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Early-Phase Satellite Cell and Myonuclear Domain Adaptations to Slow-Speed vs. Traditional Resistance Training Programs

Herman-Montemayor, Jennifer R.1; Hikida, Robert S.2; Staron, Robert S.2

The Journal of Strength & Conditioning Research: November 2015 - Volume 29 - Issue 11 - p 3105–3114
doi: 10.1519/JSC.0000000000000925
Original Research

Herman-Montemayor, JR, Hikida, RS, and Staron, RS. Early-phase satellite cell and myonuclear domain adaptations to slow-speed vs. traditional resistance training programs. J Strength Cond Res 29(11): 3105–3114, 2015—The purpose of this investigation was to identify adaptations in satellite cell (SC) content and myonuclear domain (MND) after 6-week slow-speed vs. “normal-speed” resistance training programs. Thirty-four untrained females were divided into slow speed (SS), traditional strength (TS), traditional muscular endurance (TE), and nontraining control (C) groups. Three sets each of leg press, squat, and knee extension were performed 2 days per week for the first week and 3 days per week for the following 5 weeks. The SS group performed 6–10 repetition maximum (6–10RM) for each set with 10-second concentric (con) and 4-second eccentric (ecc) contractions for each repetition. Traditional strength and TE performed 6–10RM and 20–30RM, respectively, at “normal” speed (1–2 seconds per con and ecc contractions). Traditional muscular endurance and SS trained at the same intensity (40–60% 1RM), whereas TS trained at 80–85% 1RM. Pretraining and posttraining muscle biopsies were analyzed for fiber cross-sectional area, fiber type, SC content, myonuclear number, and MND. Satellite cell content of type I, IIA, IIAX, and IIX fibers significantly increased in TS. However, SC content of only type IIAX and IIX fibers increased in SS, and there was no change in TE or C. Myonuclear number did not change in any group. Myonuclear domain of type I, IIA, IIAX, and IIX fibers increased in TS, whereas MND of only type IIA fibers increased in SS, and there was no change in TE or C. In conclusion, slow-speed resistance training increased SC content and MND more than training with a similar resistance at normal speed. However, high-intensity normal-speed training produced the greatest degree of fiber adaptation for each variable.

1Department of Biomedical Sciences, College of Osteopathic Medicine, Rocky Vista University, Parker, Colorado; and

2Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio

Address correspondence to Jennifer R. Herman-Montemayor, jmontemayor@rvu.edu.

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Introduction

Satellite cells (SCs) originate from myoblasts, which do not fuse with the myotube during development. These undifferentiated precursor cells (situated between the sarcolemma and basal lamina) were first identified by Mauro (23). They are stem cells with regard to their regenerative capacity but are termed “satellite” in reference to their distinct location relative to the myofiber. Although skeletal muscle fibers are terminally differentiated, growth and regeneration can occur through nuclei derived from SCs (6,11,26). Satellite cells are activated and proliferate to meet the muscle demands in response to growth, remodeling, or injury (11). Once activated, they undergo asymmetric divisions, producing unequal daughter cells that may differ not only in size but also in functional properties (18). For example, one may irreversibly exit the cell cycle by becoming a terminally differentiated myonucleus, whereas the other can return to quiescence.

Little attention has been given to the role of SCs during exercise-induced adaptations in human muscle (15). Most SCs are in the nonproliferative quiescent state in normal resting skeletal muscle. However, they can be activated by various stimuli linked to exercise (4,38,39). Several studies have shown an increase in the SC population after resistance training in young and old male and female subjects (17,18,21,31,35). Although additional research is needed to fully understand the various factors that may influence SC response, it is clear that exercise provides a sufficient stimulus for SC activation, proliferation, and possibly incorporation.

