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The Journal of Neuroscience, February 15, 1999, 19(4):1257-1262
Ciliary Neurotrophic Factor is a Regulator of Muscular
Strength in Aging
Catherine
Guillet1,
Patrick
Auguste1,
Willy
Mayo2,
Paul
Kreher3, and
Hugues
Gascan1
1 Institut National de la Santé et de la
Recherche Médicale (INSERM) CJF 97-08, Centre Hospitalier
Universitaire Angers, 49033 Angers Cedex, France, 2 INSERM
U259, 33077 Bordeaux Cedex, France, and 3 Laboratoire de
Neurophysiologie, Centre National de la Recherche
Scientifique-EREA 120, 49045 Angers Cedex, France
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ABSTRACT |
Ciliary neurotrophic factor (CNTF) participates in the survival of
motor neurons and reduces the denervation-induced atrophy of skeletal
muscles. Experiments performed in rats show a decrease in peripheral
CNTF synthesis during aging, associated with an overexpression of its
 -binding receptor component by skeletal muscles. Measurement of
sciatic nerve CNTF production and of the muscular performance developed
by the animals revealed a strong correlation between the two studied
parameters (r = 0.8; p < 0.0003). Furthermore, the twitch and tetanic tensions measured in the
isolated soleus skeletal muscle in 24-month-old animals increased
2.5-fold by continuous in vivo administration of CNTF.
Analyses of the activation level of leukemia inhibitory factor receptor
 - and signal transducer and activator of transcription
3-signaling molecules in response to exogenous CNTF revealed an
increased tyrosine phosphorylation positively correlated with the
twitch tension developed by the soleus muscle of the animals.
Key words:
CNTF; CNTFR; aging; muscular strength; LIFR; STAT3
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INTRODUCTION |
Ciliary neurotrophic factor (CNTF)
is a protein that promotes the differentiation and survival of a wide
range of cell types in the nervous system (Stöckli et al., 1989 ).
CNTF was largely characterized for its ability to sustain the survival
of motor neurons in vitro and in vivo (Sendtner
et al., 1990, 1997; Oppenheim et al., 1991). Additional studies have
shown that CNTF prevents the degeneration of axotomized motor neurons
and attenuates the motor deficits in several strains of mice with
neuromuscular deficiencies and that adult CNTF / mice display a weak
decrease in muscle strength (Sendtner et al., 1992a; Apfel et al.,
1993; Curtis et al., 1993; Masu et al., 1993; Mitsumoto et al., 1994).
CNTF is abundantly synthesized by Schwann cells in adult peripheral
nerves (Friedman et al., 1992; Sendtner et al., 1992b). More recently, the possibility that CNTF acts as a nerve-derived myotrophic factor was
also established (Forger et al., 1993; Helgren et al., 1994; DiStefano
et al., 1996).
CNTF uses a multimeric receptor composed of the gp130
signal-transducing protein associated with the leukemia inhibitory
factor receptor (LIFR) component (Hibi et al., 1990; Gearing et
al., 1992; Davis et al., 1993a). The CNTF receptor also includes a specific binding subunit known as CNTF receptor (CNTFR),
anchored to the membrane through a glycosylphosphatidylinositol linkage (Davis et al., 1991; DeChiara et al., 1995). Association of CNTF to its
receptor component subsequently leads to gp130-LIFR dimerization
and signaling activation events (Davis et al., 1993a). Because CNTF
cannot directly activate its receptor components in the absence of
CNTFR, expression and tissue distribution of CNTFR subunit
largely govern CNTF responses (Davis et al., 1993b). CNTFR exhibits
widespread localization in the developing nervous system of the embryo
and in the adult brain (Ip et al., 1993; McLennan et al., 1994). In
addition to its nervous system distribution, CNTFR and its
associated signaling receptors gp130 and LIFR are also abundantly
expressed by skeletal muscles (DeChiara et al., 1995; Ip et al., 1993).
After denervation, the expression of CNTF receptor components are
rapidly increased in mammalian muscles (Helgren et al., 1994).
Furthermore, exogenous administration of CNTF partially rescues
denervation-induced muscular atrophy and attenuates the reduced twitch
and tetanic tensions observed in these conditions (Helgren et al.,
1994). Age-related impairment of motor capacity has been linked to
several deleterious morphological and functional changes involving
neuromuscular interactions (Jacob and Robbins, 1990; Faulkner and
Brooks, 1995), however the causal factors responsible for these changes
are poorly understood.
