Lists of autophagic vacuolar myopathies.
Muscle diseases represent specific muscle pathology. The characteristic features as hallmarks of diseases have been historically used to diagnose the patients. The “Rimmed vacuole (RV)” (Figures 1) is one of such characteristic features in certain groups of the diseases. This structure consists of the space (vacuole) and purple granules (rim) within myofibers, while the space is sometimes occupied with cytosolic contents indicating that the space is artificially produced during the staining process and the rims have the nature of this pathological hallmark. Ultrastructurally, as discussed later, many autophagic vacuoles and multi-lamellar bodies are observed in RVs.
Skeletal muscle represents 40~50% of the human body and is one of the most important sites for the control of metabolism. During catabolic conditions, muscle proteins are mobilized to provide alternative energy substrates for the other organs. The RV formation indicates dysfunction of autophagy and breakdown of energy homeostasis in diseased skeletal muscles. In addition, it also suggests the importance of autophagy in muscle functions. There is a group of muscle disease, generally referred to as autophagic vacuolar myopathies (AVM), which are characterized by the accumulation of autophagic vacuoles on skeletal muscle pathology.
In this review, we will give an outline of general knowledge and classification on AVMs and overview the molecular processes underlying autophagic vacuoles formation in rimmed vacuolar myopathies on the basis of our experimental evidences regarding GNE myopathy.
2. Autophagic vacuolar myopathies
Dysfunctional autophagy is associated with several neurodegenerative disorders [1-3]. As for muscle disorders, these are referred to as AVMs . Since the autophagosomes are not observed in normal muscle fibers, autophagic vacuoles have been often recognized as pathologic hallmarks of numerous neuromuscular disorders. Two major categories in AVMs include lysosomal myopathies and rimmed vacuolar myopathies (Table 1) [4-6]. The former are associated with a primary defect in lysosomal proteins and the two best-described and genetically diagnosable AVMs, Pompe disease and Danon disease, are classified in this group. In contrast, autophagic vacuoles in rimmed vacuolar myopathies are secondarily caused by extra-lysosomal defects and usually observed at later stages of the disease. There are various kinds of rimmed vacuolar myopathies including sporadic inclusion body myositis (sIBM) and myofibrillar myopathies and most of them are clinically and etiologically heterogeneous disorders.
|Acid maltase deficiency (Pompe disease)||
|X-linked myopathy with excessive autophagy (XMEA)||(identified)|
|Inclusion body myositis (sIBM)||?|
|Inclusion body myopathy, Paget’s disease of bone, and frontotemporal dementia (IBMPFD)||
|Oculopharyngeal muscular dystrophy (OPMD)||
2.1. Lysosomal myopathy
Two best known disorders in AVMs are associated with primary lysosomal protein defects, namely, Pompe disease  and Danon disease . The former is caused by a deficiency of lysosomal enzymes within the vacuoles, whereas the latter is caused by a deficiency of lysosomal membrane structural protein .
2.1.1. Pompe disease
Pompe disease , also referred to as glycogen storage disease type II and acid maltase deficiency, is the best characterized lysosomal myopathy caused by a deficiency of acid α-glucosidase (GAA, also known as acid maltase). This enzyme defect results in lysosomal glycogen accumulation in multiple tissues and cell types, with skeletal and cardiac muscle cells the most seriously affected [10, 11]. The classic infantile form is a rapidly progressive disease with hypotonia, generalized muscle weakness, and hypertrophic cardiomyopathy, usually leading to death from cardiorespiratory failure or respiratory infection in the first year of life . But enzyme replacement therapy with recombinant human GAA is now available, which can dramatically improve the clinical features and life expectancy of the infantile Pompe disease patients [13-15]. The late-onset type shows less progressive clinical characteristics and absence of severe cardiomyopathy; these phenotypical differences are related to residual enzyme activity . The
On muscle pathology, cytoplasmic vacuoles are so remarkable and large that these occupy most of the space in many muscle fibers (Figure 2). The vacuoles contain amorphous materials that are presumably glycogen because of the strong reactivity with periodic acid Schiff stain. Acid phosphatase staining also shows strong signals in these vacuoles, indicating high lysosomal content . In terms of pathomechanism, the failure of the lysosomal degradation of glycogen leads to the accumulation of autophagic vacuoles, which may cause cellular dysfunction and abnormal cytoskeletal organization .
