Neurotrophin 4/5 is required for the normal development of the slow muscle fiber phenotype in the rat soleus
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
* Author for correspondence (e-mail: dcarras{at}emory.edu)
Accepted 26 March 2003
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Summary |
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Key words: neurotrophin, development, skeletal muscle, myosin heavy chain, synaptic transmission, rat
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Introduction |
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It is well known that motoneurons regulate the mechanical and biochemical
properties of their muscle fibers by means of their activity
(Ausoni et al., 1990;
Pette and Vroba, 1985
;
Salmons and Vroba, 1969
;
Windisch et al., 1998
). Based
on the above, it is likely that the MyHC switch in the neonatal rat SOL is a
direct consequence of the phasic-to-tonic transformation that occurs in the
activity pattern of SOL motoneurons during the first weeks of postnatal
development (Brocard et al.,
1999
; Navarrette and Vrbova,
1993
; Vinay et al.,
2000b
). The patterns of activity of motoneurons are determined
both by their synaptic inputs and their intrinsic properties
(Binder et al., 1996
), and both
of these determinants can be regulated by activity-dependent muscle-derived
factors (Czéh et al.,
1978
; Mendell et al.,
1994
). It is possible, therefore, that the MyHC transformation in
the neonatal rat SOL, although directly mediated by the activity-dependent
switch in the pattern of activity of SOL motoneurons, might be indirectly
determined by factors released by the SOL muscle fibers as a result of the
increased activity. The identity of the factor(s) has not yet been
determined.
Neurotrophins are well-known retrograde signaling molecules
(Curtis et al., 1995;
Koliastos et al., 1994
) that
regulate differentiation and cell survival in many central and peripheral
neurons. Three neurotrophins brain-derived neurotrophic factor (BDNF),
neurotrophin 3 (NT-3) and neurotrophin 4/5 (NT-4/5) are expressed in
skeletal muscle (Funakoshi et al.,
1995
; Griesbeck et al.,
1995
). These neurotrophins exert their effect through two classes
of cell surface receptors: p75NTR (p75) and a related
family of tyrosine protein kinase receptors referred to as Trks
(Barbacid, 1994
). In addition
to their effect on cell survival, neurotrophins play a significant role in the
modulation of neuronal plasticity (Berardi
et al., 1994
; McAllister et
al., 1999
; Thoenen,
1995
), synaptic efficacy (Wang
and Poo, 1998
) and neuronal excitability
(Kafitz et al., 1999
).
Although all of these molecules can be considered potential candidates for
retrograde specification of motoneuron properties and their synaptic inputs,
NT-4/5 is particularly attractive. The mRNA for NT-4/5 increases significantly
in muscle during postnatal development, whereas the mRNAs for BDNF and NT-3
are significantly reduced (Funakoshi et
al., 1995
; Griesbeck et al.,
1995
). In adult rats, electrically evoked muscle activation
significantly increases NT-4/5 mRNA in the SOL in a voltage-dependent manner
(Funakoshi et al., 1995
).
In the present study, we have exploited the naturally occurring MyHC
isoform switch that occurs in the postnatal rat SOL to evaluate the role of
NT-4/5 in the regulation of muscle fiber phenotype. One prediction of our
hypothesis is that increased levels of NT-4/5 should accelerate the
fast-to-slow transformation and a decreased availability of this neurotrophin
should block or reverse the MyHC isoform switch. Some of these data have been
published in an abstract form (Carrasco
and English, 2001).
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Materials and methods |
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RNA isolation and RT-PCR
Total RNA was extracted from SOL muscles of two groups of untreated rats at
postnatal ages of 4 days, 7 days, 14 days, 21 days and 28 days with
Trizol® reagent (Life Technologies, Carlsbad, CA, USA)
according to manufacturer's instructions. RNA was dissolved in 20 µl of
diethyl pyrocarbonate (Sigma)-treated H2O. Because SOL muscles from
4-day-old rats were so small, the muscles from the animals at this age were
pooled. RNA concentration was quantified by determining absorbance at a
wavelength of 260 nm and using an OD260 unit equivalent to 40 µg
ml-1. 2 µg of total RNA was reverse transcribed into
complementary DNA (cDNA) with the SuperScriptTM Preamplification
Sytem kit (Life Technologies) according to the manufacturer's instructions.
