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2-deficient dystrophic mouse are not vulnerable to eccentric contractions
1 School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia and2 School of Biomedical & Chemical Sciences, University of Western Australia, WA, 6009, Australia
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Abstract |
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2 component of the dystrophin-associated complex is mutated, to test the hypothesis that the disruption of this complex will destabilize the lipid bilayer, rendering it more susceptible to damage during eccentric contractions. We demonstrated that neither slow- nor fast-twitch dystrophic muscles were more susceptible to eccentric contractions when compared with controls. Only fast-twitch extensor digitorum longus (EDL) muscles (from both dystrophic and control mice) showed an irreversible loss of force with our eccentric contraction protocol, suggesting that it is the fast 11b fibres (not present in slow-twitch soleus) which are most susceptible to eccentric damage. We used the general anaesthetic halothane to increase the fluidity of the lipid bilayer to see if this would uncover any greater susceptibility of the dystrophic muscle to eccentric damage. This also did not reveal any greater fragility of fast- and slow-twitch dystrophic muscles. We did, however, demonstrate that halothane made both control and dystrophic fast- and slow-twitch muscles more susceptible to eccentric contraction damage. The C57BL6J/dy2j dystrophic laminopathy produced the pathophysiological and pathohistological characteristics associated with muscular dystrophy: the fast- and slow-twitch dystophic muscles produced only 55 and 53%, respectively, of the force of control muscles and 34 and 40%, respectively, of the dystrophic muscle fibres were branched. The presence of the branched fibres in the dystrophic muscles did not make them more susceptible to eccentric damage but may have contributed to the reduction in maximal force in the dystrophic muscles. We conclude that our data do not support the structural hypothesis that the dystrophin-associated complex acts as a scaffolding to support the lipid bilayer, but are consistent with channel-based hypotheses put forward to explain the dystrophic process.
(Received 5 February 2004;
accepted after revision 14 May 2004; first published online 7 June 2004)
Corresponding author S. I. Head: School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia. Email: s.head{at}unsw.edu.au
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Introduction |
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Experimental support for a structural role of the dystrophin-associated complex comes from a number of studies that have reported a greater degree of damage in dystrophic muscles compared to normal muscle following the muscle being stretched during a maximal isometric contraction (eccentric contraction). However, damage was only evident in a small percentage of fibres (Weller et al. 1990; Gillis, 1999). Further support for a structural role for the dystrophin-associated complex is provided by studies in which preventing dystrophic muscle from being used, through denervation or limb immobilization, reduces the dystrophic changes that would normally be observed in the muscle (Mizuno, 1992; Mokhtarian et al. 1999).
Other studies do not support the idea that the dystrophin-associated complex primarily plays a structural role. When muscles from the dystrophic mdx mouse were given eccentric contractions the muscles were not more susceptible to damage than control muscles (McArdle et al. 1991). Our own studies (Head et al. 1992) confirmed the findings of McArdle et al. (1991), with the single exception that the fast-twitch extensor digitorum longus (EDL) muscle from old mdx mice was damaged by a moderate eccentric contraction (66% drop in force). Moens et al. (1993) also reported that, apart from EDL muscles from older mdx mice (where nearly 100% of the fibres would be deformed; Head et al. 1992), the mdx muscles were not more susceptible to mechanical damage. Raymackers et al. (2003) also found a 69% drop in force in EDL muscles (which would contain branched fibres) from mdx mice when subjected to eccentric contractions. One interpretation of these reports of increased fragility of mdx EDL muscles is that the branched fast-twitch fibres have an increased susceptibility to eccentric contraction as a consequence of the branching itself rather than as a primary consequence of the absence of dystrophin. In a recent study (Yeung et al. 2003) using single fast-twitch fibres dissected out from the flexor digitorum brevis muscle, we showed that single mdx fibres (non-branched) were slightly more susceptible than controls to a severe (40% of initial muscle length, L0) eccentric contraction; the 100 Hz tetanus decreased to 34% in controls and 23% in mdx muscles. Importantly, the dystrophic damage did not appear be due to an increase of membrane fragility, since it was prevented by the addition Gd3+, an antagonist of mechanosensory channels. This study, along with another report (Tutdibi et al. 1999), demonstrates that the dystrophic damage is reduced in the presence of ion channel blockers and supports the hypothesis that the skeletal muscle abnormalities in dystrophies associated with mutations of the dystrophin-associated complex are due to channel-based mechanisms. Other studies also support the hypothesis that the dystrophin-associated complex plays a role in ion channel-based mechanisms in the membrane (Kong & Anderson, 1999). Further support for the channel clustering hypothesis (Carlson, 1998) is provided by our recent findings that CNS function in dystrophinopathies is altered as a result of the abnormal clustering of GABAA channels at the postsynaptic membrane (Anderson et al. 2003).
