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Relationship between age of the patients with Danon disease and number of muscle fibers with vacuoles highlighted with dystrophin or LIMP-1 on immunohistochemistry. The open circles show the only patient who had 2 muscle biopsies. The muscle fibers (circles) with intracytoplasmic vacuoles surrounded by dystrophin immuno-positive membrane (AVSFs) increased with age (r = 0.936). The muscle fibers (triangles) with overexpression of LIMP-1 showed a slight decrease with age (r = 0.353). r, Pearson’s linear correlation coefficient.
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Among the autophagic vacuolar myopathies (AVMs), a subgroup is characterized pathologically by unusual autophagic vacuoles with sarcolemmal features (AVSF) and includes Danon disease and X-linked myopathy with excessive autophagy. The diagnostic importance and detailed morphologic features of AVSF in different AVMs have not been well established, a...
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Context 1
... routine histologic studies, the vacuolar membranes in Danon disease, probable XMEA, infantile AVM and adult- onset AVM were essentially identical ( Table 1). All muscle samples showed mild to moderate variation in fiber size. There were no necrotic fibers except in muscle from adult-onset AVM, which revealed a few necrotic and regenerating fibers. There were scattered small basophilic granules rather than vacuoles in the muscle fibers in H&E-stained sections (Fig. 1). Histochemistry revealed AChE and NSE activities in the vacuolar membranes and the vacuolar structures of the granules. Immunohistochemistry also confirmed presence of AChE in those vacuoles. However, they did not bind to a -bungarotoxin, indicating the absence of acetylcholine receptors (AChRs) in the vacuolar membranes. By immunohistochemistry, the AVSF reacted for all the tested sarcolemmal and extracellular matrix proteins in the vacuolar membranes in muscle from patients with Danon disease and related AVMs, although reactivity levels of the proteins were variable (Table 1; Fig. 1). However, only collagens IV and VI showed less intense reactivity in the vacuolar membranes than that in the sarcolemma. Most of the AVSFs were scattered throughout the cytoplasm rather than clustered in the subsarcolemmal region. On serial transverse 5- m m sections, most of the AVSFs formed a closed space and the vacuolar membranes were not connected to the sarcolemma with only a few exceptions (Fig. 1Y). Longitudinal sections demonstrated the oval shape of the AVSF, confirming the closed structure of the vacuoles (Fig. 1Z). Vacuolar membranes connected to the sarcolemma were seen in only 2 patients; both were more than 20 years old. In muscle from patients with Danon disease, LIMP-1, a lysosomal membrane protein, showed accumulations scattered throughout the fibers in a distribution identical to that of the small basophilic granules on H&E-stained sections (Fig. 2; Table 2), indicating that most autophagic vacuoles in Danon disease are autolysosomes. These autolysosomal accumulations were surrounded by dystrophin-positive membranes in some fibers but not in others (Fig. 2). LAMP-1 and LIMP-2 showed slightly increased expression in fibers with LIMP-1-positive granules (data not shown). Muscle fibers with dystrophin- positive vacuoles accounted for 0.5% to 14.3%, increasing in proportion with age (y = 0.016 + 0.40x, r = 0.94; Fig. 3). Muscle fibers with autolysosomal accumulations, both with and without dystrophin-positive vacuolar membranes, accounted for 23.7% to 28.7%, showing a slight tendency to decrease with age (y = 28.6 - 0.15x, r = 0.71; Fig. 3). LDL-R, TfR, and Rab5 showed mild upregulation mainly in fibers with autolysosomal accumulations in Danon disease and related AVMs (Table 2). Cathepsin L was expressed weakly, mainly in fibers with autolysosomal accumulations. Only VAMP-7 was strongly expressed, mainly in the nonvacuolated fibers without autolysosomal accumulations. There were occasional intracytoplasmic vacuoles with sarcolemmal proteins in muscles from patients with other AVMs (i.e. DMRV/HIBM, SIBM, and AMD) but their presence was less consistent than in Danon disease and related AVMs. In addition, they never showed AChE or NSE activity. In DMRV/HIBM and SIBM, fibers with sarcolemmal protein-associated vacuoles accounted for approximately 5% to 15% of fibers with rimmed vacuoles (Fig. 4; Table 1). In AMD, sarcolemmal and extracellular matrix proteins were present in some vacuolar membranes. The frequency of fibers with sarcolemmal proteins-associated vacuoles was less than 5% of vacuolated fibers in infantile AMD, and 10% to 15% of vacuolated fibers in childhood and adult-onset AMD. In Danon disease and related AVMs, electron