Vol. 94, Issue 5, 1744-1750, May 2003
Severe muscle dysfunction precedes collagen tissue
proliferation in mdx mouse diaphragm
Catherine
Coirault1,
Bernadette
Pignol2,
Racquel N.
Cooper3,
Gillian
Butler-Browne3,
Pierre-Etienne
Chabrier2, and
Yves
Lecarpentier1,4
1 Institut National de la Santé et de la
Recherche Médicale, Laboratoire d'Optique Appliquée, Ecole
Nationale Supérieure de Techniques Avancées, Ecole
Polytechnique, 91761 Palaiseau; 2 Institut Henri
Beaufour, 91966 Les Ulis; 3 Unité
Mixte de Recherche, Centre National de la Recherche Scientifique 7000,
75634 Paris; and 4 Service
d'Explorations Cardio-Respiratoires, Hôpital de Bicêtre,
Assistance Publique-Hôpitaux de Paris, 94275 Le
Kremlin-Bicêtre, France
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ABSTRACT |
After extensive necrosis, progressive
diaphragm muscle weakness in the mdx mouse is thought to
reflect progressive replacement of contractile tissue by
fibrosis. However, little has been documented on diaphragm
muscle performance at the stage at which necrosis and fibrosis are
limited. Diaphragm morphometric characteristics, muscle performance,
and cross-bridge (CB) properties were investigated in 6-wk-old control
(C) and mdx mice. Compared with C, maximum tetanic tension
and shortening velocity were 37 and 32% lower, respectively, in
mdx mice (each P < 0.05). The total number
of active CB per millimeter squared (13.0 ± 1.2 vs. 18.4 ± 1.7 × 109/mm2, P < 0.05)
and the CB elementary force (8.0 ± 0.2 vs. 9.0 ± 0.1 pN,
P < 0.01) were lower in mdx than in C. The
time cycle duration was lower in mdx than in C (127 ± 18 vs. 267 ± 61 ms, P < 0.05). Percentages of
fiber necrosis represented 2.8 ± 0.6% of the total muscle
fibers, and collagen surface area occupied 3.6 ± 0.7% in mdx diaphragm. Our results pointed to severe muscular
dysfunction in mdx mouse diaphragm, despite limited necrotic
and fibrotic lesions.
myosin; cross bridge; skeletal muscle; myopathy; muscular dystrophy
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INTRODUCTION |
IN THE
MDX MOUSE, AS WELL AS in human Duchenne muscular
dystrophy (DMD), the devastating muscle degeneration is caused by a
mutation in the gene encoding dystrophin (20, 43).
Mechanisms whereby the lack of dystrophin leads to functional failure
of muscle fibers have not been fully elucidated. Dystrophin forms part
of a macromolecular complex that links cytoskeletal actin to components
of the extracellular matrix (43). This arrangement has
lent considerable support to the idea that muscle fiber necrosis during
DMD and in mdx mice is a result of compromised structural integrity of the sarcolemma during repetitive contractions
(26). More recently, it has been proposed that
disruption of key signaling processes mediated by the dystrophin
complex could be involved in muscle degeneration (4, 29,
39). For instance, changes in nitric oxide (NO) production in
dystrophic muscle may contribute to the pathology (30, 36,
39).
The diaphragm muscle of mdx mice undergoes a progressive
degeneration similar to that occurring in human muscles (17,
34). As the muscle tissue is no longer capable of maintaining
homeostasis during repeated cycles of degeneration and regeneration,
excessive proliferation of connective tissue leads to progressive loss
of contractile tissue and ensuing muscle weakness (17, 27,
34). However, in 3-mo-old mdx diaphragm, the 50%
decline in force-generating capacity largely exceeds that predicted
solely from the cross-sectional loss of muscle tissue
(27). Moreover, our laboratory (10, 11)
recently reported abnormal myosin function in the diaphragm from 6- and
9-mo-old mdx mice. This indicates that the contractile apparatus of regenerated muscle fibers may be intrinsically
dysfunctional in mdx diaphragm. However, at present, only a
limited amount of data are available on the mechanical performance of
mdx mouse diaphragm in the early stages of the disease
(17), i.e., before extensive fibrosis of the muscle.
