Departments of 1 Geriatrics and 2 Anatomy, University of Arkansas for Medical Sciences, and 3 Central Arkansas Veterans Health Care System, Little Rock, Arkansas 72205
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ABSTRACT |
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We have shown that cycling exercise combined with fetal spinal cord transplantation restored muscle mass reduced as a result of complete transection of the spinal cord. In this study, mechanisms whereby this combined intervention increased the size of atrophied soleus and plantaris muscles were investigated. Rats were divided into five groups (n = 4, per group): control, nontransected; spinal cord transected at T10 for 8 wk (Tx); spinal cord transected for 8 wk and exercised for the last 4 wk (TxEx); spinal cord transected for 8 wk with transplantation of fetal spinal cord tissue into the lesion site 4 wk prior to death (TxTp); and spinal cord transected for 8 wk, exercised for the last 4 wk combined with transplantation 4 wk prior to death (TxExTp). Tx soleus and plantaris muscles were decreased in size compared with control. Exercise and transplantation alone did not restore muscle size in soleus, but exercise alone minimized atrophy in plantaris. However, the combination of exercise and transplantation resulted in a significant increase in muscle size in soleus and plantaris compared with transection alone. Furthermore, myofiber nuclear number of soleus was decreased by 40% in Tx and was not affected in TxEx or TxTp but was restored in TxExTp. A strong correlation (r = 0.85) between myofiber cross-sectional area and myofiber nuclear number was observed in soleus, but not in plantaris muscle, in which myonuclear number did not change with any of the experimental manipulations. 5'-Bromo-2'-deoxyuridine-positive nuclei inside the myofiber membrane were observed in TxExTp soleus muscles, indicating that satellite cells had divided and subsequently fused into myofibers, contributing to the increase in myonuclear number. The increase in satellite cell activity did not appear to be controlled by the insulin-like growth factors (IGF), as IGF-I and IGF-II mRNA abundance was decreased in Tx soleus and plantaris, and was not restored with the interventions. These results indicate that, following a relatively long postinjury interval, exercise and transplantation combined restore muscle size. Satellite cell fusion and restoration of myofiber nuclear number contributed to increased muscle size in the soleus, but not in plantaris, suggesting that cellular mechanisms regulating muscle size differ between muscles with different fiber type composition.
muscle atrophy; satellite cells; insulin-like growth factor; myonuclear number
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INTRODUCTION |
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SPINAL CORD INJURY (SCI) is associated with a pronounced loss of mass in muscles distal to the site of injury. Muscle weight and myofiber cross-sectional area (CSA) of muscles with different fiber types is decreased, but muscles composed of mainly type 1 fiber types, which serve as postural muscles, atrophy to the greatest extent (36, 44). Skeletal muscular atrophy is associated with a loss of myofiber nuclei whether the atrophy is induced by spinal cord isolation (6), spinal cord transection (22), space flight (8), hindlimb suspension (19), or denervation (50) (for review see Ref. 7). Most studies have focused on the soleus muscle, which is a slow postural muscle composed of 85-90% type 1 myosin heavy chain (MHC)-expressing myofibers and is very susceptible to disuse atrophy. There is some controversy as to whether myonuclear loss occurs in muscles of all fiber types, but at the very least it appears that myonuclear number during atrophy is more tightly regulated in type 1 compared with type 2 MHC-expressing myofibers (8). We and others have shown that the decrease in myofiber nuclear number upon an atrophy-inducing event occurs rapidly in soleus muscles (8, 22) and is associated with an increase in apoptotic nuclei (4, 22), suggesting that "nuclear death" is a likely mechanism by which myonuclear number decreases with atrophy. Although it is equivocal as to whether atrophy in the plantaris muscle (composed of mostly type 2 MHC-expressing muscle fibers) was correlated with a loss of myofiber nuclei, hypertrophy of this muscle, induced by functional overload, was associated with an increase in myofiber nuclei (6, 43). This is consistent with a number of studies showing that hypertrophy is associated with an increase in myonuclear number (6, 12, 34, 51). Some studies suggest that proliferation of satellite cells is necessary for hypertrophy to occur (40, 41), but others found that hypertrophy in avian muscle can occur without satellite cell proliferation (33). In a previous study, we investigated the involvement of satellite cells in the attenuation of atrophy by exercise initiated shortly after SCI. Results indicated that the decreased number of myonuclei in soleus muscle after SCI was not restored by exercise, even though there was a significant increase in muscle fiber CSA (22). This indicates that increases in myofiber size can be accomplished without addition of nuclei and that there is considerable plasticity in the nuclear domain of myofibers.