Negative controls were performed in the absence of reverse transcription. 10
µl of the cDNA solution was amplified by means of polymerase chain reaction
(PCR) in the presence of oligonucleotide primers specific to either NT-4/5,
MyHC I/b or MyHC IIA in conjunction with 18S rRNA primers and competimers
(Ambion, Austin, TX, USA). The 18S rRNA and competimers were used as an
internal control for each sample. The NT-4/5 cDNA fragment (248 bp)
corresponding to nucleotides 467715 of the rat cDNA sequence (GenBank
M86742) was synthesized with the following primers: sense,
5'-CCCTGCGTCAGTACTTC-TTCGAGAC-3'; antisense,
5'-CTGGACGTCAGGCACGGC-CTGTTC-3'. The MyHC I/b and MyHC IIA
fragments (288 bp and 310 bp, respectively) were obtained using primers
previously described in the literature
(Jaschinski et al., 1998).
MyHC I/b: sense, 5'-ACAGAGGAAGACAGGAAGAACC-TAC-3'; antisense,
5'-GGGCTTCACAGGCATCCTTAG-3'. MyHC IIA: sense,
5'-TATCCTCAGGCTTCAAGATTTG-3'; antisense,
5'-TAAATAGAATCCATGGGGACA-3'. The linear portion of the
amplification curve for each transcript was defined and then utilized to
determine the appropriate number of cycles for their amplification.
Amplification conditions for the NT-4/5-specific primer pair were as follows:
3 min at 94°C followed by 30 cycles of 94°C for 30 s, 60°C for 30
s and 72°C for 1 min, followed by extension at 72°C for 10 min.
Amplification conditions for the MyCH I/b- and MyHC IIA-specific primer pairs
were as follows: 3 min at 94°C followed by 27 cycles of 94°C for 45 s,
55°C for 1 min and 72°C for 1 min, followed by extension at 72°C
for 10 min. PCR reactions were performed three times on each sample. To
quantify amplicons, PCR products were resolved in 1.5% agaroseethidium
bromide gel, visualized and photographically recorded with a UV documentation
station (FOTO/Phoresis®; Fotodyne® Inc.,
Hartland, WI, USA). The optical density of the amplicons for NT-4/5, MyHC I/b,
MyHC IIA and 18S rRNA were determined using the Scion Image software
(Frederick, MD, USA). Relative mRNA expression was determined by dividing the
optical density of each amplicon by the optical density of their corresponding
18S rRNA amplicon.
Immunohistochemistry
Serial 10 µm cross-sections from each triceps surae, which included the
widest portion (medial) of the soleus muscle, were cut in a cryostat and
placed onto subbed microscope slides. At least eight fields of view were taken
from each cryosection and used for the data analysis. The fields were taken
from the most lateral to the most medial portion of the cryosection following
a zigzag pattern (Fig. 1).
Thus, they covered very different areas of the entire cryosection. Initially,
sections were incubated for one hour in a 0.1 mol l-1
phosphate-buffered saline (PBS) solution containing 2% normal goat serum and
0.03% Triton X-100 and then in PBS containing primary antibody BA-D5 overnight
at 4°C. Antibody BA-D5 is specific for the I/b or slow MyHC isoform
(Schiaffino et al., 1989).
Sections were washed in PBS and incubated in a peroxidase-conjugated goat
anti-mouse secondary antibody (Cappel Research Products, Aurora, OH, USA) for
1 h at room temperature, followed by a standard diaminobenzidine reaction for
the demonstration of peroxidase. To better characterize the fast-to-slow MyHC
transition, sections were double-stained with antibody A4.840 and MY-32.
Antibody A4.840 is specific for I/b or slow MyHC isoform
(Hughes et al., 1993
), and
antibody MY-32 recognizes the neonatal and all of the adult fast MyHC isoforms
(Harris et al., 1989
). After
an overnight incubation at 4°C in PBS containing both antibodies, sections
were washed in PBS and incubated in a biotin-conjugated goat anti-mouse IgG
secondary antibody (Cappel Research Products) for 1 h at room temperature.
