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Effects of High-Intensity Resistance Training on Untrained Older Men. II. Muscle Fiber Characteristics and Nucleo-Cytoplasmic Relationships

^a Departments of Biomedical Sciences, College of Osteopathic Medicine
^b Biological Sciences, Ohio University, Athens, Ohio

Robert S. Hikida, Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, OH 45701 E-mail: hikida{at}ohiou.edu.

Decision Editor: Jay Roberts, PhD

	Abstract

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During growth and repair of skeletal muscle fibers, satellite cells become activated, undergo mitosis, and a daughter nucleus becomes incorporated into the muscle fiber to increase myonuclear numbers. An increase in myonuclei appears to be required for this postnatal growth. This study examined whether muscle fibers of elderly men can hypertrophy with strength training and, if so, whether they have the capacity to incorporate nuclei into the fibers. The sarcoplasmic area associated with each myonucleus was calculated in nine elderly men before and after 16 weeks of strength training, and compared to nine elderly control men. Muscle fiber type changes and myosin heavy chain composition were also compared. All major fiber types (I, IIA, IIB) became significantly larger after training, and a transition of type IIB fibers to IIA occurred with training. The area occupied by each fiber type correlated with myosin heavy chain percentage, and both of these changed similarly with strength training. The cytoplasm-to-myonucleus ratio increased, but not significantly ( ), with muscle fiber hypertrophy. Number of myonuclei per fiber and myonuclei per unit length of muscle fiber increased, but not significantly. Cross-sectional areas of the muscle fibers in untrained elderly men were much smaller than in untrained young men (when compared with our earlier studies). Training increased the sizes of the elderly muscle fibers to that of the untrained young men. This hypertrophy of muscle fibers by 30% with training resulted in no change in the cytoplasm-to-myonucleus ratio. This suggests that the myonuclear population continues to adapt to growth stimuli in the elderly muscles.

UNLIKE most types of cells, skeletal muscle fibers are multinucleated, having developed by a fusion of many mononucleated cells. Once fused, these myonuclei become post-mitotic (incapable of undergoing further mitosis). Recent studies suggest that the myonucleus exerts an influence over the structural proteins in a limited area (domain) surrounding it ⁽¹⁾. Therefore, a skeletal muscle fiber consists of a mosaic of overlapping nuclear domains ⁽²⁾.

Satellite cells are undifferentiated myogenic cells that lie under the basal lamina of the skeletal muscle fiber. Activation of these satellite cells results in their incorporation into the muscle fibers as new myonuclei ⁽³⁾. If satellite cell proliferation is inhibited, muscle fiber growth or recovery from atrophy is inhibited ⁽⁴⁾. This suggests that (a) addition of nuclei from satellite cell activation is required for growth, and (b) each myonucleus may have a finite limit to the amount or volume of fiber with which it is associated. Thus, growth of the fiber does not appear to occur without addition of more nuclei ⁽⁴⁾⁽⁵⁾.

The role of satellite cells in hypertrophy as related to aging or the aged muscle has not been investigated. Although very few studies have been conducted, it is commonly thought that satellite cells decrease with age ⁽⁶⁾⁽⁷⁾, and this reduction may contribute to the atrophy of muscle fibers in elderly people. However, it has recently been shown that no difference in satellite cell numbers occurs between young and elderly muscle fibers ⁽⁸⁾. The skeletal muscles of elderly individuals are generally smaller than those of younger human subjects. This has been attributed to both muscle fiber atrophy and hypoplasia (fewer muscle fibers). The reason for these changes with age has not been fully investigated. Reduced activity and reduction in alpha motoneuron number may also contribute to altering the size of skeletal muscles in elderly individuals.

We have recently shown that the nucleo-cytoplasmic ratio remains constant in muscles of rats that have undergone significant atrophy from 10 days of weightlessness in space ⁽⁹⁾. The number of nuclei was reduced in proportion to the atrophy of the soleus muscle. A study published at the same time ⁽¹⁰⁾ showed similar results after 14 days of space flight. In contrast, the opposite results were seen after 5 days of space flight, in which nuclear proliferation occurred in fast muscles of juvenile rats ⁽¹¹⁾. Rapid growth may have influenced the results of this latter study.

