筋疾患とオートファジー

抄録

The role of autophagy in muscle tissue has long been unknown. This is because lysosomes and autophagic vacuoles are not normally observed in normal muscle tissue morphology. However, the presence of muscle diseases in which large numbers of autophagic vacuoles are observed in muscle cells has led to increased attention to autophagy in muscle tissue. This autophagy–related muscle diseases are rare and intractable muscle diseases caused by abnormal autophagy due to lysosomal dysfunction. It is a collective term for a group of muscle diseases in which a large number of autophagic vacuoles appear in the muscle pathology, collectively called ‘autophagic vacuolar myopathies’. Autophagosomes, autolysosomes, and other vacuolar structures that appear during autophagy are thought to be “autophagic vacuoles”. They are currently classified into three categories based on etiology and morphological features.

First, Pompe disease, caused by enzymatic abnormalities within lysosomes, has historically been the most studied disease. This disease is characterized by the accumulation of excessive autophagosomes and glycogen within the lysosomes of muscle cells, occupying the entire cell ; the second is Danon disease and similar diseases caused by structural abnormalities in the lysosomal membrane. This relatively new disease concept is characterized by the appearance of specific autophagic vacuoles with sarcolemmal features (AVSFs) ; because AVSFs are highly disease specific, muscle diseases with AVSFs are termed “AVSF myopathies.” A third group of diseases in which autophagic vacuoles called rimmed vacuoles (RVs) appear are called RV–related myopathies and include a variety of conditions such as GNE myopathy and oculopharyngeal muscular dystrophy. All of these have causative genes outside the lysosome, and RV is thought to be a secondary induced autophagy abnormality.

Danon disease, a primary disorder of lysosomal dysfunction, is an X–linked disorder caused by a primary deficiency of the lysosomal membrane protein LAMP–2. In males, the disease causes cardiomyopathy, skeletal myopathy, and mental retardation ; in females, cardiomyopathy develops. Cardiomyopathy is a poor prognostic factor, and heart transplantation is currently the only treatment. It has been 40 years since the first report of Danon disease and 20 years since the identification of the causative gene, and then research has developed in various animal models. Although the pathogenesis of Danon disease remains largely unknown, the first clinical trials have finally begun.