In the present study we used the C57BL6J/dy2j, dystrophia muscularis, mouse which expresses a truncated partially functional laminin-2 protein. The C57BL6J/dy2j mouse has a more severe skeletal muscle phenotype than the C57BL/10mdx mouse, in which the Dp-427-M dystrophin component of the dystrophin-associated complex is absent. The C57BL6J/dy2j mouse exhibits extensive and progressive skeletal muscle loss and replacement of skeletal muscle with connective tissue. By 28 days of age the rear limbs are no longer functional in supporting the mouse nor are they used in locomotion, being dragged behind the animal as it pulls itself along with its front limbs (Dangain & Neering, 1993). As such, the C57BL6J/dy2j mouse is a useful model in which to examine the physiological consequences of having the laminin-2 component of the dystrophin-associated complex disrupted.
We tested the hypothesis that, by having the dystrophin-associated complex compromised at the laminin component, the skeletal muscle would be more susceptible to damage by eccentric contraction (as would be expected if the dystrophin-associated complex plays a structural role in stabilizing the fragile lipid bilayer during contraction). We found this not to be the case. Furthermore, when we used the general anaesthetic halothane to increase the fluidity of the lipid bilayer and make the membrane more fragile, the dystrophic muscle was still no more susceptible to contractile damage than control muscle in the presence of halothane. However, halothane made both control and dystrophic muscle more susceptible to eccentric contractions.
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Methods |
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Ethical approval was granted by the Animal Ethics Committee of the University of New South Wales. C57BL6J/dy2j mice and littermate controls (7–14 weeks old) were killed by cervical dislocation. The details of the muscle set-up procedure have been reported elsewhere (Head et al. 1990). Briefly, the EDL and soleus muscles were removed and attached to a force transducer. The mean weight of the control EDL and soleus was 10.15 ± 1.13 and 9.8 ± 1.9 mg, respectively; while the mean weight of the dystrophic EDL and soleus was 9.5 ± 0.88 and 9.7 ± 0.89 mg, respectively. The muscles were set to their optimal length and were continuously superfused with Krebs solution (mM): 4.75 KCl, 118 NaCl, 1.18 KH2PO4, 1.18 MgSO4, 24.8 NaHCO3, 2.5 CaCl2 and 11 glucose, bubbled with 95% O2–5% CO2 to maintain the pH at 7.4. All experiments were undertaken at 22°C. The halothane solutions were prepared by placing 20 ml of Krebs solution into a closed glass syringe containing a small stir bar. Liquid halothane (10 µl) was then injected into the syringe and stirred for 60 min to give a final concentration of 5 mM. Solutions prepared in this manner have been found by gas chromatography to be within 5% of the desired concentration. During the time course of the halothane application it was estimated that the halothane concentration in solution would not change by more than 10% (Herland et al. 1990). The mean cross-sectional area of each muscle was calculated with the product of density of mammalian skeletal muscle (1.06 g cm–3) multiplied by optimal length, divided by the wet muscle mass. A standard (Graphpad prism) two-tailed t test was used to test the significance of treatments.