2.1.2. Danon disease
Danon disease is an X-linked disorder caused by the primary deficiency of lysosome-associated membrane protein-2 (LAMP-2) . Characteristic clinical features include skeletal myopathy, cardiomyopathy, and mental retardation. Male patients usually manifest the disease in their teens and die before their 30s from cardiac problems. LAMP-2 deficiency causes accumulation of autophagic vacuoles in a variety of tissues, including skeletal and cardiac muscles . As LAMP-2 is required for the maturation of early autophagic vacuoles by fusion with endosomes and lysosomes, deficiency of LAMP-2 leads to a failure in the normal progression of autophagic maturation .
Muscle biopsy from the patients with Danon disease show scattered small basophilic granules in myofibers and lysosomal acid phosphatase activity is increased in these granules (Figure 3). Large vacuolar structures having sarcolemmal features with acetylcholine esterase activity are surrounding those lysosomal granules and these structures are known as autophagic vacuoles with sarcolemmal features (AVSF) . This characteristic pathology in Danon disease (AVSF) is also seen in a number of diseases including X-linked myopathy with excessive autophagy (XMEA) , infantile autophagic vacuolar myopathy , and X-linked congenital autophagic vacuolar myopathy . The list of this group of autophagic vacuolar myopathy is rapidly expanding  and they are expected to be related with lysosomal function because the pathologic features are quite similar to those in Danon disease.
2.2. Myopathy with rimmed vacuoles
Rimmed vacuolar myopathies comprise more various and heterogeneous disorders. The most common disease in this group is sIBM, which has been traditionally considered as an inflammatory myopathy. Myofibrillar myopathy, a group of chronic myopathies with a similar pathologic phenotype, is caused by several different genes. And VCP myopathy and GNE myopathy are well known single gene disorders which can be classified as hereditary inclusion body myopathies (hIBM). In addition, it is not uncommon that rimmed vacuoles are appreciated in numerous chronic myopathies which are not classically classified as rimmed vacuolar myopathies.
2.2.1. Inclusion Body Myositis (sIBM)
sIBM is the most common muscle disease in elderly patients [23-25]. Clinically, general progressive muscle weakness starts after age 50 years. The quadriceps muscle and finger flexors are usually affected early on. sIBM Patients may become unable to perform daily living activities and require assistive devices within 10 years of symptom onset. Muscle biopsy characteristically reveals rimmed vacuolar muscle fibers with endomysial T-cell inflammatory infiltrates. Although there still remains controversy whether sIBM is an autoimmune inflammatory myopathy or a primary degenerative myopathy with secondary inflammation, it is becoming more likely that abnormal myoproteostasis and muscle fiber degeneration with aging play primary pathogenic roles in this disorder .
Askanas and Engel  indicated that several phenomena observed in the degeneration of sIBM muscle fibers are similar to the neuronal degenerative processes occurring in both Alzheimer’s disease and Parkinson’s disease. Abnormal accumulations of various pathogenic proteins, posttranslational modifications of the accumulated proteins, abnormal protein disposal, and impaired autophagy and 26S proteasome function are common intracellular features of neurodegenerative disorders and thus suggest that sIBM is, like neurodegenerative diseases, a complex degenerative disorder caused by protein misfolding and associated with multiprotein aggregation .