Satellite cell incorporation into the muscle fiber increases the number of myonuclei and hence has an impact on myonuclear domain (MND). Myonuclear domain is the volume of cytoplasm within the multinucleated skeletal muscle fiber that is regulated by gene products from 1 myonucleus (28). Of much interest is how MND size is affected when fiber size is altered. If MND size is to be maintained during hypertrophy, then myonuclear number must increase accordingly. However, research in this area has yielded equivocal results. Myonuclear domain has been shown to be maintained in young men after 8 weeks of resistance training targeting the quadriceps femoris muscle group (12). In that study, a 25% increase in fiber size was associated with a nonsignificant increase in myonuclear number and no change in MND. In contrast, Kadi et al. reported a 17% increase in fiber cross-sectional area (CSA) of the quadriceps muscle group of young men after 3 months of resistance training, with a significant increase in MND and no change in myonuclear number (17). Similarly, results reported after 16 weeks of strength training caused an increase in fiber size in both young (∼21%) and older (∼27%) women (32). Based on studies such as these, a “ceiling” for MND has been proposed, above which the addition of more myonuclei is required (17). Existing myonuclei are not usually operating at maximal capacity at baseline and have the ability to increase protein synthesis and cytoplasmic volume up to some threshold (17). O'Connor et al. have suggested that muscle hypertrophy consists of several phases in which early upregulation of transcription and translation in existing myonuclei is then followed by SC activation, proliferation, and potential incorporation (29).

The purpose of this investigation was to evaluate adaptations in skeletal muscle SC content, myonuclear number, and MND in response to 3 different resistance training protocols. Because our initial work analyzing the response to these different training protocols showed different degrees of adaptation in strength gains, fiber CSA, and fiber type transitions (34,37), it was hypothesized that there would likewise be different degrees of adaption in SC content, myonuclear number, and MND. To our knowledge, this is the first investigation of the effects of slow-vs. normal-speed strength training of varying intensities on SC content, myonuclear number, and MND, as well as fiber type–specific changes (including fast fiber subtypes).

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Methods

Experimental Approach to the Problem

The first 2 weeks of the study involved familiarization with the training protocol, pretraining testing, anthropometric measures, and muscle biopsies. The resistance training sessions were conducted during weeks 3–8 of the study. The first week of training consisted of 2 training sessions, followed by 5 weeks of 3 sessions per week (6 weeks, 17 sessions). Each training session consisted of 3 sets of 3 exercises targeting the quadriceps muscle group: leg press, squat, and knee extension. The traditional strength (TS) group performed 1–2 seconds of concentric/eccentric (1–2 seconds con/ecc) contractions for 6–10 repetitions to failure (6–10RM). The traditional muscular endurance (TE) group performed 1–2 seconds of con/ecc contractions for 20–30RM. The slow speed (SS) group performed 10-second con/4-second ecc contractions for 6–10RM. The TS group trained at ∼80–85% 1RM, and the SS and TE groups trained at a similar work intensity (∼40–60% 1RM), which varied depending on the exercise. Resistance was progressively increased throughout the study to maintain the proper range of repetitions per set for each group. The final 2 weeks of the study (weeks 9 and 10) consisted of posttraining data collection, including strength measures and muscle biopsies. All groups performed the same tests in the same order and with each test accomplished over a 1- to 3-day period. Body composition, V[Combining Dot Above]O2max, and muscular power were determined during the first week after training, and muscular strength and endurance were determined (and after biopsies taken) during the second week. Strength and endurance measurements as well as muscle fiber type data (CSA, fiber type composition, myosin heavy chain content) have been previously reported ((34,37), respectively).

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Subjects

Thirty-four healthy untrained women (21.1 ± 2.7 years, age range 18–30 years) volunteered to participate in this 10-week study, approved by the Ohio University Institutional Review Board. All subjects provided written acknowledgment that they had been informed of risks and procedures. Medical history forms were completed, and physical examinations performed for each subject, including a thorough musculoskeletal screening to ensure that there were no contraindications to the exercise program. The subjects were all previously untrained and had not been involved in any regular exercise program for at least 6 months. The subjects were randomly assigned into 1 of 4 groups: nontraining control (C, n = 8) (age: 22.9 ± 2.4 years, height: 163.6 ± 4.5 cm), TS (n = 9) (20.6 ± 1.9 years, 165.6 ± 4.9 cm), TE (n = 7) (22.3 ± 3.9 years, 161.9 ± 8.3 cm), and SS (n = 10) (19.4 ± 1.3 years, 168.0 ± 4.2 cm). The training and methods have been described earlier (34,37), but portions are summarized here.

