Recognition

of an often dramatically increased epimuscular force transmission to antagonistic muscles (via increased endomysial and perimysial cross links) has now lead to encouraging surgical advances in this field (9, 10). It is therefore hardly surprising that an overlap between myopathies and connective tissue diseases is increasingly being recognised, involving their molecular dynamics as well as clinical expression (6). #XAV-939 keyword# For example the involvement of collagen type VI has been demonstrated for many congenital muscular dystrophies, as reviewed by Schessl et al. (11). We therefore suggest that the following observations and recommendations regarding a stronger inclusion of connective tissue components in muscular dystrophies may be viewed as part of a similar shift of attention within the larger field of neuromuscular research.

Fibrosis in DMD Generally, Inhibitors,research,lifescience,medical fibrosis is referred to as the replacement of normal tissue with scar tissue. This means that fibrous connective tissue is the result of a reactive or reparative process. The following paragraph explains the link between the primary muscle disease DMD and fibrosis. The genetic cause of DMD is an x-chromosomal mutation Inhibitors,research,lifescience,medical of the dystrophin gene. Dystrophin mechanically stabilises myofibres by linking the cytoskeleton to the basal lamina through the dystroglycan complex. Dysfunction or lack of dystrophin leads to instability of muscle fibre

membranes. As a result, the cells are less resistant to mechanical shear and prone to excess influx Inhibitors,research,lifescience,medical of electrolytes such as calcium and sodium. An increase of intracellular sodium leads to ATP depletion, because Na+/K+ pumps need to operate at full capacity. Water molecules accompanying sodium produce cellular oedema. At rest the extracellular calcium ion concentration exceeds the cytoplasmic calcium ion concentration by a Inhibitors,research,lifescience,medical factor of 10,000. This gradient promotes calcium overload, resulting in mitochondrial uncoupling and the production of reactive oxygen species (ROS) such as oxygen ions and peroxides. The biochemical downstream effects are the accumulation of acidic metabolites and the amplification TCL of inflammatory substances such as cytokines (Fig. 2). Figure 2. Flowchart: from dystrophin deficiency to fibrosis. Lactic acid was considered the key element in acidosis- induced tissue damage until the 1970s. However, lactic acid is more than 99% dissociated into La– and H+ at physiological pH. La– increases collagen promoter activity leading to an increase of procollagen messenger RNA production and finally collagen synthesis. Furthermore, La– enhances angiogenesis via stimulation of vascular endothelial growth factor (VEGF) production in macrophages (12). Chemotaxis and mechanical stimuli initiate the production of fibrous tissue.