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MATERIALS AND METHODS |
Protein analysis. Sciatic nerves or soleus muscles
from adult (6 months) and aged (24 months) male animals were
mechanically disrupted in PBS containing 0.1 mM
PMSF. The tissue extracts were obtained after two 15 min
centrifugations at 100,000 × g. After protein
determination, CNTF content in sciatic extracts was determined by
ELISA. ELISA plates were coated with a rabbit anti-rat CNTF polyclonal
antibody generated in the laboratory. After washing and a saturation
step, the samples were incubated overnight at 4°C. The 5/3/6B
anti-CNTF monoclonal antibody (Boehringer Mannheim, Mannheim, Germany)
was used as tracer antibody and added to the wells for 5 hr at 37°C.
The detection was achieved by using a goat anti-mouse polyclonal
antibody conjugated to horseradish peroxidase (Biosource, Camarillo,
CA). Sensitivity of the ELISA was 40 pg/ml. Gp130 detection in soleus
muscle extracts was determined by ELISA as well, with a goat anti-gp130
polyclonal antibody (R & D Systems, Minneapolis, MN) as coating
antibody and the previously described B-K11 anti-gp130 monoclonal
antibody as tracer (Chevalier et al., 1996). For LIFR determination
and signal transducer and activator of transcription 3 (STAT3)
analyses, the soleus muscles were homogenized in the presence of 1%
Brij 96 detergent in lysis buffer (Chevalier et al., 1996). After
protein standardization, samples were immunoprecipitated with an
anti-LIFR polyclonal antibody (Santa Cruz Biotechnology, Santa Cruz,
CA) or with the 4G10 anti-phosphotyrosine monoclonal antibody (Upstate
biotechnology, Lake Placid, NY). The proteins were then separated by
SDS-PAGE and immunoblotted by using the same anti-LIFR antibody
(Chevalier et al., 1996) or an anti-STAT3 monoclonal antibody from
Transduction Laboratories (Lexington, KY). After film exposure,
obtained signals were quantified by laser densitometry.
Northern blot analysis. Northern blots were performed using
a rat CNTF cDNA probe, a rat CNTFR cDNA probe, or a cDNA encoding for GAPDH as previously described (Robledo et al., 1996), except that
the hybridizations were performed in the presence of Quikhyb solution
from Stratagene (La Jolla, CA).
Determination of swimming speed. The swimming performance of
the animals was evaluated in a circular swimming pool adapted from the
spatial memory task of Morris (1984) and computed by a video tracking
system (Videotrack 512; Viewpoint, Lyon, France). Rats were gently put
in the water (22°C) and left to swim for 90 sec. Four nonconsecutive
trials were done each day for 3 d.
CNTF treatment and muscle physiology. Rat CNTF was produced
as a GST fusion protein by using the pGEX-4T2 gene fusion vector from
Pharmacia (Uppsala, Sweden) before being cleaved with thrombin and
further purified by a reverse-phase HPLC step. Sterile filtered CNTF
diluted in PBS or PBS alone were administered for 14 d at a flow
rate of 16 µg · kg 1 · hr1 from
a mini-osmotic pump (model 2002; Alza, Palo Alto, CA) implanted subcutaneously in the right hindlimb of male animals. Osmotic pump flow
delivery, stability, and bioactivity of CNTF were monitored in
vitro by ELISA determination and TF1 cell bioassay as described previously (Chevalier et al., 1996). Treated and control rats were
anesthesized with pentobarbital sodium, and soleus muscles were rapidly
removed, placed in an aerated (95% O2 and 5%
CO2) Ringer's solution at 22°C, and attached to a
force transducer. Muscles were directly stimulated with two silver
electrodes. An optimal length-tension relationship was established,
and the preparation was allowed to equilibrate (Witzmann et al., 1982;
Helgren et al., 1994). Maximal twitch tension was recorded after a
supramaximal 0.5 msec square wave pulse. Peak tetanic tension was
determined after a 300 msec train of a supramaximal stimulus at a
frequency of 150 Hz. After contraction experiments, the soleus muscles
from CNTF and saline-treated animals were frozen in isopentane before being cut in 5 µm cross sections. The slides were stained for acetylcholinesterase using 5-bromoindoxyl acetate, and the fibers were
visualized under the microscope and photographed. For each group,
cross-sectional pictures from 200 fibers were carefully and
individually cut and weighed. The fiber areas were calculated from the
picture paper weight and the magnification of the microscope represented by a size bar on the pictures. Specific pathogen-free animals used in the present study were bought from Charles River (Saint-Aubin-lès-Elbeuf, France) and immediately used in the experiments. All the animal experiments were performed in accordance with the French state legislation.