The first aim of our study was to determine whether intrinsic diaphragm
muscle function was impaired in 6-wk-old mdx mice. Between 3 and 4 wk, the mdx diaphragm exhibits extensive muscular necrosis followed by regeneration (32). Therefore, whereas
individual necrotic fibers can still be detected in 6-wk-old
mdx mouse diaphragm, deposits of connective tissue are still
expected to be low. In addition, at this age, maturational changes
occurring in the diaphragm in the early postnatal period are expected
to be complete (9, 37). The second aim of our study was to
determine whether potential muscle weakness was associated with changes
in the number, kinetics, and single force of cross bridges (CB).
Huxley's equations (21) were used to calculate the single
force of CB, total number of CB, rate constant for attachment and
detachment, and total duration of the CB cycle (10, 22) in
control and mdx mouse diaphragm. Two hypotheses were tested:
1) decreased intrinsic diaphragm muscle function is already
present in 6-wk-old dystrophic mice; and 2) changes in the
mechanical properties are associated with changes in CB properties.
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MATERIALS AND METHODS |
Animals
Experiments were conducted on 12 six-wk-old male mdx
mice and 11 age-matched control mice (C57BL/10ScSn) obtained from
Charles River Laboratories (St-Aubin-les-Elbeufs, France). One subgroup of eight mdx and eight controls was used for mechanical
analysis. Another subgroup of four myopathic mice and three control
mice was used for morphometric analyses. Ideally, both the mechanical and the morphological experiments should have been conducted on the
same animal. However, the mdx mouse is a highly reproducible model of muscular dystrophy. Therefore, no significant differences are
expected between the different groups of animal. Care of the animals
conformed to the Helsinski declaration, and the study was approved by
our institution (Institut National de la Santé et de la Recherche
Médicale). After brief ether anesthesia, the animals were
laparotomized and then thoracotomized.
Mechanics
Diaphragm muscle strips.
A strip of the ventral part of the costal diaphragm was carefully
dissected out from the muscle in situ. The insertions on the central
tendon and ribs were kept intact. The diaphragm strip was rapidly
mounted in a tissue chamber containing a Krebs-Henseleit solution (in
mM): 118 NaCl, 24 NaHCO3, 4.7 KCl, 1.2 MgSO4 · 7H2O, 1.1 KH2PO4, 2.5 CaCl2 · 6H2O, 4.5 glucose. The solution was bubbled with 95% O2-5%
CO2 and maintained at pH 7.4 and 26°C, so as to ensure
good mechanical stability. The costal end of the muscle strip was held
in a stationary clip at the bottom of the chamber, whereas the central
tendon end was maintained with a second clip, attached to an
electromagnetic force-transducer device (9). After a
15-min equilibration period, the muscle was supramaximally stimulated
via two platinum electrodes arranged longitudinally on either side of
the muscle (electrical field stimulation: 30 V/cm). A force-frequency
curve was determined by stimulating muscle strips at 33, 50, 75, 100, and 150 Hz (1-ms pulse duration, 300-ms train duration, 10 per minute)
(Fig. 1). Maximum isometric tension was
generally achieved at a stimulation frequency of 100 Hz. Experiments were carried out at the initial resting length corresponding to the
apex of the initial length-active tension curve
(Lo). At the end of the experiment, the
cross-sectional area (CSA; in mm2) was calculated from the
ratio of muscle weight to muscle length at Lo,
assuming a muscle density of 1.06 (7). Characteristics of
the studied muscle strips (n = 8 in each group) were as
follows: Lo, 6.8 ± 0.2 and 5.7 ± 0.3 mm in control and mdx diaphragm, respectively (P = not significant); CSA, 0.5 ± 0.1 mm2 in both control and mdx diaphragm.
