Lysosomal myopathies: An excessive build-up in autophagosomes is too much to handle

Abstract

Lysosomes are membrane-bound acidic organelles that contain hydrolases used for intracellular digestion of various macromolecules in a process generally referred to as autophagy. In normal skeletal and cardiac muscles, lysosomes usually appear morphologically unremarkable and thus are not readily visible on light microscopy. In distinct neuromuscular disorders, however, lysosomes have been shown to be structurally abnormal and functionally impaired, leading to the accumulation of autophagic vacuoles in myofibers. More specifically, there are myopathies in which buildup of these autophagic vacuoles seem to predominate the pathological picture. In such conditions, autophagy is considered not merely a secondary event, but a phenomenon that actually contributes to disease pathomechanism and/or progression. At present, there are two disorders in the muscle which are associated with primary defect in lysosomal proteins, namely Danon disease and Pompe disease. Other myopathies which have prominent autophagy in the skeletal muscle include X-linked myopathy with excessive autophagy (XMEA). In this review, these disorders are briefly characterized, and the role of autophagy in the context of the pathomechanism of these disorders is highlighted.

Introduction

Lysosomes are organelles found in plant and animal cells containing hydrolytic enzymes that digest macromolecules. These membrane-bound structures represent the final destination for many endocytic (phagic), autophagic and secretory molecules targeted for destruction or recycling [1]. Accordingly, numerous cellular processes are thought to depend on lysosomal function, including the turnover of cellular proteins, inactivation and downregulation of surface receptors, supply of endocytosed nutrients, inactivation of pathogenic organisms, repair of plasma membrane, and loading of processed antigens. Acidity in the lumen of lysosomes is maintained by vacuolar ATPases to achieve effective digestion by acid hydrolases. Lysosomes bud from the Golgi apparatus. When lysosomes fuse with phagosomes, the vesicles produced by endocytosis, they become phagolysosomes. Alternatively when they fuse with autophagosomes, which are the vesicles produced by autophagy, they are called autophagolysosomes. In this essence, lysosomes are dynamically maintained fusing with endosomes in cells.

Autophagy is a highly regulated process in an organized system that can either be involved in the turnover of long-lived proteins and whole organelles (mitochondria and endoplasmic reticulum) or can specifically target distinct organelles, thereby eliminating supernumerary or damaged organelles [2]. In general, autophagy is involved in the bulk degradation of cytoplasmic components within lysosomes. It is a process by which cells adapt their metabolism to starvation, which can be imposed by decreased extracellular nutrients or by decreased intracellular metabolites that result from the loss of growth factor signals, including insulin [3]. By the catabolism of macromolecules and bulk degradation of organelles, autophagy generates metabolic substrates and thereby allows for adaptive protein synthesis. Although it has been established that autophagy is regulated by various factors, recent works have demonstrated that autophagy could also occur as a non-regulated spontaneous process for renewal of the molecules and organelles [4].

Skeletal muscles and neuronal tissues are the primary organs where autophagy is physiologically enhanced [5]. In several neuromuscular disorders, the accumulation of autophagic vacuoles is seen in skeletal myofibers [6], [7], [8], [9], [10], [11]. Based on this pathological finding, these diseases are called autophagic vacuolar myopathies (AVM). Two disorders belonging to this group have been associated with primary lysosomal protein defects, namely, Danon disease and Pompe disease [12]. Despite the observation that generation of autophagic vacuoles can be remarkable in the skeletal and/or cardiac muscles, their precise relevance in each disorder and the mechanism by which they are formed remain to be clarified. Among AVM, in addition, a select group of myopathies has a peculiar pathological characteristic, called autophagic vacuoles with sarcolemmal features (AVSFs), because on light microscopy the autophagic vacuoles are lined by sarcolemmal proteins [13]. This latter group includes Danon disease and X-linked myopathy with excessive autophagy (XMEA). In this review, we will focus on these primary lysosomal protein deficiencies and related myopathies, highlighting the role of autophagy in the pathomechanism of the diseases.