Dystrophin is a long rod-shaped protein that connects the subsarcolemmal cytoskeleton to a complex of proteins in the surface membrane (dystrophin protein complex, DPC), with further connections via laminin to other extracellular matrix proteins. Initially considered a structural complex that protected the sarcolemma from mechanical damage, the DPC is now known to serve as a scaffold for numerous signaling proteins. Absence or reduced expression of dystrophin or many of the DPC components cause the muscular dystrophies, a group of inherited diseases in which repeated bouts of muscle damage lead to atrophy and fibrosis, and eventually muscle degeneration. The normal function of dystrophin is poorly defined. In its absence a complex series of changes occur with multiple muscle proteins showing reduced or increased expression or being modified in various ways. In this review, we will consider the various proteins whose expression and function is changed in muscular dystrophies, focusing on Ca(2+)-permeable channels, nitric oxide synthase, NADPH oxidase, and caveolins. Excessive Ca(2+) entry, increased membrane permeability, disordered caveolar function, and increased levels of reactive oxygen species are early changes in the disease, and the hypotheses for these phenomena will be critically considered. The aim of the review is to define the early damage pathways in muscular dystrophy which might be appropriate targets for therapy designed to minimize the muscle degeneration and slow the progression of the disease.

The mdx mouse lacks dystrophin and is a model of human Duchenne muscular dystrophy. Single mdx muscle fibres were isolated and subjected to a series of stretched (eccentric ] i and force. Patch-clamping experiments identified a stretch-activated channel in both wild-type and mdx myotubes which was blocked by GsMTx4. These data suggest that blockers of stretch-activated channels can ameliorate the force reduction following stretched contractions by reducing the influx of Ca 2+ into the muscle. We therefore tested whether in intact mdx mice streptomycin, added to the drinking water, was capable of reducing muscle damage. mdx mice show a period of muscle damage from 20 to 40 days of life and fibres which regenerate from this damage display central nuclei. We measured the frequency of central nuclei in control mdx mice compared to streptomycin-treated mdx mice and showed that the incidence of central nuclei was significantly reduced by streptomycin treatment. This result suggests that blockers of stretch-activated channels may protect against muscle damage in the intact mdx mouse.

The permanent extra tension after a stretch and the deficit of tension after a shortening in the soleus muscle of the anaesthetised cat were measured using distributed nerve stimulation across five channels. At low rates of stimulation the optimum length for a contraction was several millimetres longer than that when higher rates of stimulation were used, so that movements applied over the same length range could be on the descending limb of the full activation curve but on the ascending limb of the submaximal activation curve. The extra tension after stretch and the depression after shortening were present only near the peak and on the descending limb of the length‐tension curve. Effects on final tension of changing the speed and amplitude of stretches or shortenings were found to be small. Statistical analysis showed that variations in the tension excess or deficit due to changing stimulus rate could be entirely attributed to the effect of stimulus rate on the length‐tension relation, as when length was expressed relative to optimum for each rate, stimulus rate was no longer a significant determinant of the tension excess or deficit. The extra tension after stretch and the depression after shortening disappeared if stimulation was interrupted and tension briefly fell to zero. These effects were explained in terms of a non‐uniform distribution of sarcomere length changes at long muscle lengths. During stretch some sarcomeres are stretched to beyond overlap while others lengthen hardly at all. During shortening some sarcomeres shorten much further than others. These mechanisms have important implications for exercise physiology and sports medicine.