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Fig. 1.
Force-frequency relationships in control and 6-wk-old
mdx (Mdx) mouse diaphragm. Values are means ± SE
(n = 8 in each group). A: total isometric
tension is expressed in absolute values (mN/mm2).
B: total isometric tension is expressed in percentage of
maximum total tension.
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Mechanical Parameters
Maximum unloaded shortening velocity
(Vmax, in Lo/s) was
measured by means of the zero-load clamp technique (6).
Peak isometric tension, i.e., peak force normalized per CSA
(Po; in mN/mm2), was measured from the fully
isometric contraction. The tension-velocity relationship
(P-V) (19) was derived from the peak velocity
(V) of 8-10 isotonic afterloaded contractions, plotted
against the isotonic force level normalized per CSA (P) and by
successive load increments from zero load up to the total isometric
tension (Po). The P-V relationship was fitted
according to Hill's equation (P + a)(V + b) = (Po + a)b
(19), where 
a and b are the
asymptotes of the hyperbola as determined by multilinear regression.
For each muscle strip, the P-V relationship was accurately
fitted by a hyperbola (each r > 0.98). The curvature
of Hill's equation (G) is equal to
Po/a = Vmax/b (19, 42).
CB characteristics.
Force and shortening are generated by cyclic interactions between
myosin and actin, driven as one molecule of ATP is hydrolyzed (21). According to Huxley's theory (21), the
most widely accepted theory of muscle contraction, Po is
the product of the number of cycling CB/mm2 and the force
of a single CB. Huxley's model makes it possible to calculate the
total number and the elementary force of cycling CB and the kinetics of
the main steps of the CB cycle from mechanical data (10, 21,
22).
The maximum value of the rate constant for CB attachment,
f1 (in s
1), is given by
where g1 (in s1) is the
maximum value of the rate constant for CB detachment during the power
stroke, and g2 (in s1) is the
maximum value of the rate constant for CB detachment after the power
stroke
where w is the maximum mechanical work of a single CB, h is the
molecular step size (h is assumed to be equal to 11 nm), and e is the
free energy required to split one ATP molecule per contraction site
(e = 5.1 × 1020 J) (21,
42)
The elementary force per CB, 
(in pN), is given by
where l is the length between two actin binding sites
(l = 36 nm) (42). The total number of CB
per millimeter squared at Po (
) is
The total time cycle (tc; in ms) is equal to
The mean CB velocity during the stroke, 
o (in
µm/s), is given by (22)
Morphometry
Tissues from ventral costal hemidiaphragm were held in an
extended position by pinning them to a piece of cork. Then they were
snap-frozen in isopentane precooled in liquid nitrogen and stored at
80°C. Transverse cryosections of the diaphragm (10 µm) were
stained with Masson's trichrome to determine the percentage of
centrally and peripherally located nuclei, the percentage of necrotic
fibers, and the percentage of fibrosis (determined by the area of
stained collagen fibers). Central nuclei in fibers usually indicate
that these fibers have regenerated at least once. A total of 15 sections per sample were analyzed. Therefore, for each diaphragm,
fields were randomly chosen in each of the 15 sections, and a total of
1,500 fibers were counted per diaphragm (i.e., 100 fibers per section).
The percentages are thus relative to the total number of fibers
counted. Sections were observed with an Olympus BX 60 microscope. The
area of stained collagen fibers was determined by using an
image-analysis software (MetaView image analysis).
Statistical Analysis
Data are expressed as means ± SE. After ANOVA, comparisons
of mechanical parameters between mdx and control groups were
performed by using Student's unpaired t-test. Comparisons
of histological parameters were performed by using two-way ANOVA with
repeated measurements. A P value <0.05 was considered
statistically significant.