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Muscle Biopsies

Of the 34 subjects, 31 successfully donated both prebiopsy and postbiopsy samples (C, n = 7; TS, n = 9; SS, n = 9; TE, n = 6). All muscle biopsies (∼80 to 160 mg) were extracted from the superficial region of the vastus lateralis muscle using the percutaneous needle muscle biopsy technique (3). Specimens were embedded in mounting medium, frozen in methyl butane in liquid nitrogen, and stored at −80° C. Biopsy samples were thawed to −24° C, and serial cross-sections of either 12 or 6 μm thickness were cut using a cryostat microtome. Immunohistochemical analyses (Myosin Heavy Chain [MHC] and neural cell adhesion molecule [NCAM] immunohistochemical assays) were performed on 6-μm thick samples, which were placed on poly-L-lysine–coated cover slips, and mATPase histochemistry was performed on 12-μm thick sections placed on uncoated glass cover slips. Cross-sections of pretraining and posttraining biopsies from the same subject were placed on the same cover slip and stored at −40° C until further analyses were performed. Descriptions of the mATPase histochemistry, myosin immunohistochemistry, fiber CSA measurement procedures, and fiber type descriptions have been described previously (37).

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Satellite Cells and Myonuclei

Satellite cells were identified by immunohistochemical analysis using the mouse IgG monoclonal antibody against the CD56 (catalog no. 347740, Becton-Dickinson Biosciences, San Jose, CA, USA) cell surface marker (14,16,36). Anti-CD56 (also termed anti-NCAM) binds the antigen NCAM, which is expressed on SCs in human skeletal muscle. The VECTASTAIN Elite ABC kit (PK-6102; Vector Laboratories, Burlingame, CA, USA) and the DAB substrate kit for peroxidase (SK-4100; Vector Laboratories, Burlingame, CA, USA) were used for the labeling of SCs. The general instructions for the ABC kit were followed. Thereafter, sections were briefly fixed with paraformaldehyde, rinsed, and lightly stained with hematoxylin. Satellite cells and myonuclei were identified at high magnification: SCs appeared brown or as a nucleus with a brown rim, whereas myonuclei stained blue or bluish-purple (Figure 1). A mean of 291 ± 18 fibers per biopsy sample were examined for SC and myonuclear content. The following variables were assessed from cross-sections for each sample: relative percentage of SCs ([number of NCAM + cells]/[{NCAM + cells} + myonuclei] × 100), SC frequency (number of NCAM + cells per 100 fibers), and myonuclear number (mean number of nuclei associated with a fiber as viewed in cross-section) (14,16,17). These values were each calculated both as mean for specific fiber types (I, IIA, IAX, and IIX) and as general mean (independent of fiber type) to enable comparison with results from other investigations that did not report SC and myonuclear number data by fiber type.

Figure 1

Figure 1

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Myonuclear Domain

Myonuclear domain (mean fiber area per myonucleus, in square micrometer) was calculated based on the CSA and myonuclear number data for 291 ± 18 fibers per sample. The NIH Imaging software program (version 1.62) was used to obtain CSA measurements, and all area measures were made by 1 investigator. The total CSA of analyzed fibers was divided by the total number of myonuclei associated with those fibers. These values were each calculated both as mean for specific fiber types (I, IIA, IAX, and IIX) and as general mean (independent of fiber type).

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Statistical Analyses

The statistical package SigmaStat (version 2.03) was used for all analyses. Descriptive statistics were used to determine mean values and SD for all variables. Data are presented as mean ± SD, unless otherwise indicated. A 2-way analysis of variance (ANOVA) with repeated measures (2 × 4 design: 2 time points by 4 groups) was used to determine differences within group (pre-post) and between groups (C, TS, SS, and TE) for each variable. Tukey's honest significant difference (HSD) test was used for post hoc analysis where significant differences were detected for main effects. A one-way ANOVA followed by Tukey's HSD was used to assess differences in pretraining samples for MND, myonuclear number, relative percent SCs, and SC frequency. For all analyses, the significance level was set at p ≤ 0.05.