Both insulin-like growth factors (IGF-I and IGF-II) are involved in regulating satellite cell proliferation and differentiation (for review see Ref. 24). They are expressed following muscle damage or degeneration (30) and are required for muscle regeneration to occur, since neutralizing antibodies to IGFs inhibited this process (31, 32). In addition, IGF-I has been implicated in muscle fiber hypertrophy. It was shown that mRNA and protein levels of IGF-I increased under hypertrophic conditions (2, 9, 20). Moreover, overexpression of IGF-I was associated with myofiber hypertrophy in transgenic mice (17), and local infusion of IGF-I in adult animals resulted in skeletal muscle hypertrophy (3). In vitro, increased levels of IGF-I resulted in myotube hypertrophy following differentiation (38, 46, 49). However, the involvement of IGF-I in the attenuation of atrophy is controversial. A recent study showed that age-associated atrophy was reduced by overexpression of IGF-I (10); however, Criswell et al. (18) showed that atrophy induced by unloading was not prevented by overexpression of IGF-I in transgenic mice.
We have shown that muscular atrophy induced by SCI is ameliorated by two interventions: motor-assisted cycling exercise (to be called exercise) and fetal spinal cord transplantation into the lesion cavity (to be called transplantation) (21, 28, 36). If initiated shortly after SCI (5 days), exercise reduced atrophy in a number of hindlimb muscles of rats when measured after short, intermediate, and long intervals post-SCI (21, 28, 36). It has also been shown that step training on a treadmill reduced atrophy in spinal cord-injured cats (42, 44). The beneficial effects of exercise are mediated, at least in part, through reflex activity, as blocking neural activity with a conductance-blocking agent (tetrodotoxin) eliminated the beneficial effects of exercise (37). In addition, the effects of exercise are most beneficial to the soleus muscle, which is also the most severely affected by SCI (36, 44). Transplantation of fetal spinal cord tissue into the lesion site has been used as a means to replace damaged spinal cord tissue and to provide a substratum supportive of axonal regrowth (29), and there is evidence that hindlimb function can be restored following transplantation of fetal (35) or peripheral (14) neural tissue. Fetal tissue transplantation performed acutely was associated with a reduction in soleus muscle atrophy measured 90 days post-SCI (28). Thus both exercise and transplantation, initiated acutely after SCI, were successful in maintaining muscle mass and/or preventing atrophy of selected hindlimb muscles.
More recently, we showed that exercise in combination with transplantation restores muscle mass following extensive atrophy due to SCI (39). The goal of the present study was to identify possible mechanisms for the attenuation of atrophy in this model by focusing on the role of satellite cells in the restoration of muscle mass and myonuclear number and the involvement of locally expressed IGF. The soleus and plantaris muscles were used in this study to compare the response of muscles with different fiber type compositions.
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METHODS |
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Animals and experimental protocol.
All procedures were performed in accordance with institutional
guidelines for the care and use of laboratory animals. Adult female
Sprague-Dawley rats (225-250 g) were randomly divided into five
groups (n = 4, per group): control rats did not undergo
a spinal cord transection, were not exercised, and did not receive a
fetal tissue implant. All other rats underwent a complete transection of the thoracic (T10) spinal cord by creation of an aspiration lesion
2-3 mm in length while under anesthesia with ketamine (60 mg/kg)
and xylazine (10 mg/kg). Following surgery, rats received Penicillin
Procaine G and a dextrose saline injection, and for about 2 wk manual
expression of the urinary bladder was carried out twice daily until
animals regained reflexive voiding. Four weeks after transection of the
spinal cord, rats were assigned to the following four groups: rats
received no further manipulation (Tx); rats were exercised on a
motor-driven bicycle, as described previously (21, 22) and
detailed below (TxEx); rats received a fetal spinal cord tissue implant
as described (28, 29) (TxTp); or rats received a fetal
spinal cord tissue implant and were started on the exercise protocol
described below 5 days after the implant (TxExTp). Exercise was
performed using a custom built motor-driven cycling apparatus. Rats
were suspended horizontally in full body slings and their feet secured
to the pedals. Cycling speed was maintained at 45 revolutions per min
and each exercise bout consisted of two 30-min exercise periods with a
10-min rest period in between. To measure nuclei that underwent cell
division shortly after the interventions started, rats received a
continuous release pellet containing 100 mg of 5'-bromo-2'-deoxyuridine
(BrdU) (Innovative Research America, Sarasota, FL), constructed to give
a dose of 0.022 mg BrdU · g body
wt1 · day
1 (13).
Pellets were implanted subcutaneously in the subscapular region, and
the implantation was done at the same time before death in all groups,
which coincided with the day before exercise was started in the
exercise groups. Four weeks after interventions (total time postinjury
was 8 wk for all groups), animals were killed with an overdose of
pentobarbital. Soleus and plantaris muscles were dissected and weighed.