Both hypertrophy associated with increased myonuclei ^(12)(13)(14) and atrophy, resulting in fewer myonuclei ^(9)(15)(16), have suggested that changes of muscle fiber size are closely related to myonuclear number. To determine whether this relationship exists in aging muscle, this study examined the changes in nucleo-cytoplasmic relationships in the vastus lateralis muscle of elderly men after resistance training. The comparison of myonuclear numbers to cross-sectional area would indicate whether myonuclear proliferation is associated with greater cytoplasmic volume. A preliminary report of these results was presented in abstract form at the American College of Sports Medicine meetings ⁽¹⁷⁾.

	Materials and Methods

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Many of the methodological details are presented in the accompanying article [Hagerman et al. ⁽¹⁸⁾], and those procedures will be only briefly summarized here. Following approval by the Ohio University Institutional Review Board, a general description of the study and of the procedures was distributed by electronic mail throughout the university and community. An open meeting was held to discuss in detail the research and procedures, after which those still interested were asked to complete a health history questionnaire. A thorough medical examination was then administered to each potential subject as a means of screening those who might be eligible for this study. Men between the ages of 58 and 78 participated in this study. Twenty-two were randomly placed into either a control ⁽¹⁰⁾ or training ⁽¹²⁾ group after signing the informed consent. Three training and one control subject did not complete the study because of injury or aggravating prior medical conditions. The nine remaining subjects in the control group had a mean age of 66.2 ± 6.5, height 178.5 ± 5.8 cm, and weight 80.2 ± 4.51 kg. The nine remaining men in the training group were 63.7 ± 5.0 years old, 178.2 ± 8.5 cm tall, and 83.6 ± 7.6 kg weight. Percutaneous muscle biopsies were taken from the vastus lateralis muscle before and after 16 weeks of resistance training. A small portion of the sample was prepared for electron microscopy, and the remainder was frozen for subsequent immunohistochemical, histochemical, and electrophoretic analysis.

Training consisted of three lower limb exercises: knee extension, double leg press, and half squat. Each bout was performed slowly (4–6 s) with approximately 2 min rest between sets and exercises. The subjects trained twice weekly for 16 weeks. Every workout began and ended with 5–10 min of stretching and low-intensity warmup on either a rowing or cycle ergometer. Each specific lower-limb exercise was preceded with a warmup set (10 repetitions of 50% of the subject's workout load). Subsequently, the subjects performed three sets of 6–8 repetitions to failure for each set. Weights were increased as necessary to maintain the range of 6–8 repetitions per set. Maximal strength was determined at the beginning and end of the study. This was the maximal amount of weight the individual could lift once for each exercise ⁽¹⁸⁾.

The frozen portion of the biopsy sample was stored at -70°C until ready to be sectioned, when it was thawed to -20°C, cut in cross sections (12 µm thick), and placed onto cover glasses. The sections were prepared for either myofibrillar ATPase (mATPase) histochemistry ⁽¹⁹⁾ or prepared for immunohistochemistry using an anti-dystrophin monoclonal antibody [Mandys 8, Sigma Chemical Co., St. Louis, MO ⁽⁹⁾] or electrophoresis ^(19)(20).

The cross-sectional areas from selected regions of the dystrophin preparation and from the mATPase preparations were measured independently using the NIH Image 1.55 analysis program. At least 200 fibers were measured for each dystrophin preparation. Thereafter, each measured fiber was analyzed for its myonuclear content. From these data, the number of myonuclei per fiber, nuclei per mm of circumference, cross-sectional area per nucleus, and nuclei per mm of fiber length were calculated. The latter calculation was based on the formula by Schmalbruch and Hellhammer ⁽²¹⁾: , in which X is the number of nuclei per fiber segment, N is the number of myonuclei per cross section of the fiber, L is the segment length, l is the mean length of a myonucleus (measured to be 11.8 µm), and d is the thickness of the section.