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Results

Satellite Cells, Myonuclei, and Myonuclear Domain

A total of 8,402 pretraining fibers and 7,911 posttraining fibers from 31 subjects (291 ± 18 fibers per biopsy sample) were analyzed for the relative percentage of satellite cells (%SC), satellite cell frequency (SC frequency), myonuclear number, and MND. There was no indication of fiber damage observed in any of the pretraining or posttraining biopsies. The results for each variable are reported as general group mean and mean per fiber type for each group.

At baseline (i.e., before training), SC frequency was greater in type I and IIA fibers than in type IIX fibers, and type IIA SC frequency was greater than type IIAX (Table 1). There was little variability in % SC between fiber types, except for a greater %SC in type IIA fibers compared with IIAX (Table 1). There were significant differences between fiber type in myonuclear number at baseline (Table 1). The myonuclear number of type IIX fibers was significantly less than that of type I, IIA, and IIAX fibers. The myonuclear number of type IIAX fibers was less than that of type I and IIA fibers. There was no significant difference in MND of fiber types I, IIA, IIAX, or IIX at baseline (Table 1).

Table 1

Table 1

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Satellite Cell Population

Both %SC and SC frequency increased after training in TS only (Table 2). For %SC, there was a significant main effect of group, training effect, and group by time interaction. Only TS had a significant increase in %SC after training. Significant between-group differences were found where posttraining %SC in TS exceeded that of each other group. A similar trend was observed for the effect of training on SC frequency (Table 2). There was a significant main effect of group, training effect, and group by time interaction. Post hoc testing isolated the significant differences to TS, which had increased SC frequency from pretraining values. Posttraining SC frequency in TS was significantly greater than each other group. When the effects of training on the SC population were focused by comparison of specific fiber types within each group, additional between-group differences became apparent (Table 3). In agreement with the trend observed in the general group data (Table 2), TS showed significant within-group training-induced increases in both %SC and SC frequency for each fiber type (Table 3). Significant between-group differences were also detected for both %SC and SC frequency variables within the posttraining time point. SC frequency was significantly greater for type I, IIA, IIAX, and IIX in TS than in each other group. Posttraining %SC for type I, IIA, and IIAX fibers exceeded each other group, and %SC for type IIX was greater than that of TE and C group (Table 3). Slow Speed also demonstrated training-induced adaptations within a subset of the fast fiber population (Table 3). Both %SC and SC frequency for type IIX and type IIAX fibers were increased in SS after training. For both %SC and SC frequency, the posttraining values associated with type IIAX fibers were greater in SS compared with C. There were no significant pretraining to posttraining differences observed for %SC or SC frequency of any fiber type for either TE or C (Table 3).

Table 2

Table 2

Table 3

Table 3

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Myonuclear Number

When a number of nuclei per muscle fiber cross-section was considered before and after training for each group, independent of fiber type, only a between-group difference within the pretraining time point was detected (Table 2). The myonuclear number in TS was less than C. There were no significant changes in myonuclear number from pretraining to posttraining for any group, but a nonsignificant trend toward increased myonuclear number in TS was noted.

There were also no significant within-group changes in myonuclear number between pretraining and posttraining values for any fiber type (Table 4). Significant between-fiber type differences in myonuclear number were found both within group and within time point. Significantly fewer nuclei were associated with type IIX fibers than type I and type IIA for each of the following: C, pre and post; SS, pre; TE, pre, and post (Table 4). The myonuclear number of type IIAX fibers showed a tendency to exceed that of type IIX fibers within the pretraining time point for both C (p = 0.051) and TS (p = 0.065).

Table 4

Table 4

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Myonuclear Domain

The results of training effect on mean MND for each training group are presented in Table 2. The overall MND, independent of fiber type, showed a significant training effect and group by time interaction. This training effect was due to the significant within-group increase in MND for TS only (Table 2 and Figure 2). No within-group changes in MND were noted after training for any other group. Significant between-group differences occurred within the posttraining time point. Traditional strength MND was greater than each other group. Results for mean fiber CSA data are also presented (Table 2 and Figure 2). Traditional strength and SS had significantly increased mean fiber CSA after training. There were no changes in TE or C.