Muscles from one leg were embedded in freezing medium and snap frozen
at resting length in liquid nitrogen cooled isopentane and stored at
70°C for use in immunohistochemistry, whereas muscles from the
other leg were snap frozen in liquid nitrogen and stored at
70°C
for Northern analysis.
Immunohistochemistry.
Cross sections of soleus and plantaris muscles were cut on a cryostat
(8 µm), air dried, and stored at 20°C. MHC isoform detection was
performed as described previously (21, 28). Muscle fiber
CSA was determined by using NIH Image and by analyzing a region of 200 fibers (21). Detailed description of changes in fiber type
distribution and MHC expression in these animals is reported elsewhere
(39).
Northern analysis for IGFs. RNA isolation and detection were performed as described (21). Briefly, total RNA was isolated from muscles using the guanidinium thiocyanate-phenol-chloroform extraction method as described by Chomczynski and Sacchi (15). Ten micrograms of total RNA were electrophoresed through 1% agarose/2% formaldehyde HEPES/EDTA-buffered gels and separated for 2-3 h at 70 V. RNA was then transferred to a nylon membrane (Zeta-Probe; Bio-Rad, Richmond, CA) using a blotting unit (BIOS, New Haven, CT) and UV cross-linked using a Stratalinker (Stratagene, La Jolla, CA). Membranes were sequentially hybridized with the following probes: IGF-I, IGF-II, and 18S rRNA. IGF-I and IGF-II probes have been described previously (45), and 18S rRNA probe was an EcoR 1 fragment from 18S RNR* (23). Labeling of the probes was performed using the random prime method (Decaprime II kit, Ambion, Austin, TX). Hybridization was performed according to Church and Gilbert (16). Briefly, filters were hybridized overnight in rotating flasks in a hybridization oven (Robbins Scientific, Sunnyvale, CA) at 65°C in buffer containing 0.5% crystalline grade BSA (Calbiochem, San Diego, CA), 1 mM EDTA, 0.5 M NaPO4, pH 7.2, and 3% SDS. Filters were washed sequentially in wash solution A (1 mM EDTA, 40 mM NaPO4, pH 7.2, and 5% SDS), wash solution B (1 mM EDTA, 40 mM NaPO4, pH 7.2, and 1% SDS), and in postwash (1.6× SSC, 5 mM Tris, pH 8.0, 1 mM EDTA, and 0.1% SDS) at 65°C for 40 min each. Filters were exposed to film, and densitometry was performed on the scanned films using NIH Image. Hybridization with IGF-I and IGF-II probes yielded a number of transcripts of different sizes as described previously (27, 47). The most prominent transcripts for IGF-I (1.8 kb) and for IGF-II (3.8 kb) were analyzed. Density of bands of interest for IGF-I and IGF-II was normalized to density of the bands for 18S rRNA and expressed as arbitrary density units.
Statistics. To test for statistically significant differences, ANOVA was used; in the case of significant differences, the Tukey multiple comparisons test was applied. Statistical significance was assumed at P < 0.05.
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RESULTS |
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Exercise and transplantation combined restore muscle size.
After spinal cord transection, mean myofiber CSA was decreased 55% and
34% in soleus and plantaris muscles, respectively (Fig. 1). A detailed description of changes in
muscle mass, muscle-to-body mass ratio, in MHC distribution, and in
oxidative capacity is presented elsewhere (39). Exercise
alone (TxEx) increased plantaris CSA to levels not different from
control, but in soleus the effect of exercise alone failed to reach
significance compared with transection alone (P = 0.076). Moreover, fetal tissue transplantation alone (TxTp) did not
restore the loss in CSA. However, the combined intervention of exercise
and transplantation resulted in an increase of CSA in both muscles
compared with muscles from Tx animals. In plantaris, CSA was
restored to levels not significantly different from control, whereas
CSA in soleus muscle increased 28%, but remained different from
control. Therefore, exercise and transplantation combined have a
beneficial effect on muscle size even if initiated well after spinal
cord transection.
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Restoration of myofiber nuclear number in soleus is correlated with
CSA.
To investigate whether the changes in muscle size are associated with
changes in the number of myofiber nuclei upon transection and following
exercise and/or transplantation, myofiber nuclei of soleus and
plantaris muscles were counted. Figure 2
shows representative cross sections of soleus muscles from control
(Fig. 2A), Tx (Fig. 2B), and TxExTp (Fig.