2.2.2. Myofibrillar myopathies
RVs are often appreciated in large numbers of myofibrillar myopathies [29-31], which is a group of hereditary myopathies pathologically characterized as markedly disorganized myofibrils with cytoplasmic inclusion. Clinical symptoms of myofibrillar myopathies are very variable. The onset age rages from infancy to the eighth decade. Some patients show limb girdle muscle involvement, whereas others show distal myopathy. Cardiomyopathy is often involved and even can be seen in patients with no obvious skeletal muscle weakness. Seven disease-related genes have been identified (
In the cardiomyocytes-restricted
2.2.3. Inclusion Body Myopathy, Paget’s disease of the bone, and Frontotemporal Dementia (IBMPFD); Valosin-Containing Protein (VCP) myopathy
Inclusion body myopathy (IBM) with Paget’s disease of bone (PDB) and frontotemporal dementia (FTD), now called IBMPFD or valosin-containing protein (VCP) myopathy, is a progressive autosomal dominant disorder caused by mutations in the
2.2.4. Other myopathies often related with rimmed vacuoles
Although they are not pathognomonic, RVs are often accompanied in various chronic myopathic conditions including Marinesco-Sjögren syndrome and oculopharyngeal muscular dystrophy (OPMD). It is interesting that these clinically and genetically different disorders are sharing a similar pathologic feature in skeletal muscles.
Marinesco-Sjögren syndrome is an autosomal recessive disorder clinically characterized by cerebellar ataxia, cataracts from infancy, mental retardation, and myopathy . Loss of function mutations in
OPDM is known to be caused by repeat expansion mutations in
3. GNE myopathy
GNE myopathy is one of the well described rimmed vacuolar myopathies. It is an autosomal recessive myopathy originally reported in 1981 by Nonaka et al. [43, 44], and thus is also referred as distal myopathy with rimmed vacuoles (DMRV) or Nonaka myopathy. In 1984, Argov and Yarom  reported a similar disorder among Iranian Jews with the title of ‘rimmed vacuolar myopathy sparing quadriceps’. And the term ‘quadriceps sparing myopathy’ and ‘hereditary inclusion body myopathy (hIBM)’ has also been used to refer this disease. Since these two disorders are thought to be identical and caused by GNE mutations , it would be better to harmonized the naming of this disease. The experts have recently designated the disease to be called “GNE myopathy”.
Among the AVMs secondarily caused by extra-lysosomal defects, GNE myopathy has some advantages for the pathomechanism research. It is a single gene disorder with a homogeneous phenotype and the model mice which evidently display similar features of a human GNE myopathy have been generated . Regardless of the upstream causes, autophagy in myopathies is thought to be mainly attributed to abnormal lysosomal function regarding their effects on myofiber breakdown in common and RVs appreciated in various kinds of myopathies is known to share similar histological and biochemical features. Thus, a comprehensive review of achievements and addressed issues in GNE myopathy research can broaden our understanding of this common pathomechanism of autophagy in rimmed vacuolar myopathies.
3.1. Clinical and pathologic features of GNE myopathy
Clinically, GNE myopathy is an early adult-onset progressive myopathy that affects the tibialis anterior muscle preferentially but spares quadriceps femoris muscles. The symptoms of distal limb muscle weakness start to affect the patient from the second or third decades, and most of the patients become wheelchair-bound between twenties and sixties with a median time to loss of ambulation of 17 years after disease onset . Although the tibialis anterior muscle is most significantly affected, gastrocnemius, hamstrings, paraspinal, and sternocleidomastoid muscles are also involved from an early stage. Cardiac and respiratory muscles are less involved. Serum creatine kinase (CK) levels are normal to mildly elevated .
Muscle pathology (Figure 5) is characterized by the presence of RVs predominantly in atrophic fibers, which are occasionally aggregated and form small groups. These RVs are actually clusters of autophagic vacuoles and multi-lamellar bodies. They often contain congophilic amyloid material and deposits that are immunoreactive to β–amyloid and its precursor protein, ubiquitin, and tau protein. Ultrastructurally, the filamentous inclusions measuring 15-20 nm in diameter are seen in both cytoplasm and nucleus with the presence of autophagic vacuoles. Necrotic and regenerating fibers can be rarely seen in GNE myopathy [4, 43, 44, 49].