Eccentric contraction protocols
In initial studies we showed that the maximal muscle force was not affected by up to 20 maximal tetani of 7 s duration (data not shown). The muscles were maximally tetanically stimulated at 100 Hz for 7 s. The first 500–1500 ms of each contraction was isometric. During the remaining period of stimulation, the muscle was stretched by 12% of its length at a velocity of approximately 1 mm s–1 for 4 s and was then returned to its original position. For more details of the eccentric contraction protocol see our earlier study, Head et al. (1992).
Each muscle was given a control tetanus (1.5 s) at the start of each experimental run to determine the maximum force response, and this was followed by three stretch tetani of 7 s, at intervals of 2 min. The muscles were rested for 20 min before a final control tetanus (1.5 s) was given.
The eccentric contraction protocol was then repeated in the presence of 5 mM halothane (the muscles were preincubated in halothane for 10 min before the protocol commenced). After removal of the halothane, the muscles were again stimulated using the control protocol. Thus the control tetani before and after the eccentric contraction protocol were measured in the absence of halothane. In some experiments (3 EDL control and 3 soleus control) the halothane was presented at the beginning of the protocol in order to demonstrate that it was the halothane alone that caused the increased susceptibility to eccentric contractions and not the fact that the muscles had previously been subjected to a series of eccentric contractions. When done in this order, the halothane had the same effect on increasing the susceptibility of dystrophic and control muscles to the eccentric contraction protocol (data not shown).
Digesting the muscle
After experimentation, the muscles were removed, weighed, and incubated for 2 h at 35°C in Krebs solution with 0.2% collagenase IV (to help break up the muscle into individual fibres). The muscle was suspended in relaxing solution (in mmol l–1): 117 K+, 36 Na+, 1 Mg2+, 60 Hepes (N-[2-hydroxyethyl] piperazine-N'-[2-ethanesulphonic acid]), 8 ATP, 50 EGTA2– (ethyleneglycol-bis[ß-aminoethyl ether]N,N,N',N'-tetraacetic acid), and free [Ca2+] of 10–7M. Single fibres were obtained by trituration and viewed under an Olympus dissection microscope at 40x magnification (see Head et al. 1990 and Head et al. 1992 for more details).
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Results |
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The fast EDL and slow soleus muscle from the adult dystrophic mice could develop only 54 and 53%, respectively, of the maximal tetanic force compared with the force developed by the same muscles isolated from control animals (Table 1). When enzymatic techniques were used to isolate single muscle fibres it was striking that a significant proportion of the muscle fibres from dystrophic animals were morphologically abnormal (Table 1). The morphological abnormalities ranged from simple ‘Y’-type branching of the fibres to more complex disruptions of the normal cylindrical fibre geometry (Fig. 1). These fibre deformities were similar to those reported previously in adult dystrophic mdx muscle (Head et al. 1992) and 129 ReJ-dy/dy muscle (Head et al. 1990), and extend the findings of Ontell & Feng (1981) who reported branched regenerating myotubes in the C57BL6J/dy2j laminin-deficient mouse strain. These deformities may account for some of the loss of force that we observed in the dystrophic muscle (Table 1).
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Control EDL and soleus muscles were subject to the moderate eccentric contraction protocol. Both, the dystrophic and control EDL muscles had an irreversible loss of force in the time period examined (Figs 2A and B and 4A). In contrast, both the dystrophic and control soleus muscles were unaffected by the eccentric contraction protocol and recovered to produce the same maximal tetanic force as before the eccentric contraction (Figs 2C and D and 4A). Given that in adult mice the EDL is a mixture of IIa and IIb fibres in an approximate ratio of 50:50 while the soleus muscle is a mixture of type I and IIa in a ratio of 45:55 (Anderson et al. 1988), these results suggest that the type IIb fibres are the most susceptible to eccentric contractions in both the dystrophic and control EDL muscles (IIb fibres are known to be the most susceptible to eccentric damage in normal animals; Proske & Morgan, 2001).