2C) rats. The sections were stained with Hoechst 33258 dye
to identify nuclei and immunoreacted with a dystrophin antibody to
visualize the sarcolemma. All nuclei residing within the sarcolemma
were considered myofiber nuclei. The results of the myonuclear counts
are illustrated in Fig. 3A. In
soleus muscle the number of myofiber nuclei decreased 40% with
transection, and neither exercise nor transplantation alone restored
myofiber nuclear number. However, the combined treatment of exercise
and transplantation restored the number of myofiber nuclei in the soleus to a level not significantly different from control. In plantaris muscle there was no change in myofiber nuclear number with
any of the experimental manipulations. Since the extent of myofiber
nuclear loss and the decrease in CSA were very similar in soleus but
very different in plantaris muscle, we examined the correlation between
the two variables. Figure 3B shows that there is a strong
correlation between myofiber nuclear number and myofiber CSA in soleus
(r = 0.85) but not in plantaris muscles (r = 0.51). Therefore, in soleus muscle only, the
combination of exercise and transplantation after transection is
associated with an increase in myofiber nuclei, which is strongly
correlated with myofiber size.
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Fusion of satellite cells with muscle fibers provides a mechanism
for the restoration of myonuclear number.
Since in plantaris the myofiber nuclear number did not change with the
experimental procedures, the following experiments were only performed
on soleus muscles. To investigate whether satellite cell proliferation
and fusion was involved in restoration of myofiber nuclear number with
exercise and transplantation combined, rats were implanted with BrdU
release pellets. BrdU incorporation identified cells that have
undergone S-phase of the cell cycle, and the nuclei from these cells
were followed by immunoreacting muscle sections with a BrdU antibody.
BrdU-positive myonuclei located within the sarcolemma, identified by
dystrophin staining, were assumed to be from satellite cells that have
divided and fused into the existing myofibers. The number of
BrdU-positive nuclei in the TxExTp group appeared higher [control = 6.7 ± 1.2; Tx = 3.3 ± 0.5; TxEx = 9.0 ± 2.2; TxTp = 4.8 ± 1.7; TxExTp = 20.5 ± 8.3 (BrdU-positive nuclei per 100 fibers; mean ± SE)], although the
difference between groups failed to reach significance because of the
very high variability in the TxExTp group. Therefore, we investigated
the two highest labeled soleus muscles for evidence of fusion of
satellite cells into muscle fibers. As illustrated in Fig.
4, A and B,
numerous BrdU labeled nuclei were observed both outside (white arrow)
and inside the sarcolemma (black arrows), indicating that satellite
cells had divided and frequently fused into the myofibers in TxExTp
muscles.
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IGF-I and IGF-II transcript levels are not correlated with late
changes in muscle size.
IGF-I and IGF-II mRNA abundance was assessed to investigate whether
these growth factors are involved in the activation and proliferation
of satellite cells and in the response to combined exercise and
transplantation. Figure 5 and Table
1 show the results of these experiments.
In both soleus and plantaris muscles, IGF-I transcript levels decreased
significantly with spinal cord transection and were not restored with
exercise or transplantation alone or with the combined intervention.
There was no difference in IGF-II mRNA abundance in soleus or plantaris
muscle with any of the experimental procedures. Thus, at the time point
measured in this study, IGF mRNA levels are not correlated with muscle
mass.
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DISCUSSION |
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Restoration of muscle size. A dramatic loss of mass in muscles distal to the level of injury is associated with SCI. In previous studies it was shown that exercise or transplantation alone attenuated this atrophy if implemented shortly after the injury (21, 28, 36). We show here that with a long postinjury interval prior to intervention, exercise or transplantation alone did not restore muscle size in soleus and plantaris muscle but that the combination of exercise and transplantation restored muscle size in both muscles. This indicates that, even though the extent of atrophy is similar at 10 days post-SCI (21) and at 30 days post-SCI (36), the reaction of the muscle tissue to interventions is different. Some studies report beneficial effects of exercise even if started after a delayed period following transection, but these exercise regimens were performed for extended periods of time (42, 44). We chose the time point reported here, as we expected to see a restoration in size of soleus muscle with exercise alone. Based on our previous studies, very short (5 days) periods of exercise or a longer period comparable to the one reported here yielded an increase in muscle size if implemented shortly following transection (21, 36). There may be a window of time in which it is most beneficial to start the exercise and there may be a minimal duration of exercise required if started well after injury to show atrophy-reducing effects. Transplantation alone has been shown to be beneficial in attenuating atrophy if performed early after the injury in both soleus (28) and tibialis anterior muscles (36). However, atrophy-reducing effects in soleus were only seen after a long period (90 days) following transplantation and not after 4 wk (36). It is possible that it takes more time for the transplants to restore muscle mass, particularly if the effects of a transplant depend upon axon growth into the graft tissue or for synaptic connections to be made. The mechanisms underlying the increase in muscle size with the combined treatment, but not with either treatment by itself, are unclear. It is possible that the transplants release some factor(s) that requires muscle activity to exert their action, or alternatively, there could be factors released from exercising muscles that are involved in neuronal outgrowth. Neurotrophin-4 is a possible candidate, since its expression increases with increased muscle activity, its expression is greater in type 1 than type 2 muscle fibers, and it mediates nerve sprouting (25). Future studies need to be directed toward investigating the response of this and other activity-dependent neurotrophic factors.
