The membrane hypothesis of duchenne muscular dystrophy: Quest for functional evidence

Summary

(1) The location of dystrophin in normal muscle, its molecular structure and associations, characterize it as a component of the submembrane cytoskeleton. When dystrophin is missing the cystoskeleton will therefore be defective, and it has been supposed that this renders the muscle membrane more vulnerable to mechanical damage. With the discovery of animal strains lacking in dystrophin, this hypothesis has been put to experimental tests. Contradictory results have been obtained by workers using different exercise regimens and different indices of fibre damage.

(2) Direct measurements of the tensile strength of the membrane have been made on patches of cultured myotubes or isolated muscle fibres, and on sarcolemmal vesicles by pipette aspiration. Neither method has revealed a difference in the tensile strength between normal and dystrophic membrane. The most plausible explanation is that the tensile strength of the membrane is a property more of the lipid bilayer than of the cytoskeleton.

(3) In another experimental approach tensile membrane stress has been produced by exposing isolated muscle fibres and myotubes in culture to hypotonic solutions. In such experiments fibres and myotubes lacking dystrophin have been found to lyse more readily than do normal ones. This difference does not conflict with the similarity in tensile strength of normal and dystrophic fibre membranes noted above. Rather, the predisposition to osmotic lysis of dystrophic fibres and myotubes may signify a lower ratio of membrane surface to cell volume, perhaps as a result of loss of some of the spare membrane normally possessed by skeletal muscle fibres and myotubes.

(4) In red blood cells the membrane cytoskeleton functions to maintain membrane deformability and stability. Deficiency in spectrin, the main cytoskeletal component, predisposes red cells to cytoskeletal rupture and membrane loss when they experience shear stress. Skeletal muscle fibres, especially long fibres contracting eccentrically, are susceptible to shear stress as a result of uneven contraction along their length. In that event, fibres lacking dystrophin may similarly shed membrane more readily.