Six muscle fiber types (I, IC, IIC, IIA, IIAB, IIB) were distinguished using routine myofibrillar mATPase histochemistry after preincubation pH values of 4.3, 4.6, and 10.2 ^(19)(22). Cross sections of pre- and post-training muscle samples from each individual were placed on the same coverslip so they could be assayed simultaneously for mATPase activity. Type I fibers were stable in the acid ranges but labile in the alkaline. Type IIA fibers displayed a reverse pattern. All fibers stable at pH 4.6 and 10.4, but labile at pH 4.3 were classified as either type IIB or IIAB depending upon their staining intensity following preincubation at pH 4.6 (the type IIAB fibers stained intermediate between IIB and IIA fibers). Fibers classified as type IC or IIC remained stable (to varying degrees) throughout the pH range. The cross-sectional areas were determined for each major fiber type (I, IIA, IIB) by measuring at least 50 fibers per type using the NIH Image program. Subsequently, the percentage fiber type area was determined by condensing the six fiber types into the major types (I, IIA, IIB) using the following formulas: ++++. This was necessary to compare the percentage of the total area occupied by the major fiber types and the percentage myosin heavy chain content.

For each biopsy sample, four to six serial cross sections (12 µm thick) were lysed for 10 min at 60°C in 0.5 ml of a medium containing 10% (w/v) glycerol, 5% (v/v) 2-mercaptoethanol, and 2.3% (w/v) sodium dodecylsulfate (SDS) in 62.5 mM Tris-HCl buffer (pH 6.8). The extracts were subsequently loaded for electrophoresis on 4–8% gradient SDS-polyacrylamide gels with 4% stacking gels, run overnight (17–19 h) at 120V, and stained with Coomassie Blue. The myosin heavy chain (MHC) isoforms were identified according to their apparent molecular masses compared with those of marker proteins, and migration patterns from single fiber analysis. Gels were scanned to determine the MHC content.

Fiber type percentages were log transformed and then analyzed. A mixed analysis of variance (ANOVA) with a repeated measure (pre- versus post-training) and one between-groups (training vs control) was used to analyze all results. Several of the data sets were not normally distributed, so the difference between the pre- and post-training results were compared between control and trained groups and tested by a t test or Mann-Whitney rank order test. SuperAnova version 1.1, InStat 2.0, and SigmaStat 2.03 were used for analysis. Significance was established as p < .05.

	Results

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Myonucleus to cytoplasm relationship
Light microscopic analyses of the biopsy samples showed no structural abnormalities in any of the individuals (Fig. 1). The cross-sectional areas of the dystrophin preparations (irrespective of fiber types) of the pretraining muscle fibers were no different between the nine training and nine control subjects (Table 1 ). After 16 weeks of high-intensity resistance training, the muscle fibers were 30% larger compared to the nontrained control men, whose muscle fibers had not changed from their first pretraining biopsies (Table 1 ).

View larger version (87K): [in this window] [in a new window]   Figure 1. Cross section of the vastus lateralis of an untrained elderly man, reacted against the dystrophin antibody, and counterstained with hematoxylin. The membrane is outlined in each fiber by the immunoperoxidase staining for dystrophin, and the nuclei are stained by the hematoxylin. .

The values for cross-sectional area/nucleus, which takes the increased fiber sizes into account, were unchanged between the control and trained subjects. The control group had a large mean difference between the first and second biopsies, but had much variation between subjects. The two-way repeated measures ANOVA showed no significant difference for group ( ), time ( ), or interaction ( ). Because the standard deviation of the control and training groups differed, the nonparametric Mann-Whitney U-test was used to compare post/pre differences between controls and trained groups to corroborate the ANOVA results. This nonparametric test indicated no significant difference between the control and trained groups, although there was a tendency for these to be different ( ), as suggested by the interaction between Group and Time in the ANOVA described above.

Strength gains
These are discussed in detail in the accompanying article ⁽¹⁸⁾. The three training regimens designed to strengthen the vastus lateralis muscle of the quadriceps femoris group produced the following significant increases in strength: leg extension, 50.4%; leg press, 72.3%; half squat, 83.5% in the trained group. The mean strength of the control group did not change.

Fiber type percentages
Analysis of fiber type percentage changes was done only on the major fiber types (I, IIA, IIB, and IIAB) because the minor fiber types usually made up less than 1% of the fiber population. The biopsies of the control group did not change in the proportion of fiber type percentages. In contrast, the percentage of type IIB fibers was significantly decreased with resistance training, and type IIA fibers were correspondingly increased (Table 2 ). Training did not influence the percentages of type I and IIAB fibers.