3.2. Molecular pathomechanism of GNE myopathy
GNE myopathy is caused by mutations in the gene encoding a key enzyme in sialic acid biosynthesis, UDP-
After the identification of
4. Animal model: A
Gne knock out mouse expressing human GNE D176V mutation
Since the null mutation in
The muscle weakness, decreased whole muscle mass and reduced contractile power appeared in an age-related manner . After 20 weeks of age, the GNE myopathy mice started to show physiologic muscle weakness, observed as impaired motor performance and reduced force generation of the skeletal muscle. This reduction of the force might be attributed to muscle atrophy, as specific twitch and tetanic forces per cross-section area are maintained at this age. The reduction in gross size of the skeletal muscle is accompanied by an increase in the number of small angular fibers. After 30 weeks of age, specific force generation in the gastrocnemius and tibialis anterior muscles was notably reduced, while myofiber size variation became more remarkable. Intracellular deposition of amyloid and other various proteins was appreciated in the gastrocnemius muscle at this age. After 40 weeks, the muscle force generation worsened, as reflected by increased twitch/tetanic ratio, which might be due to the appearance of the characteristic RV and accumulation of autophagic vacuoles . With these results, the GNE-/-hGNED176VTg mouse is the only existing pathogenic model for GNE myopathy up to date.
Muscle pathology of GNE myopathy mice reveals RVs after 40 weeks of age (Figure 6). Intense acid phosphatase staining and expression of lysosomal-associated membrane proteins (LAMPs) and LC3 imply that autophagic process is activated in skeletal muscles of the model mice . Inclusion bodies are also appreciated with expression of various protein markers.
4.1. Autophagy in a mouse model of GNE myopathy
The characteristic RVs are observed after 40 weeks in the GNE myopathy model mouse. Like human muscle pathologic findings, these vacuoles have high acid phosphatase activity and strongly stained by various lysosomal antibodies (Figure 6) . Ultrastructurally, the RVs contain multi-lamellar bodies, electron-dense bodies, and heterogeneous cytoplasmic debris which are surrounded by double membranes, indicating these are autophagic vacuoles (Figure 7). In the near areas, several vacuoles have a single limiting membrane and some cellular debris have no membrane, indicating degradated or ruptured vacuoles. Interestingly, filamentous or granular deposits considered as amyloid often appear with the autophagic vacuoles. And these probable amyloid deposits are also observed in the normal areas, which may suggest that the deposition of protein precede the accumulation of autophagic vacuoles .
5. Prophylactic treatment with sialic acid metabolites in the GNE myopathy model mice
A possibility of the development of therapy for GNE myopathy was demonstrated in our model mice. As the addition of sialic acid metabolites has been shown to recover overall hyposialylation in cells , we have challenged in administering sialic acid compounds
Sialic acid metabolites administration also led to a marked change in the muscle pathology of GNE myopathy mice (Figure 9) . Although all mice in the control-treated group showed RVs in the gastrocnemius muscles, only a few in the treatment groups showed RVs. As RVs are autophagic in nature, we checked for acid phosphatase staining and found decreased staining. The expression of LC3 and Lamp2, which are markers for autophagosomal structures, were not observed in the muscle sections of ManNAc treated mice, except for one mouse that had few RVs in the muscle. The amounts of LC3-I and LC3-II, used as an index to analyze autophagic induction in tissues, were lower after treatment. Treatment also increased muscle cross-sectional area (CSA) and diminished congophilic, amyloid-positive and tau-positive inclusions.
Our successful prophylactic treatment results on the model mice supports the current concept that hyposialylation is one of main factors contributing the pathogenesis of GNE myopathy. This concept suggests that GNE myopathy is a potentially treatable disease and A phase I clinical trial for human patients using oral sialic acid therapy is recently underway in Japan.