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We also incubated some muscles with halothane in order to increase the ‘fluidity’ of the lipid bilayer (Ueda, 1991). The rationale behind this procedure is that it could unmask any excessive fragility of the lipid bilayer in the dystrophic muscles and increase their susceptibility to damage caused by eccentric contraction. In the EDL the damaging effect, as measured by the reduction of the maximal tetanic force, of the eccentric contraction protocol was significantly enhanced by the presence of halothane (Figs 3A and B and 4B). The dystrophic and control soleus muscles were also slightly susceptible to eccentric contraction damage in the presence of halothane (Figs 3C and D and 4B). This demonstrates that our proposition that using a volatile general anaesthetic to increase the muscle membrane fluidity would increase its susceptibly to eccentric contraction damage was correct. However, exposure to halothane did not unmask any greater susceptibility to eccentric contraction damage in the dystrophic muscles (Fig. 4B).
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Discussion |
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This study showed that the absolute force per cross-sectional area was decreased in both slow- and fast-twitch muscles from C57BL6J/dy2j mice when compared with age-matched controls. This adds to other work that has demonstrated that mouse laminin-deficient dystrophies result in skeletal muscles that produce less force (Fink et al. 1986; Dangain & Neering, 1992). These dystrophies are characterized by an infiltration of connective tissue when the skeletal muscle degenerates and this increase in non-contractile tissue would result in whole muscles that produce less force per cross-sectional area. However, the increase in connective tissue is not the whole explanation for the loss in force, because in a study using single skinned fibres where only the contractile proteins were present the laminin-deficient fibres only produced 80 and 60% of the maximal force of control EDL and soleus fibres, respectively (Fink et al. 1986) compared with 54 and 53% in whole EDL and soleus, respectively, reported in the present study. It is also probable that part of the reduction in force is a consequence of the increased number of branched fibres present in the dystrophic muscles, since the branched fibres have previously been shown to generate lower maximal forces (Head et al. 1990). Skeletal muscle fibre branching appears to be a characteristic of all the muscular dystrophies that are associated with mutations of the dystrophin-associated complex. Muscle fibre branching has been reported in boys with Duchenne muscular dystrophy (Schmalbruch, 1984) and in the muscles from mdx mice (Head et al. 1992; Lefaucheur et al. 1995; Bockhold et al. 1998), in the ReJ-dy/dy mouse (Isaacs et al. 1973; Head et al. 1990), and also previously in the C57BL6J/dy2j mouse (Ontell & Feng, 1981).
Eccentric contractions
We wanted to test whether the mutation of the laminin-2 chain of the dystrophin-associated complex made the C57BL6J/dy2j muscle more susceptible to eccentric contractions. During an eccentric contraction the muscle is stretched by certain types of physical activity or by the experimenter while the muscle fibres are being maximally activated (Morgan & Allen, 1999). It is well documented that the greatest forces experienced by normal skeletal muscle occur during eccentric contractions (see Allen, 2001 for review). It has also been reported that fast-twitch fibres, in muscles which most commonly undergo eccentric contractions, are the first to show damage in Duchenne muscular dystrophy (Webster et al. 1988). If the primary role of the dystrophin-associated complex is to protect the membrane from stress-induced damage, then it would seem reasonable that muscles in which the dystrophin-associated complex is altered would be more prone to stress-producing contractions than normal. The striking result from the present study was that this was not the case in the C57BL6J/dy2j mice. In fact, it was surprising how similar the responses of the control and the dystrophic muscles were to the eccentric contraction protocol. When both the soleus and EDL muscles (control and dystrophic) were subjected to our moderate eccentric contraction protocol, only the EDL muscles (control and dystrophic) experienced a loss of force. Given that the EDL is a mixture of type IIa and IIb fibres while the soleus is a mixture of type I and IIa, this suggests that the type IIb fast fibres are the most prone to eccentric injury, as has been widely reported (see Proske & Morgan, 2001 for review). In our previous studies (Head et al. 1990, 1992) we reported that under some conditions branched fibres can sustain less force than unbranched normal controls. The rationale behind this can be seen in part by examining the middle panel of Fig. 1, which shows a fibre branching into two parts of unequal diameter. During intense contractile