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RESULTS |
Diaphragm Morphometry
Limited areas of necrotic muscle fibers were observed in 6-wk-old
mdx mice (Fig. 2). Percentages
of fiber necrosis represented 2.8 ± 0.6 and 0.1 ± 0.1% of
the total muscle fibers in the mdx and control diaphragm,
respectively (P < 0.05). Very little fibrosis was
observed in the diaphragm muscles of 6-wk-old mdx mice,
although the collagen surface area was significantly larger than in
controls (3.6 ± 0.7 compared with 1.1 ± 0.1%,
P < 0.05). The percentage of fibers having central
nuclei was 24.9 ± 2.8% in the mdx and 0.3 ± 0.1% in the control mice.
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Fig. 2.
A: transverse section of a 6-wk-old control mouse
diaphragm showing normal muscle morphology. B: transverse
section of a 6-wk-old mdx mouse diaphragm. C:
higher magnification of a field in B. *Necrotic muscle
fiber; arrows, fibrous connective tissue (blue/green). Masson's
trichrome, magnifications: ×50 (A and B); ×200
(C).
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Contractile Performance of the Diaphragm Muscle
Mechanical parameters of the diaphragm muscle are presented in
Fig. 3. Po was 37% lower in
6-wk-old mdx than in controls (P < 0.01).
Moreover, compared with controls, there was an almost 32% decline in
Vmax in the mdx group
(P < 0.001). Compared with controls, the G
of the force-velocity hyperbola was significantly lower in
mdx mice (5.9 ± 0.7 compared with 3.6 ± 0.4, P < 0.01; Fig. 4).
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Fig. 3.
Mechanical parameters in control (C) and 6-wk-old
mdx mouse diaphragm. A: peak isometric force
normalized per cross-sectional area (Po). B:
maximum unloaded shortening velocity (Vmax).
Values are means ± SE (n = 8 in each group).
 P < 0.01,  P < 0.001 compared with control. Lo is the initial muscle
length at which active tension is maximum.
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Fig. 4.
Force-velocity relationships in control and 6-wk-old mdx
mouse diaphragm. A: absolute tension (P) and shortening
velocity (V) values were used to determine the
P-V relationships. B: normalized P and
V values were used to determine the G curvature
of the hyperbola. Pmax, maximum absolute tension.
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Diaphragm CB Properties
CB number and force in mdx and control diaphragm are
presented in Fig. 5. Compared with
controls, the 6-wk-old mdx diaphragm exhibited an ~30%
reduction in the total number of active CB per millimeter squared
(P < 0.01). The elementary force per CB was significantly lower in mdx than in controls (percent
difference between mdx and controls 
18%,
P < 0.01). CB kinetics in control and mdx
mice are presented in Fig. 6. The rate
constant for CB detachment g2 was significantly
lower in mdx than in controls (P < 0.05).
There was no difference in the rate constant for CB attachment
f1 between groups. The total duration of the CB
cycle was significantly shorter in mdx than in controls.
Compared with controls, the mean CB velocity during the power stroke
was significantly higher in mdx (P < 0.01).
In both mdx and control groups, there was a strong linear
relationship between Po and the total number of active CB
(Fig. 7): the higher the CB number, the
higher the Po. Conversely, there was no significant
relation between Po and the CB single force (Fig. 7).
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Fig. 5.
Total number of cross bridges (CB)
(109/mm2; A) and elementary force
per CB (; B) in control and 6-wk-old mdx mouse
diaphragm. Values are means ± SE (n = 8 in each
group). * P < 0.05, P < 0.001 compared with control.
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Fig. 6.
CB
kinetics in control and 6-wk-old mdx mouse diaphragm.
A: peak value for rate constants of detachment
(g2). B: total duration of the CB
cycle. C: peak value for the rate constant for CB attachment
(f1). D: mean
velocity of CB during the power stroke (o). Values are
means ± SE (n = 8 in each group).