Following a wash in PBS, sections then were incubated with Texas
Red®-conjugated streptavidin (Jackson Immunoresearch
Laboratories, Inc., West Grove, PA, USA) for 1 h. After a wash in PBS,
sections were incubated in fluorescein isothiocyanate (FITC)-conjugated goat
anti-mouse IgM secondary antibody (Jackson Immunoresearch Laboratories, Inc.)
for 1 h at room temperature. By using the double-staining protocol, we were
able to differentiate between fibers containing the slow MyHC only (slow;
FITC-labelled) or fast MyHC only (fast; Texas Red-labelled) from fibers
containing both isoforms (hybrid). Images of double-stained sections were
acquired using appropriate epifluorescence illumination via a cooled
CCD camera (Optronics, Goleta, CA, USA) and captured using the Scion Image
software.
|
Data analysis
The number of fibers that react positively with each antibody as well as
those stained positively with both antibodies (double stained) were counted
and expressed as a percentage of the total number of fibers in the field. A
minimum of 250 fibers was analyzed from each muscle. Two-way (treatment
X phenotype) contingency tables, using the original counts, were used
to evaluate whether differences in fiber type proportions observed between
groups were the result of the different treatment conditions rather than
differences in sample sizes. Except for the 2-week data, all the contingency
table analyses provided significantly greater values than 9.21, which is the
critical c2 value for a=0.01 and d.f.=2. Thus, the differences in
fiber type proportions observed between the groups are indeed due to the
different treatments and not due to sampling error. Differences in fiber
phenotype proportions between SOL muscles from treated and control groups were
determined using a two-way (treatment X phenotype) analysis of
variance (ANOVA). Post hoc comparisons were performed using the
Fisher least significant difference (LSD) test. The a level of significance
P<0.05 was used for all comparisons.
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Results |
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Effect of reducing availability of endogenous NT-4/5 on MyHC isoform
content
The simplest explanation of these findings might be to hypothesize that the
fast-to-slow MyHC isoform transformation normally observed in rat SOL during
development might be mediated by endogenous NT-4/5. To evaluate this
hypothesis, we decreased the availability of endogenous TrkB ligands to the
SOL muscle by injecting rats with TrkBIgG, a recombinant protein that
binds to both NT-4/5 and BDNF. Injections followed the same time course as
that used for NT-4/5. Since the MyHC content in SOL muscles from NT-4/5- and
saline-treated rats was not different at 2 weeks of age, animals in the
TrkBIgG groups were euthanized only at the end of the fourth and sixth
weeks of postnatal life. Treatment with TrkBIgG blocked or attenuated
the fast-to-slow MyHC transformation normally observed in the SOL of rat
neonates. At 4 weeks of age, SOL muscles from TrkBIgG-treated animals
contained significantly less slow fibers and significantly more fast fibers
than SOL muscles from control animals (Figs
3,
4C). At 6 weeks of age, SOL
muscles from TrkBIgG-treated animals contained significantly fewer fast
and slow fibers and significantly more hybrid fibers than SOL muscles from
controls animals (Fig. 4D). The
fact that the percentage of slow fibers was reduced below 50%, which is lower
than the proportion of slow fibers normally found in the rat soleus at 1 week
of age (Wigston and English,
1992), clearly indicates that endogenous NT-4/5 is required by SOL
muscle fibers to express the slow phenotype. The increase in the population of
hybrid fibers, therefore, comes at the expense of a significant number of slow
fibers, which, due to the reduced levels of endogenous NT-4/5, are now also
expressing the fast MyHC.
Effect of exogenous BDNF on MyHC isoform content
To determine whether the acceleration of fast-to-slow MyHC isoform switch
in developing SOL muscle observed with NT-4/5 treatment is specific to NT-4/5
and is not a general effect of the TrkB ligands, five animals were injected
with 15 µg of BDNF, as described above, and euthanized at the end of the
fourth week of postnatal life. We think that this dose is appropriate because
a similar concentration of BDNF injected into the gastrocnemius muscles of
adult rats was shown to increase both the catalytic activity and the
phosphorylation state of Trk receptors
(Bhattacharyya et al., 1997).
The number of fast, hybrid and slow fibers was not significantly different
between BDNF- and saline-treated rats (Fig.
