The skeletal muscle dystrophies (MD) are skeletal muscle diseases that cause progressive weakness and muscle degeneration. Duchenne muscular dystrophy (DMD), the most severe form of MD, results in respiratory muscle failure and/or cardiomyopathy leading to death. DMD results from the loss of the protein dystrophin from the dystrophin-associated glycoprotein complex (DGC). Deficiency of another DGC protein, caveolin-3, causes a milder limb girdle form of MD (LGMD-1c).
The function of dystrophin and caveolin-3 is not clearly understood. Interestingly, although these proteins are normally present in the embryo, DMD is usually not diagnosed until ages 2–5 years, by which time the pathology of the disease is well established. A possible explanation is that these proteins have a key functional role in the genesis of skeletal muscle and the heart. Understanding the role of these proteins during embryogenesis could be exploited for the benefit of earlier diagnosis and treatment of DMD children.
In this study, the authors use two mouse models of MD, mdx (deficient in dystrophin) and cav-3−/− (lacking caveolin-3) to examine the impact of these proteins on skeletal muscle development. In mdx embryos, skeletal muscle formation is delayed and stem cell behaviour is perturbed. In cav-3−/− embryos there is a later and less severe disruption of stem cell behaviour and muscle formation, consistent with the milder pathology of LGMD-1c compared with DMD. These data establish a key role for dystrophin in early muscle formation and demonstrate that caveolin-3 and dystrophin are essential for correct fibre-type formation and for emergent stem cell function.
It is now clear that early treatment significantly improves life expectancy and quality of life for DMD children. However, diagnosis is often delayed until the disease is well underway. This study suggests that understanding the role of dystrophin and its associated proteins may also lead to earlier diagnoses and treatment for DMD/LGMD patients, which would in turn lead to enhanced quality of life for individuals affected by these diseases.