Changes in myonuclear number. It has been reported that the decrease in soleus muscle size is associated with a decrease in myofiber nuclei such that the nuclear domain (DNA-to-cytoplasmic ratio) remains relatively constant, irrespective of how atrophy was induced (6, 7, 8, 19, 50). Even though we did not measure the actual size of nuclear domains, but instead myonuclear number and CSA, the same trend was observed in this study. Myofiber nuclear number was very closely associated with muscle size as measured by myofiber CSA. The decrease in myofiber nuclear number associated with transection was restored with the combined treatment of exercise and transplantation as was muscle size. In a previous study we showed that myofiber nuclear number was not restored by short-term exercise even though loss in fiber size was attenuated (21). This indicates that even in soleus, the ratio of myofiber nuclei to CSA is not constant and suggests that restoration of nuclear domain size by addition of nuclei may lag behind restoration of myofiber size. For plantaris muscles the concept of a constant nuclear domain has not been investigated in great detail. In one study it was reported that nuclear domain remained constant in plantaris muscles under hypertrophying conditions (43). The results from our current study indicate that the size of plantaris muscles can vary considerably without a change in myonuclear number, and therefore the size of the nuclear domain in plantaris muscles is not as regulated as appears to be the case for soleus muscles.
Satellite cell involvement in restoration of muscle size. The current understanding of the process by which myofiber nuclei are added to myofibers is that activated satellite cells proliferate and fuse into existing fibers (1, 11). It has been suggested that proliferation of satellite cells is required for hypertrophy to occur, since irradiated muscles lose the capacity to increase in size (40, 41). Whether satellite cells also are involved in the restoration of muscle size after atrophy is less clear. It has been shown that attenuation of atrophy by IGF/growth hormone treatment combined with resistance exercise during hindlimb suspension was associated with a decrease in myofiber nuclear loss (5). This could have been accomplished by either a decrease in the loss of nuclei or addition of new nuclei. Indeed, it was shown that resistance exercise during hindlimb suspension decreased apoptotic nuclear loss (4), the mechanism thought to be responsible for the loss of nuclei during atrophy. However, in the current investigation myofiber nuclear loss had already occurred by the time the interventions were started, suggesting that to restore myofiber nuclear number, satellite cells must be involved. Indeed, BrdU-positive nuclei were observed inside the sarcolemma of TxExTp soleus muscles, indicating that fusion of satellite cells had occurred in muscles with an increased myonuclear number. Since myofiber nuclear number is higher in type 1 than type 2 MHC-expressing myofibers (6, 26, 48), we investigated whether satellite cells fused preferentially with myofibers expressing MHC type 1. In soleus muscles of the experimental animals, a switching of MHC isoforms to a faster phenotype occurs during the experimental manipulations described here (39), and there are only a few fibers that continue to express only one MHC. Nonetheless, BrdU-positive nuclei were observed in fibers expressing all MHCs, arguing against preference for fusion of satellite cells to a particular fiber type. It is interesting that myofiber nuclear number was restored in soleus muscles even though the fiber type of most of the myofibers had changed from slow, MHC type 1, to fast, MHC type 2 (39), which in normal muscle have a lower myonuclear number. In plantaris muscles consisting primarily of type 2 MHC-expressing myofibers, no change was observed in myofiber nuclear number even though considerable changes in muscle size occurred. This observation requires further investigation.
IGF involvement in controlling muscle size. The possible involvement of locally expressed IGF-I and IGF-II in the restoration of muscle size and myofiber nuclear number also was investigated in this study. IGF-I and IGF-II are growth factors that contribute to satellite cell proliferation and differentiation in vivo and in vitro (24), and IGF-I has been implicated in skeletal muscle hypertrophy (3, 17, 38, 46). Therefore, we hypothesized that IGF-I would be increased with restoration of muscle size in TxExTp muscles. The results indicate that IGF-I mRNA abundance in soleus and plantaris muscles decreased with spinal cord transection, indicating that it potentially serves a role in normal muscle to maintain muscle size. However, exercise and/or transplantation were not associated with an increase in IGF-I or IGF-II mRNA abundance when measured 30 days after the intervention in either soleus or plantaris muscle compared with transection. Therefore, IGF-I mRNA levels are not correlated with restoration of muscle mass. However, a role for IGFs in the decrease in atrophy and restoration of myonuclear number cannot be ruled out, as it is possible that a transient increase in IGF occurred shortly after initiation of the interventions.