View larger version (122K): [in this window] [in a new window]   Figure 2. Serial cross sections of muscle samples taken from a control subject at the beginning (a, b, c) and end (d, e, f) of the study, and a strength-trained subject at the beginning (g, h, i) and after 16 weeks of high-intensity training ( j, k, l). Sections were assayed for mATPase activity after preincubation at pH values of 10.4 (a, d, g, j), 4.3 (b, e, h, k), and 4.6 (c, f, i, l). I, type I; IC, type IC; IIC, type IIC; IIA, type IIA; IIAB, type IIAB; IIB, type IIB. .

View larger version (17K): [in this window] [in a new window]   Figure 3. Myosin heavy chain (MHC) analysis of biopsies obtained from a control (C) and a training (T) subject at the beginning (pre) and end (post) of the study. Note the decrease in the band corresponding to MHCIIb from pre to post for the training subject. MHCIIb, myosin heavy chain IIb; MHCIIa, myosin heavy chain IIa; MHCI, myosin heavy chain I.

	Discussion

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Muscle weakness associated with aging begins in the 20s and 30s, and declines progressively ^(23)(24). By the 80s, strength of the upper extremity is 50–70% of that at age 20. This weakness is brought about by many factors, including atrophy, decrease in number of fibers ⁽²³⁾, and loss of motor units ⁽²⁵⁾, especially beginning at age 60 ⁽²⁶⁾. This study investigated whether the nucleo-cytoplasmic relationship is influenced by aging, and whether strength training would alter this relationship by causing muscle fiber hypertrophy.

As demonstrated in other studies, this study has shown that high-intensity resistance training induces an increase in muscle fiber size as well as the strength gains. As with younger men or women, heavy resistance training induces a transformation from a type IIB to IIA ⁽²⁷⁾. In the training studies of elderly subjects, relatively few have incorporated muscle biopsy procedures for analyzing muscular changes. Because of this, fiber type changes have not been commonly reported. In addition, prior studies incorporating muscle biopsies have usually been of short duration ⁽²⁸⁾ or low intensity ⁽²⁹⁾. The training intensity of the current study was 80–85% of maximum, which may have caused a greater fiber hypertrophy than other studies have reported ⁽³⁰⁾. Therefore, hypertrophy of type I (45%), IIA (34%), and IIB (52%) fibers is greater than what has been observed in many prior studies. Cross-sectional areas increase by about 30% after 12–15 weeks of training ^(30)(31), and type II fibers may take longer to respond than the type I fibers ⁽³¹⁾. However, our prior studies have shown a significant hypertrophy in muscles of young women as early as 6 weeks after beginning resistance training ⁽³²⁾. Much of the early increase in strength may be due to neural adaptation ⁽³³⁾. However, previous work from our laboratory ⁽²⁷⁾ indicated that significant muscular adaptations are also taking place during the early phase of training. For example, a significant decrease in percentage of type IIB fibers occurred after only 2 weeks of training in the young women. However, changes in cross-sectional area were gradual for both the men and women, amounting to approximately 19–24% for the type II fibers, and 11–16% for the type I after 8 weeks of training. The elderly men in this study had sufficient time for the muscular adaptation, although strength continued to increase, even at the end of the study [data not shown; ⁽¹⁸⁾].

On the basis of hypertrophy of the trained muscle fibers, it is clear that resistance training can slow or partially reverse the process of aging atrophy of skeletal muscles. Untrained college-age young men have fiber sizes of 5,033 ± 1741 (type I), 6573 ± 2063 (type IIA), and 5399 ± 1957 µm² (type IIB) ⁽²⁷⁾. Training for 9 weeks increased their mean size to 5474 ± 1167, 7800 ± 1478, and 6457 ± 1458 µm², respectively ⁽²⁷⁾. The elderly men in this study had fiber sizes from 3400 to 4000 µm² prior to training, and training increased the fiber sizes to that of untrained young men (approximately 5500 µm² for all fiber types). Significant hypertrophy of elderly muscles with training did not affect the fiber types preferentially. This uniform effect would be expected if the muscles are performing very heavy resistance work, which would also transform type IIB fibers to IIA ⁽²⁷⁾.