* P < 0.05, P < 0.001 compared with control. Only significant difference is figured.
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Fig. 7.
A: relationship between Po and the
total number of CB (; 109). Within groups, there was a
close linear relationship between Po and in both
control (Po = 6.9 + 23.9; r = 0.979, P < 0.001) and mdx
(Po = 8.4 13.7; r = 0.970, P < 0.001) diaphragm. B: conversely, in
both control and mdx diaphragm, there was no simple
relationship between maximum isometric tension and .
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DISCUSSION |
The main result of the present study is that diaphragm muscle
performance was markedly impaired in 6-wk-old mdx mice,
i.e., at a stage at which muscle necrosis and/or fibrosis remained
limited. As CB interactions were accounted for, our study suggested
early CB abnormalities in the dystrophic diaphragm. Such abnormalities may well play a role in repetitive cycles of diaphragm muscle fiber
degeneration, a point that deserves further studies.
The genetic similarities between mdx and DMD have made the
mdx mouse an extremely attractive model for the study of
human muscular dystrophy. Previous studies have described the time
course of progressive muscle weakness and deterioration with age
throughout the life of mdx mice (17, 24). In
2-wk-old mdx mice, few abnormalities have been detected in
leg (24) and diaphragm muscles (17). Although
it would be of interest to analyze diaphragm CB interactions before 3 wk of age, maturational changes occur in the diaphragm in the early
postnatal period (37). These result from quantitative and/or qualitative changes in actomyosin interactions (9)
that may complicate the interpretation of the data. After extensive muscle necrosis at the age of 3 wk, early imbalance between
degeneration and regeneration leads to progressive fibrosis and severe
diaphragm muscle weakness (17, 34). On the one hand, the
percentage of muscle tissue to total diaphragm CSA averages only 72 and
44% of control values in 3- and 22-mo-old mdx diaphragm,
respectively (27). On the other hand, diaphragm tetanic
strength in the mdx mouse shows a 35-50% (14,
27), 50% (10), and 80% reduction (27,
34) at 3, 6, and 16 mo of age, respectively. However, it has
been suggested that the force-generating capacity of the diaphragm is
more impaired in 3-mo-old mdx than that expected from loss
of contractile tissue (27). In 6-wk-old mdx
mice, we found that diaphragm muscle function was severely impaired, despite limited necrotic and/or fibrotic lesions (2.8 and 3.6%, respectively). Thus, although progressive diaphragm fibrosis
undoubtedly impairs muscle strength by 3 mo of age, our results pointed
to severe muscle dysfunction as an intrinsic characteristic in
regenerated mdx diaphragm, which cannot be accounted for by
necrosis and fibrosis.
According to Huxley's equations, muscle force depends on the
elementary force produced per CB and the total number of CB generating contractile force (21, 22). Therefore, a severe decline in muscle strength, despite limited morphometric muscle damage, strongly suggests that CB recruitment and/or unitary force generated per CB are
altered in 6-wk-old mdx diaphragm. We found that both active CB and the elementary force generated per actomyosin interaction were
significantly lower in dystrophic than in control diaphragm (Fig. 5).
Associated changes in CB kinetics, as manifested by the shorter
duration of the CB cycle and longer time for CB dissociation, i.e.,
lower g2 value, further attested to qualitative
modifications in CB cycling in dystrophic diaphragm (Fig. 6). However,
the finding that total isometric tension (Po) was strongly
related to the total number of CB, but not to unitary CB force (Fig.
7), indicated that the 30% decrease in active CB played a preponderant
role in the impaired respiratory muscle force in the dystrophic mouse. These results are consistent with those previously reported in 6-mo-old
mice, although the reduction in force produced per myosin head between
control and mdx mouse diaphragm appeared higher in mdx mice from 6 wk of age (18% at 6 wk compared with
5% at 6 mo) (10).