In summary, atrophy induced by spinal cord transection was reversed by the combination of exercise and transplantation implemented after a long postinjury interval in soleus and plantaris muscles. However, different cellular mechanisms appear to contribute to the restoration of mass in muscles with different fiber type compositions. Myofiber nuclei lost in soleus following spinal cord transection were restored with the combination of the interventions but not with either intervention alone. Satellite cell fusion is a potential mechanism by which these beneficial effects of the combined intervention are accomplished. Although IGFs do not appear to be involved in the restoration of muscle size or myofiber nuclear number, early responses to the interventions remain to be explored. On the other hand, plantaris muscles atrophied without significant loss of myofiber nuclear number and restoration of mass were not correlated with a change in myofiber nuclear number, suggesting that considerable variability exists in the response of different muscles to stimuli that alter muscle size. ![]() |
ACKNOWLEDGEMENTS |
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This research was supported by National Institutes of Health Grant HD-35096. E. E. Dupont-Versteegden was supported by a National Institute of Arthritis and Musculoskeletal and Skin Diseases National Research Service Award, and R. J. L. Murphy was supported by a postdoctoral fellowship from the Natural Sciences and Engineering Research Council of Canada.
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FOOTNOTES |
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Present address of R. J. L. Murphy: School of Recreation Management and Kinesiology, Acadia University, Wolfville, Nova Scotia BOP 1XO, Canada.
Address for reprint requests and other correspondence: C. A. Peterson, Univ. of Arkansas for Medical Sciences, Reynolds Center on Aging, Rm. 3121, 629 South Elm St., Little Rock, AR 72205 (E-mail: petersoncharlottea{at}exchange.uams.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 14 April 2000; accepted in final form 30 June 2000.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Adams, GR.
Role of insulin-like growth factor-I in the regulation of skeletal muscle adaptation to increased loading.
Exerc Sport Sci Rev
26:
31-60,
1998[ISI][Medline].
2.
Adams, GR,
and
Haddad F.
The relationships among IGF-1, DNA content, and protein accumulation during skeletal muscle hypertrophy.
J Appl Physiol
81:
2509-2516,
1996
3.
Adams, GR,
and
McCue SA.
Localized infusion of IGF-1 results in skeletal muscle hypertrophy in rats.
J Appl Physiol
84:
1716-1722,
1998
4.
Allen, DL,
Linderman JK,
Roy RR,
Bigbee AJ,
Grindeland RE,
Mukku V,
and
Edgerton VR.
Apoptosis: a mechanism contributing to remodeling of skeletal muscle in response to hindlimb unweighting.
Am J Physiol Cell Physiol
273:
C579-C587,
1997
5.
Allen, DL,
Linderman JK,
Roy RR,
Grindeland RE,
Mukku V,
and
Edgerton VR.
Growth hormone/IGF-1 and/or resistive exercise maintains myonuclear number in hindlimb unweighted muscles.
J Appl Physiol
83:
1857-1861,
1997
6.
Allen, DL,
Monke SR,
Talmadge RJ,
Roy RR,
and
Edgerton VR.
Plasticity of myonuclear number in hypertrophied and atrophied mammalian skeletal muscle fibers.
J Appl Physiol
78:
1969-1976,
1995
7.
Allen, DL,
Roy RR,
and
Edgerton VR.
Myonuclear domains in muscle adaptation and disease.
Muscle Nerve
22:
1350-1360,
1999[ISI][Medline].
8.
Allen, DL,
Yasui W,
Tanaka T,
Ohira Y,
Nagaoka S,
Sekiguchi C,
Hinds WE,
Roy RR,
and
Edgerton VR.
Myonuclear number and myosin heavy chain expression in rat soleus single muscle fibers after spaceflight.
J Appl Physiol
81:
145-151,
1996
9.
Awede, B,
Thissen JP,
Gailly P,
and
Lebacq J.
Regulation of IGF-I, IGFBP-4 and IGFBP-5 gene expression by loading in mouse skeletal muscle.
FEBS Lett
461:
263-267,
1999[ISI][Medline].
10.
Barton-Davis, ER,
Shoturma DI,
Musaro A,
Rosenthal N,
and
Sweeney HL.
Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function.
Proc Natl Acad Sci USA
95:
15603-15607,
1998
11.
Bischoff, R.
The satellite cell and muscle regeneration.
In: Mycology, edited by Engel AG,
and Franzini-Armstrong C.. New York: McGraw Hill, 1994, p. 97-118.
12.
Cabric, M,
and
James NT.
Morphometric analyses on the muscles of exercise trained and untrained dogs.
Am J Anat
166:
359-368,
1983[ISI][Medline].
13.
Carson, JA,
and
Alway SE.
Stretch overload-induced satellite cell activation in slow tonic muscle from adult and aged Japanese quail.