Elderly men who trained by running, swimming, or resistance work were compared to sedentary young and elderly men in a cross-sectional study ⁽³⁴⁾. Muscle biopsies of the vastus lateralis and biceps brachii were analyzed for their fiber types (histochemically and immunohistochemically) and their myosin heavy chains. The percentages of fiber types of the vastus lateralis were similar to the present study. In addition, the type I and IIA fiber sizes were similar in the two studies, both in control and strength-trained subjects. These results suggest that 16 weeks of training (the present study) produced similar fiber compositions and sizes to vastus lateralis muscles of elderly men training for 12 to 17 years.

The presence of the different myosin heavy chain isoforms in the biopsy samples matches the fiber type percentages. Because human muscle fiber types form a continuum ⁽³⁵⁾, this range of types is reflected in alterations of the myosin heavy chain isoforms in the fibers due to changes in muscular activity ⁽³⁶⁾. Therefore, as training occurs, more MHC IIa is formed in the former type IIB fibers, converting this first to type IIAB, and ultimately to type IIA as the percentage of the "new" MHC IIa increases to become the sole form. In the Klitgaard and associates study ⁽³⁴⁾, type IIB fibers of the elderly strength-trained men were largest and made up a significant percentage (13%) of the biopsy, but the IIb myosin heavy chain composition made up only 6% of the total. The type IIAB fiber population was not identified in that study, but many fibers identified as IIB may have been IIAB, as suggested in the discussion of that study.

No prior studies have examined muscle fiber subtypes in elderly subjects with training. Generally, the longer or more intense the training, the more complete the transformation of type IIB to IIA, eventually resulting in almost no type IIB fibers. If this indicates that the type II population is easily transformed between IIA and IIB with activity, then we would expect to see a larger percentage of type IIB fibers in the individuals that are inactive. The control elderly men had approximately 17% type IIB fibers, which corresponds well with the 16% IIB percentages in young untrained men ⁽²⁷⁾. This suggests that the elderly subjects in this study were as active as control young men.

Nucleo-cytoplasmic relationships
The concept of the nuclear domain suggests that a nucleus controls a finite portion of the sarcoplasm, and that the muscle fiber is a mosaic of overlapping nuclear domains. A consideration of this concept leads to several questions: (a) do myonuclei, which are postmitotic, have finite domains? Can the myonuclei accommodate an unlimited increase in muscle fiber hypertrophy, or do more (satellite cell) nuclei have to be incorporated into the muscle fiber to accommodate the hypertrophy? (b) Does the ability to enlarge or to incorporate nuclei become reduced with age? (c) Does the nucleo-cytoplasmic relationship change with age, and does this relationship change with strength training between young and elderly muscles?

Some of these questions cannot be answered because the relationships have not yet been studied in young people; however, we recently found that satellite cells make up the same percentage in elderly and young muscles, and the elderly subjects have the same amount of sarcoplasm associated with each myonucleus ⁽⁸⁾.

Muscle fiber size and the nucleo-cytoplasmic relationship
When feline muscles undergo hypertrophy, the nuclear numbers increase ⁽¹²⁾, again indicating a finite limit to the sarcoplasmic area a nucleus can control. Although our studies ⁽⁹⁾ and those of Allen and colleagues ^(10)(12) have shown a decreased number of myonuclei with atrophy induced by either space flight ⁽¹⁰⁾ or disuse ⁽¹²⁾, Kasper and Xun ⁽¹¹⁾ have shown just the opposite, in that space flight caused the expected fiber atrophy but the nuclear numbers increased. However, their sample sizes were quite small (3 or 6 fibers each for control, suspended, or space animals); the animals were rapidly growing juveniles; and it was not clear whether satellite cells and fibroblasts were excluded from counts of the myonuclei.

A recent abstract ⁽³⁷⁾ has shown that skeletal muscle fibers of very old (36 months) rats induced to undergo compensatory hypertrophy by synergist ablation fail to enlarge. What this may suggest is that the myonuclei were already at their maximum sarcoplasmic capacity, and satellite cells could not be activated to increase myonuclei. This combination of factors would prevent the hypertrophy.

This study considers whether the nucleo-cytoplasmic relationship changes in elderly people. In spite of the muscle fibers of the training group hypertrophying by 30%, the cytoplasm per nucleus ratio did not change significantly. Both number of myonuclei per cross section and number of nuclei per mm of fiber length increased, but not significantly. These results suggest that elderly muscle fibers can maintain the nucleo-cytoplasmic ratio to accommodate the hypertrophy induced by training. However, the results are confounded by the variability seen in the untrained control group.