Figure 2

Figure 2

A significant group by time interaction for each fiber type is shown in Table 4. This overall training effect was primarily driven by TS. Only TS had a significant posttraining increase in MND of each fiber type. A significant posttraining increase occurred in the MND of type IIA fibers. The posttraining MND of both type I and IIA fiber in TS exceeded those of C, and the MND of type I in TS was also significantly greater than that of TE and SS (Table 4). The maximum mean MND did not exceed 2,000 μm2 after training for any fiber type in any training group (range: 1,359 ± 78 to 1,981 ± 370 μm2). For comparison, detailed CSA results by fiber type (I, IIA, and IIX) have previously been published for these subjects (37). Briefly, TS had significant fiber hypertrophy of type I, IIA, and IIX fibers after training, and SS had significant fiber hypertrophy of type IIA and IIX fibers after training. There were no changes in fiber size of any fiber type in TE or C (37).

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Discussion

Limited information is available on specific fiber type differences in SC content, myonuclear number, and MND in humans, particularly for the fast fiber subtypes.

In this study, the more oxidative fibers (types I and IIA) had a greater SC frequency (NCAM+/100 fibers) compared with IIX fibers, and type IIA fibers had a greater %SC and SC frequency than type IIAX fibers. These findings differ from that of Kadi et al. who reported no difference in the number of SCs between types I and II fibers in human vastus lateralis muscle (16). Although both this study and that of Kadi et al. (16) used the same mAb against NCAM, Kadi et al. did not report the SC content of the fast fiber subtypes. Therefore, potential differences between fiber types may have been masked (16). Indeed, our findings support what has previously been described in small mammals (9,11). These data suggest that those fibers recruited first and used more frequently may be more likely to be injured and require a greater number of SCs to mediate repair of the damage (11,16,38).

Scant information is also available concerning fiber type–specific relationships of myonuclear number and MND in human muscle. Hikida et al. reported that type II fibers had significantly more myonuclei and a smaller MND than type I fibers in control human subjects (12). However, Ohira et al. analyzed single fiber fragments from pre-bed rest soleus muscle samples and reported no difference in fiber CSA, myonuclear number, or MND between fibers expressing MHCI, MHCI + IIa, or MHCIIa (30). In this study, we found a hierarchy in myonuclear number, which paralleled the differences in CSA by fiber type such that there was no difference in MND between fiber types.

Interestingly, in this study, heavy-load resistance training was found to induce a number of fiber type–specific changes in SC content and MND size. Compared with the other groups, the high-intensity training of TS induced the greatest increase in SC numbers. When specified by fiber type, the SC content increased in all fiber types (I, IIA, IIAX, and IIX) in TS and for only the fast subtypes IIAX and IIX in SS. Although there was a trend found for TS (p = 0.07), resistance training did not change the myonuclear number of any fiber type in any of the groups in this study. These results are similar to many other resistance training studies, which have also demonstrated SC activation and proliferation without incorporation into the muscle fiber myonuclear population (e.g., (5,7,14,31,32)).

Although the anti-NCAM labeling has made the identification of SCs possible using light microscopy (36), the state of SC activity cannot be determined. This is a limitation because NCAM labels all SC populations (quiescent, activated, proliferating, and differentiating) (20). Because of the complexity of SC activity, the heterogeneous nature of SC populations, and the limitations of assessment of alterations in SC activity, an observation of increased SC content without corresponding myonuclear incorporation raises questions concerning the role played by the increased SC pool in response to resistance training. Satellite cells may contribute to regenerating fibers, replicate to increase the size of the existing pool of available stem cells, or fuse with existing fibers to provide additional myonuclei (1). Thus, depending on the training protocol and individual responses, SCs can be activated and (a) not proliferate, (b) proliferate and then return to quiescence, or (c) proliferate, differentiate, and be incorporated as new myonuclei (15).