Am J Physiol Cell Physiol
270:
C578-C584,
1996
14.
Cheng, H,
Cao Y,
and
Olson L.
Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function.
Science
273:
510-513,
1996[Abstract].
15.
Chomczynski, P,
and
Sacchi N.
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
Anal Biochem
162:
156-159,
1987[ISI][Medline].
16.
Church, GM,
and
Gilbert W.
Genomic sequencing.
Proc Natl Acad Sci USA
81:
1991-1995,
1984[Abstract].
17.
Coleman, ME,
DeMayo F,
Yin KC,
Lee HM,
Geske R,
Montgomery C,
and
Schwartz RJ.
Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myofiber hypertrophy in transgenic mice.
J Biol Chem
270:
12109-12116,
1995
18.
Criswell, DS,
Booth FW,
DeMayo F,
Schwartz RJ,
Gordon SE,
and
Fiorotto ML.
Overexpression of IGF-1 in skeletal muscle of transgenic mice does not prevent unloading-induced atrophy.
Am J Physiol Endocrinol Metab
275:
E373-E379,
1998
19.
Darr, KC,
and
Schultz E.
Hindlimb suspension suppresses muscle growth and satellite cell proliferation.
J Appl Physiol
67:
1827-1834,
1989
20.
DeVol, DL,
Rotwein P,
Sadow JL,
Novakofski J,
and
Bechtel PJ.
Activation of insulin-like growth factor gene expression during work-induced skeletal muscle growth.
Am J Physiol Endocrinol Metab
259:
E89-E95,
1990.
21.
Dupont-Versteegden, EE,
Houlé JD,
Gurley CM,
and
Peterson CA.
Early changes in muscle fiber size and gene expression in response to spinal cord transection and exercise.
Am J Physiol Cell Physiol
275:
C1124-C1133,
1998
22.
Dupont-Versteegden, EE,
Murphy RJL,
Houlé JD,
Gurley CM,
and
Peterson CA.
Activated satellite cells fail to restore myonuclear number in spinal cord transected and exercised rats.
Am J Physiol Cell Physiol
277:
C589-C597,
1999
23.
Erickson, JM,
Rushford CL,
Dorney DJ,
Wilson GN,
and
Schmickel RD.
Structure and variation of human ribosomal DNA: molecular analysis of cloned fragments.
Gene
16:
1-9,
1981[Medline].
24.
Florini, JR,
Ewton DZ,
and
Coolican SA.
Growth hormone and the insulin-like growth factor system in myogenesis.
Endocr Rev
17:
481-517,
1996[Abstract].
25.
Funakoshi, H,
Belluardo N,
Arenas E,
Yamamoto Y,
Casabona A,
Persson H,
and
Ibanez CF.
Muscle-derived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons.
Science
268:
1495-1499,
1995[ISI][Medline].
26.
Gibson, MC,
and
Schultz E.
The distribution of satellite cells and their relationship to specific fiber types in soleus and extensor digitorum longus muscles.
Anat Rec
202:
329-337,
1982[ISI][Medline].
27.
Glazner, GW,
and
Ishii DN.
Insulin-like growth factor gene expression in rat muscle during reinnervation.
Muscle Nerve
18:
1433-1442,
1995[ISI][Medline].
28.
Houlé, JD,
Morris K,
Skinner RD,
Garcia-Rill E,
and
Peterson CA.
Effects of fetal spinal cord tissue transplants and cycling exercise on the soleus muscle in spinalized rats.
Muscle Nerve
22:
846-856,
1999[ISI][Medline].
29.
Houlé, JD,
and
Reier PJ.
Transplantation of fetal spinal cord tissue into the chronically injured adult rat spinal cord.
J Comp Neurol
269:
535-547,
1988[ISI][Medline].
30.
Jennische, E,
and
Hansson HA.
Regenerating skeletal muscle cells express insulin-like growth factor I.
Acta Physiol Scand
130:
327-332,
1987[ISI][Medline].
31.
Lefaucheur, JP,
Gjata B,
Lafont H,
and
Sebille A.
Angiogenic and inflammatory responses following skeletal muscle injury are altered by immune neutralization of endogenous basic fibroblast growth factor, insulin-like growth factor-1 and transforming growth factor-1.
J Neuroimmunol
70:
37-44,
1996[ISI][Medline].
32.
Lefaucheur, JP,
and
Sebille A.
Muscle regeneration following injury can be modified in vivo by immune neutralization of basic fibroblast growth factor, transforming growth factor 1 or insulin-like growth factor I.
J Neuroimmunol
57:
85-91,
1995[ISI][Medline].
33.
Lowe, DA,
and
Alway SE.
Stretch-induced myogenin, MyoD, and MRF4 expression and acute hypertrophy in quail slow-tonic muscle are not dependent upon satellite cell proliferation.
