which fiber growth requires addition of myonuclei; but based on the highly variable MND size in DIAm fibers and the fact that MND size changes proportionate to fiber size, our results do not support this concept.
REFERENCES
Ohio University
To the Editor: These contrasting views (1, 6) on the necessity of myonuclear addition for muscle hypertrophy are not surprising since my laboratory has come to both conclusions in different studies. We recently examined muscles from a population of birds that undergoes seasonal atrophy of their flight muscles due to inactivity of several months. Shortly before migration, they exercise and regain their pectoral mass and cross-sectional area (from 230 to 900 µm2). Analysis of 30 birds at different stages of atrophy/recovery showed that cross-sectional area predicts nuclear domain size, as shown by regression analysis (slope = 1.41, r2 = 0.66, F1,28 = 55.45, P < 0.0001). Thus nuclear domains of these muscles increased with increasing fiber size, with no increase in nuclear numbers. So from our own and other (5) recent studies, we have shown that myonuclei are not added in elderly men after strength training (2) and in these bird flight muscles (unpublished data); in contrast, nuclei are added in young men after weight training (4), and nuclei are reduced in number in rat soleus muscles atrophied after 10 days of space flight (3). A 2,000 µm2 threshold for human muscles has been suggested for increases in cross-sectional area before myonuclei must be added. For smaller bird or rat muscles, the threshold must be smaller, but the results presented here indicate that over a threefold increase in cross-sectional area has no effect on nuclear number. It is clear that different factors (species, age) contribute to whether maintenance of myonuclear domain plasticity is maintained.
REFERENCES
University of Missouri
To the Editor: In their article entitled: "Counterpoint: Satellite cell addition is not obligatory for skeletal muscle hypertrophy," McCarthy and Esser (1) cite my publications (2, 3) as providing "evidence... contraction-induced growth in which satellite cell addition does not occur as measured by DNA content." Their application of my data as supporting their viewpoint is questionable based on the knowledge that total DNA per whole muscle is not an index of satellite cell activity as suggested by 1) other cell types (macrophages, fibroblasts, endothelium, smooth muscle, and adipocytes) are contained within skeletal muscle, each with their own ability to increase/decrease; thus impacting total whole muscle DNA content, independent of satellite cell addition; and 2) myonuclear DNA lost due to fiber damage could be replaced by the addition of satellite cell DNA for fiber regeneration, without a net change in total whole muscle DNA content. Therefore, total DNA per whole muscle, as I reported (2, 3), is not a valid index of satellite cell activity as it pertains to muscle hypertrophy.
McCarthy and Esser (1) also state that "the eccentrically loaded TA muscle exhibited...no change in total DNA per muscle." On the contrary, the chronic, eccentrically trained TA muscle from my publication (3) did indeed have significant increases in total DNA per whole muscle (Table 3, p. 1721).
In summary, my data do not provide evidence to support McCarthy and Esser's (1) contention that "contraction-induced skeletal muscle growth in which satellite cell addition does not occur as measured by DNA content."
REFERENCES
Department of Health Sciences
Örebro University
To the Editor: In this letter, the Point:Counterpoint issue (1, 5) is addressed solely by referring to studies in humans. The analysis of histological sections from skeletal muscle of power lifters with many years of practice leaves no doubt about the role of satellite cells as myonuclei donors in the hypertrophied muscle fiber. The larger the cross-sectional area of fibers, the higher the number of myonuclei per cross-section (2, 4). Importantly, the strong relationship between the cross-sectional area of fibers and the number of myonuclei (r = 0.86; P < 0.0001) is obtained with a range of areas between 2,500 and 14,000 µm2 (4). Existing myonuclei are able to sustain an initial hypertrophy of the muscle fiber as long as the transcriptional activity of existing myonuclei does not reach its maximum (2, 3, 5). Satellite cells become myonuclei donors when fiber size reaches the ceiling size (2, 3, 5). Additionally, we should not forget that satellite cells are also donors of myonuclei to newly generated myotubes (2, 4). The intensity of exercise and the initial fiber area of the subjects included in a training program are important factors governing whether daughter cells generated by satellite cell activation and proliferation provide new myonuclei to existing myofibers or to newly generated myotubes. Finally, in parallel with these events, some of the daughter cells can escape differentiation and facilitate renewal of the satellite cell pool. Efforts should be made to better understand key elements guiding the fate of satellite cells.
REFERENCES
University of California, Davis
To the Editor: While the role of satellite cells in muscle regeneration is well established and accepted, the role of satellite cells in hypertrophy of adult skeletal muscle is less clear and widely debated as demonstrated by the recent Point:Counterpoint (4, 5). To clearly demonstrate that myonuclei addition is required to induce hypertrophy in adult muscle, we must develop better techniques to eliminate satellite cells in postnatal muscles. To date, the best demonstration that myonuclei are added to growing muscle fibers is the synergist ablation model; however, the timing of the myonuclei addition is unknown since myonuclei counts have usually been done at later time points such as 3 mo (1, 2). Furthermore, synergist ablation is an extreme model of chronic loading where fiber growth can exceed 2.5-fold (2). Myonuclei addition during hypertrophy induced by more modest resistance loading that does not cause muscle injury has not been clearly demonstrated. In the synergist ablation model, significant growth occurs within the first 2 wk, and it is likely that this growth is not related to the addition of myonuclei, but rather to increases in translation efficiency (3). While gamma-irradiation prevents overall muscle growth following synergist ablation, it does not completely suppress growth in the early phase (1). Furthermore, gamma-irradiation may interfere with the initiation of protein translation through the suppression of S6K1 and 4EBP1 activation (1). The role of satellite cells in muscle hypertrophy will only be settled with the development of better techniques to manipulate satellite cell proliferation and differentiation.
REFERENCES
University of Minnesota
To the Editor: Whether satellite cell addition is obligatory for hypertrophy of skeletal muscle appears to have a temporal condition, as stated in the Point (5). The early or acute hypertrophic responses will be the focus of this letter. Acute responses to a hypertrophic stimulus such as enhanced transcriptional activities are initially governed by myonuclei, not satellite cells, and data from stretch-overload models indicate that acute responses can lead to considerable hypertrophy (1, 2). For example, muscle masses and protein contents doubled in response to 7 days of stretch overload in gamma-irradiated quails, illustrating the potential of myonuclei to regulate a significant amount of hypertrophy. This robust, acute hypertrophy in the absence of proliferating satellite cells supports the Counterpoint (4). Another advantage of the stretch-overload model, in addition to being a strong stimulus for hypertrophy, is that it is noninvasive and does not involve an inflammatory reaction, thus allowing for the analysis of acute hypertrophic responses without confounding factors such as edema and immune cell infiltration. It is not clear why acute hypertrophic responses, particularly large ones as in the example provided, should be dismissed (5; Rebuttal). Biological cells are not usually designed to operate "on the edge." Accordingly, it seems unlikely that fibers are designed on the brink of their myonuclear domain ceiling and as such some degree of hypertrophy should be expected without satellite cell addition. In certain situations this ceiling is low (3), whereas in others the ceiling is high and the amount of hypertrophy is quite significant (2).
REFERENCES
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