EDL and soleus muscles of the C57BL6J/dy2j laminin-alpha2-deficient dystrophic mouse are not vulnerable to eccentric contractions.

摘要

Many muscular dystrophies arise as a consequence of mutations in a series of interconnected proteins associated with the sarcolemma. This group of proteins is collectively referred to as the 'dystrophin-associated complex'. We used the C57BL6J/dy(2j), dystrophia muscularis, dystrophic mouse, in which the laminin-alpha(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/dy(2j) 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.