Autophagic vacuolar myopathy: Danon disease and related myopathies

Abstract

In morphological observations of normal muscle tissues, the presence of lysosomes or autophagic vacuoles is rarely noted. Hence, for a long time, the role of autophagy in muscle cells remained unclear. The importance of autophagy in muscle cells, however, started to attract attention with the identification of a subgroup of muscle diseases accompanied by many autophagic vacuoles in muscle cells. Myopathies caused by autophagy abnormality in skeletal muscles are called autophagic vacuolar myopathies. They collectively represent muscle diseases defined by conditions in which autophagic vacuoles present in muscle cells. 1 Currently, this subgroup can be categorized into three subtypes according to its pathomechanical and morphological characteristics (Table 1).The first subtype is Pompe disease, also known as glycogen storage disease type II. This is an autosomal recessive inherited disorder caused by a deficiency in acid alpha-glucosidase, a lysosomal enzyme. 2 Muscle pathology found that excessive glycogen accumulated in lysosomes and observed the formation of large autophagic vacuoles that occupy the entire cell. 3 The second subtype is a group of diseases caused by abnormalities in the structure and function of lysosomes. Since this subtype is characterized by the presence of specific autophagic vacuoles known as autophagic vacuoles with sarcolemmal features (AVSF), it is referred to as AVSF myopathies, 4 which is the focus of this article.Danon disease, a representative disease, is caused by a primary deficiency of lysosomal-associated membrane protein 2 (LAMP-2). 5,6 This subtype includes a few diseases besides Danon disease.The third subtype is a group of diseases with distinctive autophagic vacuoles called rimmed vacuoles. This subtype, rimmed vacuolar myopathy, is listed along with many diseases. 7,8 However, since all the causative genes identified in this subtype are present outside lysosomes, formation of rimmed vacuoles may be caused by an autophagy abnormality due to secondary lysosomal dysfunctions.

The Biology of Lysosomes: From Order to Disorder

“…Impaired GCase transport [43,103] PSAP Saposin C deficiency and impaired GCase function [9,104,105] Danon Disease (Dominant X-linked) LAMP-2 LAMP-2A dysfunction [119] Accumulation of immature autophagic vacuoles [136]. Glycogen accumulation in autophagic vacuoles [137].…”

A conserved STRIPAK complex is required for autophagy in muscle tissue

“…, 2000 ; Rowland et al. , 2016 ; Kazuma, 2021 ). Mutations in vacuolar ATPase assembly factor VMA21 result in excessive autophagy and patients with Duchenne muscular dystrophy exhibit lower levels of the microtubule-associated protein 1A/1B-light chain 3-II (LC3 II) and excess p62 ( De Palma et al.…”

Protein Aggregates and Aggrephagy in Myopathies

“…Autophagic vacuolar myopathies (AVMs) and protein aggregate myopathies (PAMs) represent a series of clinically heterogeneous myopathies characterized by lysosomal or extralysosomal accumulation of proteins or other substances, with varied ages of onset, progressive disease course and variable degree of severity [4][5][6].…”

“…The third group is defined by secondary lysosomal dysfunction leading to rimmed vacuoles, popcorn-like clear membrane-bound organelles with a densely blue rim by hematoxylin and eosin staining. This group comprises inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD), hereditary and sporadic inclusion body myopathy (hIBM and sIBM) and oculopharyngeal muscular dystrophy (OPMD), among others [4,7]. Recently, a new AVM caused by mutations in the PLIN4 gene has been described [8].…”