5).
|
Analysis of NT-4/5 and MyHC isoform mRNA
If NT-4/5 is indeed involved in the fast-to-slow MyHC transformation of the
SOL muscle, one would predict that the upregulation of this neurotrophin
should occur before the upregulation of the slow MyHC isoform. To test this
possibility, RNA extracted from SOL muscles of rats of different postnatal
ages was reverse transcribed and submitted to PCR using oligonucleotide
primers specific to NT-4/5, MyHC I/b and MyHC IIA. Consistent with the
prediction, the upregulation of NT-4/5 mRNA occurred significantly earlier
(approximately 2 weeks earlier) during postnatal development than did the
upregulation of MyHC I/b mRNA (Fig. 6A, C,
D). MyHC IIA mRNA was significantly upregulated by postnatal day
14 and was followed by a continuous downregulation during the rest of the
study period (Fig. 6B, D). The
patterns of expression of both MyHC mRNAs are consistent with the normal
developmental MyHC isoform transitions that occur in the rat SOL during this
period of time. During the first week of life, approximately half of the
fibers in the rat SOL contain embryonic and neonatal MyHCs. After that, the
majority of these fibers start to express only MyHC IIA, and a subset of these
fibers begin to express MyHC I/b by 4 weeks of age
(Butler-Brown and Whalen,
1984).
|
Role of neuromuscular signaling in the effect of exogenous
NT-4/5
To evaluate whether neuromuscular signaling is required for the effects of
NT-4/5, in one group of rats we blocked synaptic transmission using botulinum
toxin (BTX) and in another group of rats, in addition to blocking synaptic
transmission, we injected recombinant NT-4/5. Both groups received
intramuscular injections of BTX on postnatal day 8. In the group receiving
NT-4/5, injections started on postnatal day 8 and were continued twice a week
as described above. Rats in both groups were euthanized at the end of the
fourth week of postnatal life. Blockade of neuromuscular synaptic transmission
with BTX significantly decreased the number of slow and fast fibers and
significantly increased the number of hybrid fibers. Treatment of BTX-blocked
muscles with NT-4/5 did not significantly alter the changes produced by
neuromuscular paralysis (Fig.
7).
|
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Discussion |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It is well known that motoneurons regulate the mechanical and biochemical
properties of their muscle fibers by means of their activity
(Ausoni et al., 1990;
Pette and Vroba, 1985
;
Salmons and Vroba, 1969
;
Windisch et al., 1998
). Early
in rat postnatal development, approximately 50% of the motoneurons innervating
the triceps surae muscle are unable to generate more than a single action
potential. By the second week of life, however, the majority of these
motoneurons are able to fire repetitively for prolonged periods of time
(Brocard et al., 1999
;
Navarrette and Vrbova, 1993
;
Pflieger et al., 2002
;
Vinay et al., 2000a
). Based on
the above, we believe that the changes in MyHC isoform expression that occur
in the neonatal rat SOL are a direct consequence of the change in pattern of
activity of the motoneurons that occurs during this developmental period.
The gradual acquisition of the repetitive pattern of discharge of
developing motoneurons has been attributed to the development of synaptic
inputs onto them and the maturation of their membrane intrinsic properties
(Brocard et al., 1999;
Navarrette and Vrbova, 1993
).
Since both the synaptic and intrinsic properties of motoneurons can be
regulated retrogradely by activity-dependent muscle-derived factors
(Czéh et al., 1978
;
Mendell et al., 1994
), all the
muscle-derived neurotrophins could influence motoneuron activity and thereby
muscle fiber phenotype. We decided to focus on the role of NT-4/5 on the
determination of SOL muscle fiber phenotype for the following reasons. First,
the mRNA for NT-4/5, but not for BDNF or NT-3, is upregulated in the muscle
during postnatal development (Funakoshi et
al., 1995
; Griesbeck et al.,
1995
). Second, this upregulation occurs during the first weeks of
postnatal development (Funakoshi et al.,
1995
) and, as demonstrated in the present study, it occurs
significantly earlier than the upregulation of MyHC I/b mRNA associated with
muscle fiber transformation. This difference in gene transcription timing is
consistent with the idea that NT-4/5 is involved in early events that lead to
the upregulation of the slow MyHC isoform in this muscle. Third, NT-4/5
synthesis by muscle fibers is modulated by electrically evoked muscle activity
in a dose-dependent manner (Funakoshi et
al., 1995
). Finally, the fact that treatment with ciliary
neurotrophic factor (CNTF) + NT-4/5, but not with CNTF + NT-3, attenuates the
reduction of the proportion of slow fibers that occurs in the rat SOL after
sciatic nerve crush (Mousavi et al.,
2002
) provides additional support that this neurotrophin is
involved in the determination of the slow muscle phenotype in the rat SOL.