The hypothesis tested in this study was that trained and control groups had a similar area/nucleus ratio, even after the trained group's muscle fibers hypertrophied. The control group tended to have a reduced area/nucleus with time. If this ratio is valid, it can be altered in this way if muscle fibers atrophy, if myonuclei proliferate, or if a combination of these factors occurs. Similarly, the trained group had a slightly larger area/myonucleus ratio. Because hypertrophy had occurred, this larger ratio suggests that the myonuclei lag slightly behind the increased fiber size in maintaining a constant ratio.

This study could possibly have missed a true change in some of the parameters, which a larger sample size would have demonstrated. Therefore, although no significant difference was indicated by the statistical analysis, there was a tendency for the muscle area per myonucleus or myonuclear number per fiber to increase in the trained group. For example, the area per myonucleus decreased nonsignificantly by 17% in the control group, whereas it increased by 8% in the training group. However, the Time by Group interaction (which compares changes between groups) was not significant. Because so much variability occurred in the elderly muscles, and especially in the control group, our results must be qualified.

The fiber type may affect the nucleo-cytoplasmic relationship in muscles from sedentary subjects because the amount of activity (metabolism) of the fiber influences the size of the nuclear domains ⁽³⁸⁾. Fiber type-specific changes in nucleo-cytoplasmic relationships were not studied here, but another study ⁽⁸⁾ suggested that any fiber type differences in this relationship in control subjects were lost with strength training. This indicates that muscle fiber size is a greater determinant in myonuclear composition than fiber type. This relationship has been supported by a recent study by Kadi and colleagues ⁽³⁹⁾, who compared trapezius muscles of power lifters with control men. The mean number of myonuclei increased linearly with the mean cross-sectional area. That study found the number of myonuclei to be higher in type II fibers than type I, but this was related to the larger size of the type II fibers.

Other factors affecting the nucleo-cytoplasmic relationship
The content of mitochondria and myonuclear number is highly correlated ⁽³⁸⁾. Therefore, fiber types have different domain sizes, depending upon oxidative activity. In humans, mitochondrial content is highest in type I fibers and lowest in IIB fibers ⁽⁴⁰⁾. The activity levels of human subjects create large overlaps between groups of subjects to the extent that IIB fibers of runners have a higher mitochondrial content than IIA fibers of sedentary subjects ⁽⁴¹⁾.

Oxygen consumption and mitochondrial volume of skeletal muscle in different species of mammals generally vary with body mass. The smallest mammals have the highest mitochondrial content and oxygen consumption ^(42)(43). Because of this, one would expect myonuclear numbers to be lower in human muscles than in the other animals that have been studied, and this is the case. In addition, because of the reduced oxidative activity of humans relative to lower mammals, muscle fiber type differences do not involve as large a difference in oxidative activity as in lower mammals. Finally, strength training affects type II fibers most strongly, and an increase in oxidative activity of this fiber type would bring this activity closer to the levels of the type I fibers. The range of activities engaged in by humans compared to caged animals creates more variability in the fiber type and myonuclear relationship. In fact, our studies indicate that young college-age males have more myonuclei in type II fibers than type I, but strength training tends to diminish this difference ⁽⁹⁾.

Conclusions
On the basis of the few studies completed on lower mammals and the present study, the aging process does not appear to affect the normal myonuclear turnover (if this occurs) and increase of myonuclear numbers in skeletal muscle fibers. The nucleo-cytoplasmic relationship appears to be less tightly controlled in the sedentary elderly than in sedentary young muscle fibers, as suggested by the large variability seen in untrained elderly men. The results of this study suggest that the cytoplasm to myonucleus ratio is maintained in elderly muscles even with significant muscular hypertrophy induced by resistance training. Comparison of young and elderly muscle fibers shows that fibers from sedentary elderly men are much smaller than fibers from sedentary young men, and training increases fiber size to that of sedentary young muscles. Whether there are limits to the hypertrophy or increase in number of myonuclei that can occur in the elderly muscles can not be answered at this time.

Received August 24, 1998

Accepted December 30, 1999

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