Abnormal CB recruitment and qualitative changes in CB cycling suggest
functional alterations leading to impaired CB activation and/or
intrinsic molecular modifications of the myosin head structure (33). Recent studies have suggested that the dystrophin
complex has a scaffold function that recruits signaling proteins to the membrane (29, 38). The absence of dystrophin and its
associated proteins causes redistribution of neuronal NO synthase from
the membrane to the cytosol in muscle cells (5). These
abnormalities are associated with both a reduction in NO-mediated
protection against ischemia (36) and an increase
in cellular susceptibility to oxidant challenges (16, 18,
30). A number of studies have provided evidence that muscle
pathology in DMD and mdx mice is, in part, mediated by
free-radical species (28). Oxidative damage may induce
lipid peroxidation of membranes (3, 12), a mechanism that
could favor the development of diaphragm sarcolemmal injury in
dystrophic mice. Moreover, oxidative stress may induce oxidative
modifications of thiol residues involved in excitation-contraction coupling (1) and direct inhibition of CB interactions by
modulating critical thiols on the myosin head (23).
Modifications in isometric force, CB recruitment, and CB cycling
observed in the dystrophic diaphragm were fairly consistent with
previously reported effects of oxidative stress in skeletal muscle
(25). Subtle changes in amino acid integrity within the
myosin molecule itself may, in turn, contribute to the reduced CB
unitary force, given that in vitro motility assays have previously
revealed abnormal myosin function in purified actin and myosin
molecules from the mdx diaphragm (11).
Therefore, it seems likely that oxidative stress may contribute to
severe diaphragm dysfunction in 6-wk-old mdx mice.
Oxidative-stress-mediated myosin damage combined with sarcolemmal
vulnerability to mechanical stress would be predicted to favor the
development of diaphragm muscle injury.
Alternatively, the absence of the dystrophin complex leads to
disorganization of the costameric cytoskeleton, the cytoskeletal lattice that links the sarcomeric apparatus to the sarcolemma (41). This, in turn, may favor nonhomogeneity in sarcomere
length within muscle fibers and/or abnormal orientation of the myosin molecules relative to the actin filament axis, thereby altering interactions between the myosin head and actin filament (13, 35). One might also hypothesize that diaphragm dysfunction is linked to the regenerative process itself. Indeed, transitory expression of embryonic and neonatal myosin heavy chain (27, 40) and immature Ca2+ transient in fibers undergoing
regeneration (8, 15) may influence diaphragm contractile
properties (31). However, several findings argue against
such a hypothesis. First, limb muscles from 6-wk-old mdx
mouse exhibit functional recovery (17). Therefore, impaired force-generating capacity appears to be specific, either to
the diaphragm or to chronically active muscle (2). Second, it has been previously reported that progressive transitions in the
relative expression of the different myosin isoforms are not associated
with changes in CB unitary force value during postnatal development, at
least in the diaphragm muscle of the hamster (9) and the
rat (23). These observations strongly suggest that factors other than myosin heavy chain isoforms contribute to the impaired CB
kinetics in mdx diaphragm.
In conclusion, our study demonstrates that, in 6-wk-old mdx
mice, diaphragm weakness cannot be related to the presence of extensive
necrotic or fibrosis areas. Irrespective of the cause, the reduced
diaphragm muscle weakness may render the muscle more prone to
degeneration, as only a fraction of active CB is forced to carry the
ventilatory workload of the diaphragm.
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ACKNOWLEDGEMENTS |
This work was supported in part by the Fondation de France.
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FOOTNOTES |
Address for reprint requests and other correspondence:
C. Coirault, INSERM-LOA-ENSTA-Ecole Polytechnique,
Batterie de l'Yvette, 91761 Palaiseau Cedex, France (E-mail:
coirault{at}enstay.ensta.fr).
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.
10.1152/japplphysiol.00989.2002
Received 25 October 2002; accepted in final form 6 January 2003.
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