In the present study, the normal fast-to-slow MyHC isoform switch was
disrupted in BTX-treated muscles, and exogenous administration of NT-4/5
failed to restore the normal course of this transformation. Based on this
finding, and the fact that NT-4/5 is retrogradely transported by developing
motoneurons and adult sensory neurons
(Curtis et al., 1995;
Koliastos et al., 1994
), we
believe that the effect of NT-4/5 is not directly on the muscle fibers but
that it forms or activates a type of retrograde signal to motoneurons. It is
possible that our NT-4/5 treatment enhanced the change in synaptic strength
occurring at the Ia/motoneuron synapses during this period
(Seebach and Mendell, 1996
)
and, via this mechanism, accelerated the acquisition of the
repetitive pattern of discharge of SOL motoneurons and, consequently, the
fast-to-slow MyHC transformation in the SOL muscle
(Fig. 8A). However, we believe
that this is unlikely. Seebach et al.
(1999
) show that treatment
with BDNF depresses and TrkBIgG increases excitatory postsynaptic
potential (EPSP) amplitude at Ia/motoneuron synapses during postnatal
development. If changes in the pattern of activity of SOL motoneurons leading
to the MyHC isoform transformation in rat SOL muscle fibers during postnatal
development were produced by an increase in synaptic strength, then one would
have predicted that BDNF would prevent and TrkBIgG would have
accelerated the transformation. Instead, BDNF did not affect its normal course
and TrkBIgG prevented or even reversed it. Therefore, we believe that
NT-4/5 exerts its effect indirectly on SOL muscle fiber MyHC isoform
expression by mechanisms other than increasing synaptic strength. In the study
of Seebach et al. (1999
),
neither input resistance nor rehobase were altered after the treatment with
BDNF or NT-3. However, the fact that treatment with TrkBIgG in the same
rats significantly increased rehobase indicates that this property is
influenced by NT-4/5, the other TrkB ligand. Based on the above, it is
possible that our NT-4/5 treatment influenced some of the membrane intrinsic
properties of SOL motoneurons and, via this mechanism, accelerated
the acquisition of the repetitive pattern of discharge of SOL motoneurons and,
consequently, the fast-to-slow MyHC transformation in this muscle
(Fig. 8B).
|
Administration of NT-4/5 and BDNF into the rat SOL produced very different
effects. When compared with controls, NT-4/5 accelerated the fast-to-slow MyHC
isoform transformation whereas BDNF did not alter the course of this
transformation. Several mechanisms could be responsible for the different
effects produced by NT-4/5 and BDNF. The binding of these two neurotrophins
might promote different conformational changes in the receptor and different
downstream signaling. Point mutation of the Shc-binding site of the TrkB
receptor mainly affects NT-4/5 signaling in vivo and in
vitro without producing major effects on BDNF signaling
(Fan et al., 2000;
Minichiello et al., 1998
). The
differential effectiveness of NT-4/5 and BDNF could also be related to the
subcellular location at which they bind and activate the TrkB receptor.
Signaling pathways activated by the internalization and activation of the Trk
receptor at the nerve terminals differ from those activated at the cell bodies
(Watson et al., 2001
).
Finally, the fact that NT-4/5- and BDNF-mutant mice exhibit significantly
different phenotypes (Conover,
1995
) is a clear demonstration that endogenous NT-4/5 and BDNF
perform different functions in vivo.
In conclusion, we have provided evidence demonstrating that NT-4/5 is
required for the normal development of the slow muscle fiber phenotype of the
rat SOL. Based on the results from previous studies and the present study, we
believe that muscle-derived NT-4/5 probably forms or activates a retrograde
signal that influences the pattern of activity of SOL motoneurons and,
via this mechanism, leads to changes that promote the upregulation of
the slow MyHC isoform in the SOL muscle. We cannot entirely rule out a role of
NT-4/5 of motoneuronal origin (Buck,
2000) as a source of developmental changes in motoneuron
properties or synaptic inputs. However, the fact that sequestration of
muscle-derived NT-4/5 with TrkBIgG prevented the SOL MyHC isoform
transformation from occurring makes this possibility unlikely.
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Acknowledgments |
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