Although some studies have suggested SCs to be involved in fiber type transitions (22), others describe their role as more important for growth (19). The idea of a SC role in fiber type transition does not appear to be supported by our findings in that the TE group experienced similar alterations in fiber type composition as both SS and TS (decreased percent type IIX and increased percent type IIAX) (37), despite a lack of increase in SC content. Recent work indicates that SCs form at least 2 functional populations in mouse muscles: one for growth and the other for regeneration (27). However, both fiber hypertrophy and muscle regrowth after atrophy have been shown to occur in SC-depleted muscle fibers of the mouse after either hindlimb suspension or compensatory hypertrophy, and the number of myonuclei did not change with either hypertrophy or atrophy (13,25).

Although it is well established that SCs may serve as nuclear donors during fiber growth in the postmitotic adult muscle, the factors that directly impact whether myonuclear proliferation occurs in response to resistance training in humans have been somewhat unclear. Two factors appear to be critical for myonuclear proliferation: (a) MGF (mechano growth factor) has been proposed to be critical for SC activation and proliferation and (b) myogenin appears to have a role in driving proliferating SCs toward terminal differentiation (10). Both of these factors have been shown to be differentially upregulated in subjects who demonstrate extreme hypertrophy (XTR: 58%) compared with those experiencing modest (MOD: 28%) or no hypertrophy (NON) (2). Few other studies have examined the effects of resistance training on myonuclear number and MND in humans. Both young men (17) and young women (32) have shown a very similar response to that of TS in this study, with a significant increase in SC content, no change in myonuclear number, and an increase in MND due in conjunction with an increase in fiber CSA. On the contrary, some studies have shown MND to be maintained during hypertrophy in young men (12,32) and young women (18). Although there has been much debate as to whether adding myonuclei are required for hypertrophy (24,28,29), the findings of this study and others (17,32,33) suggest that fiber hypertrophy occurs before the incorporation of new myonuclei. In fact, significant hypertrophy can occur in mice that are lacking most of their SCs (25). However, there may be an MND “ceiling” beyond which additional nuclei are required to support further growth of the myofiber (17,29,32). For example, power lifters with very large fiber CSA (>7,000 μm2) have been shown to have an average MND size (1,300–1,500 μm2) (8). A “ceiling” of a relative increase in fiber size of ∼26 to 27% has been suggested (17,32) or an MND of ∼2,000 μm2 (32). As such, existing myonuclei may be able to accommodate moderate increases in cytoplasmic volume before requiring the addition of nuclei. The present findings support the assertion that myonuclear addition is not required before reaching the “ceiling.” In fact, as was evidenced by TS, a relative increase in fiber size of ∼39% and a 2,025 μm2 MND were observed in conjunction with only a nonsignificant trend to increase the myonuclear number.

In conclusion, high-intensity resistance training at a normal speed resulted in significant fiber type–specific adaptations (increased MND, SC content, and SC frequency) compared with low-intensity training at both normal speed and SS. The increased SC content concomitant with increased MND suggests a delay in SC incorporation into the muscle fiber until a critical size is reached (MND ceiling). Overall, these data extent and support previous findings from our laboratory (34,37). Although low-load training at SS appears to have some merit compared with low-load training at “normal” speed, high-intensity (80–85% 1RM) resistance training optimizes adaptations within the muscle for increasing size and strength (34,37).

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Practical Applications

Low-intensity resistance training has merit and is often used for specific populations (e.g., elderly) and rehabilitation. Both this study and previous work from our laboratory (34,37) have demonstrated that low-intensity training at SS appears to be more beneficial compared with low-intensity training at normal speed. However, a high-intensity resistance training protocol (∼85% 1RM) will yield the greatest overall adaptive response within the skeletal muscle fiber. Therefore, individuals who are seeking to optimize adaptations within the muscle for improvements in size and strength should focus on heavy-load high-intensity resistance training.

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Acknowledgments

We would like to thank all of the volunteers who participated in the study, both the subjects and those who supervised the training sessions. We would also like to recognize the following individuals for their contribution to the project: Roger M. Gilders, Fredrick C. Hagerman, Sharon R. Rana, and Kerry E. Ragg. The authors have no conflicts of interest to report.

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Keywords:

human skeletal muscle; fiber types; myonuclei; training speed; training intensity

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