activation there would be significant shear stresses placed on the point where the smaller branch comes off and this may be enough to cause a rupturing or tearing of the fibre. In the present study, however, neither the dystrophic EDL (34% branched fibres) nor the dystrophic soleus (40% branched fibres) showed an increased susceptibility to damage. A possible explanation for this lies in the fact that in dystrophic muscles which showed greater susceptibility to damage compared with controls, the percentage of branched fibres was considerably higher and ranged from 60 to 100% (Head et al. 1990, 1992). Therefore, in the present case it is possible that the branched fibres could have been supported by the majority of unbranched fibres, protecting them from eccentric contraction-induced damage. The reduced ability of the dystrophic muscles to produce force may have contributed to a reduced level of damage caused by the eccentric contraction. However, because the relationship between the lengthening contraction given to the intact muscle and resultant shear stresses placed on the individual muscle fibres will not be the same for dystrophic and control muscles due to an increase in intramuscular connective tissue mixed in with branched fibres in dystrophic muscle, this would suggest that proportionally greater lengthening contractions would have to applied to the dystrophic muscle in order to place the equivalent shear stress on the membrane of individual fibres compared with control muscle, as was the case in the present study. If inactivity in the dystrophic EDL muscle causes a switch in fibre type from IIb to IIa then this would confer a degree of protection against damage induced by eccentric contraction. However, in two previous studies (Fink et al. 1986; Head et al. 1990) using a more severe phenotype of the laminin-deficient mouse where the rear limbs are also not functional, we and others have shown, using skinned fibre techniques, that even though muscle inactivity has some small effects on the contractile properties of the IIb fibres in EDL, functionally the properties are still more reminiscent of IIb than IIa fibres.
Eccentric contractions in the presence of halothane
In an attempt to uncover subtle weakening effects that may occur due to the mutation of the laminin-2 component of the dystrophin-associated complex we used the general anaesthetic halothane to increase the fluidity of the membrane (Ueda, 1991). These experiments clearly demonstrated that the application of a general anaesthetic makes fast-twitch skeletal muscle significantly more susceptible to eccentric damage. However, again the dystrophic muscle was affected to the same degree as the control. In both the control and dystrophic soleus muscles which had previously been undamaged by the eccentric contraction protocol the application of halothane increased the membrane fluidity to the extent that the eccentric contraction protocol now produced a reduction in the maximal force. This loss of force was the same in dystrophic as in control soleus. Therefore, it would seem reasonable to conclude that the increase in fluidity due to halothane had now made the IIa fibres (present in both soleus and EDL) more vulnerable to eccentric damage. Clearly the volatile anaesthetic makes the membrane more susceptible to damage by eccentric contractions, but the alteration of the dystrophin-associated complex at the level of laminin does not appear to make the lipid bilayer structurally less stable. The disruption of the laminin-2 component of the dystrophin-associated complex does, however, result in skeletal muscle necrosis, a muscle which can only produce in the order of 50% of normal maximal force, and branched fibres.
Conclusions
The present findings do not support the structural hypothesis for the function of the dystrophin-associated complex and are consistent with a channel-mediated mechanism of dystrophic degeneration.
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References |
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indicate the start and finish of the eccentric contraction, while 
indicate the start and finish of the muscle stimulation. A, control EDL; there is an irreversible decrease in the maximum isometric force after the lengthening contraction protocol. B, C57BL6J/dy EDL; there is an irreversible decrease in the maximum isometric force after the lengthening contraction protocol. Although the absolute force is less than for the controls, the relative change in force as a consequence of the lengthening contraction protocol is not significantly different from controls. C, control soleus; the muscle recovers its full isometric tetanic force (* twice as long in order to clearly display it) after the lengthening contraction protocol. D, C57BL6J/dy soleus; the muscle recovers its full isometric tetanic force (* trace displaced for clarity as both the control and recovery tetanus overlapped each other) after the lengthening contraction protocol. The period between the 