Cell Tissue Res
296:
531-539,
1999[ISI][Medline].
34.
McCall, GE,
Allen DL,
Linderman JK,
Grindeland RE,
Roy RR,
Mukku VR,
and
Edgerton VR.
Maintenance of myonuclear domain size in rat soleus after overload and growth hormone/IGF-1 treatment.
J Appl Physiol
84:
1407-1412,
1998
35.
Miya, D,
Giszter S,
Mori F,
Adipudi V,
Tessler A,
and
Murray M.
Fetal transplants alter the development of function after spinal cord transection in newborn rats.
J Neurosci
17:
4856-4872,
1997
36.
Murphy, RJL,
Dupont-Versteegden EE,
Peterson CA,
and
Houle JD.
Two experimental strategies to restore muscle mass in adult rats following spinal cord injury.
Neurorehab Neural Repair
13:
125-134,
1999[ISI].
37.
Murphy, RJL,
Peterson CA,
Dupont-Versteegden EE,
and
Houlé JD.
Electrical activity has a role in the training-induced increases in skeletal muscle mass in spinal cord injured rats (Abstract).
Can J Appl Physiol
23:
496,
1998.
38.
Musaro, A,
McCullagh KJA,
Naya FJ,
Olson EN,
and
Rosenthal N.
IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1.
Nature
400:
581-585,
1999[ISI][Medline].
39.
Peterson, CA,
Murphy RJL,
Dupont-Versteegden EE,
and
Houlé JD.
Cycling exercise and fetal spinal cord transplantation act synergistically on atrophied muscle following chronic spinal cord injury in rats.
Neurorehab Neural Repair
14:
85-91,
2000[ISI].
40.
Phelan, JN,
and
Gonyea WJ.
Effect of radiation on satellite cell activity and protein expression in overloaded mammalian skeletal muscle.
Anat Rec
247:
179-188,
1997[ISI][Medline].
41.
Rosenblatt, JD,
Yong D,
and
Parry DJ.
Satellite cell activity is required for hypertrophy of overloaded adult rat muscle.
Muscle Nerve
17:
608-613,
1994[ISI][Medline].
42.
Roy, RR,
and
Acosta LJ.
Fiber type and fiber size changes in selected thigh muscles six months after low thoracic spinal cord transection in adult cats: exercise effects.
Exp Neurol
92:
675-685,
1986[ISI][Medline].
43.
Roy, RR,
Monke SR,
Allen DL,
and
Edgerton VR.
Modulation of myonuclear number in functionally overloaded and exercised rat plantaris fibers.
J Appl Physiol
87:
634-642,
1999
44.
Roy, RR,
Talmadge RJ,
Hodgson JA,
Zhong H,
Baldwin KM,
and
Edgerton VR.
Training effects on soleus of cats spinal cord transected (T12-13) as adults.
Muscle Nerve
21:
63-71,
1998[ISI][Medline].
45.
Sarbassov, DD,
Stefanova R,
Grigoriev VG,
and
Peterson CA.
Role of insulin-like growth factors and myogenin in the altered program of proliferation and differentiation in the NFB4 mutant muscle cell line.
Proc Natl Acad Sci USA
92:
10874-10878,
1995[Abstract].
46.
Semsarian, C,
Wu MJ,
Ju YK,
Marciniec T,
Yeoh T,
Allen DG,
Harvey RP,
and
Graham RM.
Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signalling pathway.
Nature
400:
576-581,
1999[ISI][Medline].
47.
Shimatsu, A,
and
Rotwein P.
Mosaic evolution of the insulin-like growth factors. Organization, sequence, and expression of the rat insulin-like growth factor I gene.
J Biol Chem
262:
7894-7900,
1987
48.
Tseng, BS,
Kasper CE,
and
Edgerton VR.
Cytoplasm-to-myonucleus ratios and succinate dehydrogenase activities in adult rat slow and fast muscle fibers.
Cell Tissue Res
275:
39-49,
1994[ISI][Medline].
49.
Vandenburgh, HH,
Karlisch P,
Shansky J,
and
Feldstein R.
Insulin and IGF-I induce pronounced hypertrophy of skeletal myofibers in tissue culture.
Am J Physiol Cell Physiol
260:
C475-C484,
1991
50.
Viguie, CA,
Lu DX,
Huang SK,
Rengen H,
and
Carlson BM.
Quantitative study of the effects of long-term denervation on the extensor digitorum longus muscle of the rat.
Anat Rec
248:
346-354,
1997[ISI][Medline].
51.
Winchester, PK,
and
Gonyea WJ.
A quantitative study of satellite cells and myonuclei in stretched avian slow tonic muscle.
Anat Rec
232:
369-377,
1992[ISI][Medline].