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RESULTS |
Regulation of CNTF and its receptor component in aging
CNTF expression in sciatic nerves was analyzed as an indicator of
its peripheral synthesis in 6- and 24-month-old rats. Initial experiments were performed in several rat strains, and despite some
variations observed in the average production of CNTF between the
studied strains, a twofold to fourfold decrease in CNTF expression was
consistently observed in aged animals compared with younger adult
animals (Fig. 1A). To
determine whether the observed variation in CNTF content was caused by
a decrease in CNTF production or in the protein stability, the
regulation of CNTF transcription in young adult and aged Sprague Dawley
rats was examined. A decrease in the expression of CNTF transcripts was
observed in 24-month-old animals (Fig. 1B). Reduced
CNTF mRNA and protein expression in aged rats compared with young
adult rats indicates a transcriptional regulation of CNTF in aging.
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Figure 1.
CNTF expression in sciatic nerve of adult (6 months) and aged (24 months) rats. A, ELISA detection of
CNTF in sciatic nerve extracts from two different strains of rats. The
results are expressed in nanograms per milligram of total protein.
Values are mean ± SEM. Left, Adult rats,
n = 4; aged rats, n = 3;
*p < 0.05; Student's t test.
Right, Adult rats, n = 7; aged rats,
n = 8; **p < 0.001; Student's
t test. B, CNTF and GAPDH mRNA levels in
sciatic nerves from male Sprague Dawley rats were determined by
Northern blot and quantified by laser densitometry. Adult rats,
n = 3; aged rats, n = 8;
*p < 0.05; Student's t test.
Values are mean ± SEM.
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To examine the expression of CNTFR in adult and aged animals,
Northern blot analysis was performed on RNA extracted from various
sciatic nerve target muscles including the soleus, the extensor
digitorum longus (EDL), the gastrocnemius, and the tibialis posterior
muscles. CNTFR expression was readily apparent in all muscle types
examined, and interestingly, its mRNA expression increased 10- to
20-fold between 12- and 24-month-old animals (Fig.
2A). Representativeness
of the observed phenomenon was further assessed by analyzing the
CNTFR expression on a group of six young adult and seven aged
animals. Analyses performed on the soleus muscle strongly reinforced
the kinetic observations and indicate that the observed elevation in
CNTFR in skeletal muscles was a general phenomenon in aging
population (Fig. 2B). In a third set of experiments,
levels of proteins for the two other components of the functional CNTF
receptor complex, gp130 and LIFR, were studied. LIFR and gp130
were also readily detectable, but their expression levels remained
unchanged in aged and adult animals (Fig. 2C). These results
indicate a specific regulation of CNTF and of its receptor subunit
during aging.
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Figure 2.
Regulation of CNTF receptor components in skeletal
muscles during aging. A, Expression of CNTFR mRNA in
different hindlimb muscles. Experiments were performed in the soleus,
extensor digitorum longus (EDL), gastrocnemius
(gastroc.), and tibialis posterior
(tib.post.) muscles of male
Sprague Dawley rats aged of 3, 6, 12, 18, and 24 months.
B, CNTFR mRNA expression in the soleus muscles from
six adult (6 months) and seven aged (24 months) male Sprague Dawley
rats. CNTFR mRNA was also readily detectable in soleus muscle from
adult rats after a longer exposure time, as shown in A.
C, Expression of CNTF receptor subunits in the soleus
muscle from adult (hatched bars) and aged (black
bars) male Sprague Dawley rats. CNTFR expression detected in
the soleus muscle by Northern blot analysis was quantified by laser
densitometry, and the obtained values were presented as a
CNTFR/GAPDH ratio. Gp130 content was determined in the same muscles
by ELISA detection after total protein content determination, and the
results were expressed in nanograms per milligram of protein. LIFR
determination was achieved by immunoprecipitation and Western blotting,
and the signals were quantified by laser densitometry. Adult rats,
n = 6; aged rats, n = 7;
*p < 0.0001; Student's t test.
Values are mean ± SEM.
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Evidence for a strong correlation between muscle strength developed
by the animals and sciatic CNTF synthesis
We have further analyzed the relationship between CNTF synthesis
and the skeletal muscle response by measuring in adult and aged animals
both peripheral CNTF production and their functional performance. To
assess a global image of whole animal muscular activity, an analysis of
its average swimming speed was recorded in a swimming pool by using a
video tracking system (Morris, 1984). CNTF concentration, as determined
by ELISA, and average swimming speed measurements revealed a
strong correlation between these two parameters (r = 0.8; p < 0.0003) (Fig.