6. Future issue 1 — Hypothesized pathway from hyposialylation to RVs formation
Although it has been already demonstrated that hyposialylation is a key factor in the pathomechanism of GNE myopathy and sialic acid metabolites administration can prevent the development of myopathic phenotype in GNE myopathy model mouse, there still remains an unexplained link between hyposialylation due to GNE mutations and the pathognomonic findings in the muscle. However, since the the model mice exhibit hyposialylation and intracellular amyloid deposition before the characteristic RVs appear, we can appreciate that the dysfunctional autophagy is a downstream phenomenon to hyposialylation and amyloid deposition in GNE myopathy.
In normal macroautophgy process, cytoplasm and organelles are enclosed by an isolated membrane (phagophore) to form an autophagosome. The outer membrane of the autophagosome fuses with the lysosome, and the internal material is degraded in the Autolysosome . However, in hyposialylated condition, the autophagy does not progress normally. As hyposialylation can lead to abnormal protein configuration or misfolding, an excessive amount of misfolded glycoproteins which were not degraded in the ER may cause abnormal autophagy in GNE myopathy (Figure 10). Hyposialylation may also lead to abnormal protein processing which can induce abnormal protein deposits in cytoplasm. In addition, there are several reports that suggested oxidative stress is involved in the upstream pathways to amyloid deposition and/or RVs formation. One previous report showed that autophagic vacuoles were associated to be a site of amyloidogenic amyloid precursor protein processing and intra-lysosomal amyloid-β accumulation was induced by oxidative stress . And another report demonstrated that reactive oxygen species may contribute to the formation of autophagosomes . An experimental result implying a biologic function of sialic acid as an oxygen radical scavenger suggests hyposialylation can directly contribute to the increase of oxidative stress and support the above concept .
7. Future issue 2 — The common molecular processes underlying autophagic vacuoles formation in rimmed vacuolar myopathies
Regarding the pathomechanism of rimmed vacuolar myopathies, it is interesting to figure out how various kinds of myopathies from different etiologies can share the similar pathology and undergo similar pathogenic process. One of the most impressive finding is that the accumulation of misfolded proteins and subsequent activation of autophagy are observed in all kinds of rimmed vacuolar myopathies commonly and constantly, which bring us that intra-myofiber accumulation of conformationally modified proteins plays a primary pathologic role in these disorders. However, up-regulation of autophagy alone may not be enough to form RVs if the pathways are operating properly. The primary role of autophagy is to protect cells under stress conditions and it is widely accepted that in most of neurodegenerative diseases, activation of autophagic process is an adaptive response against disease-related stress conditions. The fact that not all myofibrillar myopathy muscles show RVs suggests that the other pathways are necessary to complete RV formation.
Dysfunctional autophagy is another important common feature in rimmed vacuolar myopathies. It was already demonstrated that autophagy is impaired in sIBM, IBMPFD, GNE myopathy, and Marinesco-Sjögren syndrome [26, 37, 40, 61]. Regardless of upstream process, autophagosomes are proliferated and enlarged with lysosomal dysfunction and macroautophagy disregulation, and it might be contribute or worsen the abnormal accumulation of various proteins such as amyloids, p-tau, α-synuclein, and p62. This two major common process, up-regulated and dysfunctional autophagy, possibly develop characteristic RVs in skeletal muscle pathology.
Herein we presented the current knowledge on AVMs and recent approaches to the pathogenesis of rimmed vacuolar myopathies. With the model mice, we proved that hyposialylation is a key factor in the pathomechanism of GNE myopathy. And we also provided evidences that prophylactic treatment with sialic acid metabolites prevents the myopathic phenotype and substantially reduced the number of RVs in the GNE myopathy mice. Since rimmed vacuolar myopathies have revealed to share common pathways regarding the autophagic vacuoles formation irrespective of heterogeneous clinical phenotype and etiology, our experimental achievement can broaden the general understanding on the common pathomechanism of AVMs.
This work is supported by JSPS KAKENHI Grant Number 23390236, by Comprehensive Research on Disability Health and Welfare from the Ministry of Health and Labour, and by Intramural Research Grant (22-5) for Neurological and Psychiatric Disorders of NCNP.
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