3). These results indicate that either
CNTF production and muscular strength developed by the animals are
coregulated through a common mechanism present throughout the life of
the animals or that CNTF interaction with its receptor complex
expressed on the skeletal muscles more directly controls the muscular
performances of the animals. To answer this question, animals were
treated with subcutaneous administration of CNTF, and their functional
response was studied. A previous study indicated that CNTF did not
noticeably enhance performance of innervated muscles in 1-3-month-old
rats (Helgren et al., 1994), and only aged animals were treated. The
cytokine was slowly delivered by using an osmotic pump implanted under
the right hindlimb skin of the animal. A low CNTF plasma concentration
of 1370 ± 1082 pg/ml was detected during the treatment. After a
14 d treatment no significant variation in the weight was observed
between nontreated or saline-treated and CNTF-treated animals
(p = 0.55 and p = 0.12, respectively; Student's t test) (Fig.
4), indicating that subcutaneous delivery
of CNTF under these conditions did not affect the general metabolism of
the animals in a noticeable way.
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Figure 3.
Swimming speed as a function of CNTF content in
the sciatic nerve. Swimming speed was determined as described in detail
in Materials and Methods and sciatic CNTF content was monitored by
ELISA. A positive correlation between the two parameters was observed,
r = 0.80; p < 0.0003.
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Figure 4.
Effect of CNTF treatment on rat weight. Control
aged rats, n = 4; saline-treated animals,
n = 4; CNTF-treated animals, n = 6. No significant variation of rat weight is observed between control
or saline-treated and CNTF-treated rats; p = 0.55 and p = 0.12, respectively (Student's
t test). Values are mean ± SEM.
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To evaluate muscle strength, the aged rats were submitted to a swimming
test as described above after the administration of a 14 d CNTF or
saline treatment. No significant difference was observed between the
mean swimming speed of CNTF or saline-treated animals
(p = 0.14; Student's t test).
Considering that CNTF could act locally at the site of the pump
implantation, we assessed the muscular capacity by directly studying
the contractile properties of the soleus muscle after treatment. Twitch
tension was observed in response to a single electric stimulus, whereas
tetanic tension was the force generated in response to high-frequency
supramaximal pulses. The values for twitch tension of isolated soleus
muscle in vehicle-treated aged animals were similar to that of
nontreated aged animals and were ~50% lower than that in adults of 6 months of age (Fig. 5A). When
treated with CNTF, the twitch tension in aged animals was improved by
2.5-fold (Student's t test; p < 0.001) (Fig. 5A). This enhancement of muscle strength in
CNTF-treated animals was also apparent for the tetanic isometric
tension determinations when compared with control groups
(p < 0.01 for the CNTF- vs saline-treated group) (Fig. 5B). The obtained values for the contralateral
muscle were not significantly different between the vehicle- and
CNTF-treated animals (Student's t test; twitch tension,
p = 0.09; tetanic tension, p = 0.3),
indicating that CNTF mainly improved the contractile properties of
skeletal muscles at the site of the treatment that corroborates the
obtained results in the swimming test.
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Figure 5.
Effect of CNTF treatment on physiological
properties of soleus muscle. Twitch tension (A)
and tetanic tension (B) were determined after
electrical stimulation of the isolated muscles after treatment, as
described in Materials and Methods. The forces are expressed in
percentage (tensions in millinewtons per milligram of muscle wet
weight), and the control aged group values defined the 100% reference.
Control aged animals of 24 months, n = 4;
saline-treated aged animals, n = 4; CNTF-treated
aged animals, n = 6; control adult rats of 6 months, n = 5. Values are mean ± SEM.
*p < 0.001; different from saline-treated animals,
Student's t test. C, Effect of CNTF
treatment on cross-sectional area of soleus muscle fibers in aged
animals. **p < 0.05; different from saline-treated
animals; Student's t test. Values are mean ± SEM.
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Several reports show that neurotrophins and cytokines, including CNTF,
could modulate the potentiation of neuromuscular synapses and
transmitter release (Stoop and Poo, 1995). In the present study, twitch
and tetanic tension measurements were performed by direct electric
stimulation of the soleus muscle, indicating that a sensitization of
the synaptic transmission was not a requirement to record the obtained
responses. Morphological studies were performed, and the
cross-sectional areas of muscular fibers in saline- and CNTF-treated
muscles in aged animals were determined. After a 14 d CNTF
treatment, a significant myotrophic effect of the cytokine on
cross-sectional areas of fibers was observed corresponding to a 17.3%
increase of their surface (Student's t test;
p < 0.05) (Fig. 5C). The obtained values
support the idea of a direct effect of CNTF on the twitch fibers and
their contractile properties in aged animals.
CNTF treatment activates signaling mechanisms in muscle
To assess this hypothesis, we evaluated the activation level of
STAT3, a major transcriptional factor involved in the CNTF response
(Stahl et al., 1995). Analyses were performed on soleus muscle after
CNTF or saline treatment. A noticeable increase in STAT3 tyrosine
phosphorylation was observed in CNTF-treated animals (Fig.
6A) that strongly
correlates with the twitch tension measurements (r = 0.852; p < 0.01) (Fig. 6B).
Specificity of STAT3-mediated signaling was reinforced by analyzing the
tyrosine phosphorylation of LIFR on the same muscles. Similar to the
results observed for STAT3, an increased activation of the LIFR
linked to the twitch tension developed by the soleus muscle was
detected after CNTF treatment (r = 0.772;
p < 0.02) (Fig. 6C). Altogether, these results demonstrate that CNTF directly exerts its action on muscle tissue by activating its receptor complex and the associated
intracellular mechanisms of signaling.
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Figure 6.
Activation of STAT3 and LIFR after CNTF
treatment. A, Equal amounts of tissue extracts from
soleus muscle treated with CNTF or vehicle were immunoprecipitated with
an anti-phosphotyrosine monoclonal antibody. Samples were then
submitted to SDS-PAGE and Western-blotted onto a membrane.
Phosphorylation level of two STAT3 isoforms and LIFR were determined
by staining the membranes with an anti-STAT3 monoclonal antibody and an
anti-LIFR polyclonal antibody, respectively. B,
C, STAT3 and LIFR phosphorylation as a function of
the twitch tension developed by saline-treated (closed
circles) or CNTF-treated (open circles) aged
rats. Signals from the blots (A) were quantified
by laser densitometry and expressed in arbitrary units. Twitch tension
is expressed in newtons per gram of soleus wet muscle. For each panel,
a positive correlation between the two parameters was observed;
r = 0.852, p < 0.01 and
r = 0.776, p < 0.02 for STAT3
and LIFR phosphorylation, respectively.
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DISCUSSION |
We have observed that CNTF expression level decreases with the
senescence of the animal. In the muscle, expression of the receptor
component increases dramatically from 12 to 24 months of age. It is
noteworthy that CNTF level is well correlated with muscle strength and
that these two parameters decrease with age. When aged animals are
treated with exogenous CNTF, muscle strength comes back to that
detected in adult rats, demonstrating that CNTF can be an important
factor for the maintenance of muscle integrity in noninjured aged
animals. Overexpression of CNTFR in the muscles of aged animals
might be involved in a compensatory phenomenon to maintain a CNTF
response similar to that present in adult animals. Only a mild loss of
motor neurons leading to a minor muscle weakness was observed in
CNTF/ adult mice (Masu et al., 1993). In contrast, the CNTFR
moiety is essential for motor neuron survival during development, and
mice harboring an homozygous CNTFR null mutation shortly die after
birth (DeChiara et al., 1995). In line with our observations, we can
hypothesize that CNTF/ mice could display a more pronounced muscle
strength deficiency when they will become aged, suggesting that the
phenotype observed in CNTF gene inactivation might reflect a premature
muscle aging of these animals.
CNTF was shown to prevent lesion-mediated degeneration of motor neurons
(Sendtner et al., 1990, 1997) and to reduce denervation-induced atrophy
of skeletal muscle (Helgren et al., 1994). It also displays protective
effects in several animal models of neurodegenerative diseases
(Sendtner et al., 1992a; Mitsumoto et al., 1994). The present study
shows that in normal aged animals that display a reduced muscular
activity, CNTF can partially attenuate the functional skeletal muscle
modifications. These overall observations tend to ascribe to CNTF a
more general role of rescue factor in response to a suffering state of
the neuromuscular axis observed in various situations.
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FOOTNOTES |
Received Aug. 6, 1998; revised Dec. 2, 1998; accepted Dec. 7, 1998.
This work was supported by a grant from Association Française
contre les Myopathies. C.G. was funded by a fellowship from Conseil
Général du Maine et Loire and by Comité du Maine et Loire de la Ligue contre le Cancer. We thank Dr. J.F. Leterrier for the
initial sciatic nerve samples, and Dr. Bruce Koppelman for his careful
reviewing of this manuscript. We also thank J. Froger for her technical
assistance and J.P. Gislard for assistance with photography.
Correspondence should be addressed to Hugues Gascan, Institut National
de la Santé et de la Recherche Médicale CJF 97-08, 4 rue
Larrey, Centre Hospitalier Universitaire Angers, 49033 Angers Cedex, France.
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Abstract
Introduction