microscopy revealed scattered clusters of autophagic vacuoles containing cytoplasmic debris, electron dense materials, and myeloid bodies. Some of these autophagic vacuoles had basal lamina on the luminal side, while other clusters were not limited by a membrane (Fig. 5). Immunoelectron microscopy showed many autophagic vacuoles; however technical limitations posed by preparing samples from frozen tissue without prefixation prevented us from clearly defining vacuolar membranes. At higher magnifi- cation, dystrophin signals were detected on the cytoplasmic side of the vacuolar membrane and along the periphery of the vacuoles (Fig. 5). In contrast, the LIMP-1 antibody signals were associated with autophagic materials including glycogen particles and cytoplasmic debris within the vacuoles, suggesting that the vacuoles are limited by membranes with sarcolemmal features and contain multiple small autophagic vacuoles derived from autolysosomes. Muscles from LAMP-2-deficient mice at both 4 and 18 months of age showed features of AVSFs at both light and electron microscopic levels. There were slight variations in fiber size and small vacuoles with basophilic granules by H&E. The granules contained acid phosphatase-positive material. These AVSFs had AChE and NSE activities similarly to those in Danon disease. The frequency of muscle fibers with the AVSFs decorated by NSE and AChE activities was 0.4% at 4 months and 8% at 16 months (data not shown). On immunohistochemistry, the vacuolar membranes were stained with antibodies against dystrophin and other sarcolemmal proteins as well as extracellular matrix proteins, whereas LAMP-2 was completely absent in the muscle. On electron microscopy, there were scattered intracytoplasmic autophagic vacuoles with glycogen particles and cytoplasmic debris (data not shown). In muscle from patients with Danon disease and related AVMs, the membranes of AVSF showed immunoreactivity for all of the sarcolemmal and extracellular matrix proteins tested. Dystrophin and dystrobrevin are cytoskeletal proteins localized along the cytoplasmic side of the sarcolemma (15). Sarcoglycans and b -dystroglycan are transmembranous proteins and are components of ‘‘dystrophin bolts’’ (16). Utrophin is a submembranous protein structurally similar to dystrophin and is widely expressed, albeit at low levels, in the sarcolemma (17). Integrin b 1 and a 7 are transmembranous proteins and form a complex with each other in the sarcolemma (18). Dysferlin and caveolin-3 are also sarcolemmal proteins and are responsible for limb-girdle muscular dystrophy (LGMD) 2B and LGMD 1C, respectively (19, 20). Extracellular proteins, collagen IV, perlecan, fibronectin, agrin, and laminin, are the main components of the basal lamina. Collagen VI is present in the interstitium but is associated directly with collagen IV (21). We observed very little staining of only collagens IV and VI in vacuolar membranes, indicating that the membranes hardly contain these collagens. Based on our findings, we deduce that the vacuolar membrane of AVSFs in Danon disease and related AVMs have most of the sarcolemmal proteins ranging from cytoplasmic dystrophin to the extracellular laminin. The vacuolar membranes of AVSF have abundant activities of AChE similar to neuromuscular junctions. Nevertheless, they are distinct from motor endplates because the membranes lacked AChRs. In the early stages of formation of the neuromuscular junction, AChE and AChRs are localized diffusely throughout the sarcolemma. When axon terminals make contact with muscle cells, postjunctional folds are quickly formed. In this process, AChE and AChRs accumulate at junctions and disappear from the extra-junctional sarcolemma (22, 23). These facts support our hypothesis that the vacuoles are intracellular enclosed spaces, because, if AVSF were derived from ...
Context 2
... routine histologic studies, the vacuolar membranes in Danon disease, probable XMEA, infantile AVM and adult- onset AVM were essentially identical ( Table 1). All muscle samples showed mild to moderate variation in fiber size. There were no necrotic fibers except in muscle from adult-onset AVM, which revealed a few necrotic and regenerating fibers. There were scattered small basophilic granules rather than vacuoles in the muscle fibers in H&E-stained sections (Fig. 1). Histochemistry revealed AChE and NSE activities in the vacuolar membranes and the vacuolar structures of the granules. Immunohistochemistry also confirmed presence of AChE in those vacuoles. However, they did not bind to a -bungarotoxin, indicating the absence of acetylcholine receptors (AChRs) in the vacuolar membranes. By immunohistochemistry, the AVSF reacted for all the tested sarcolemmal and extracellular matrix proteins in the vacuolar membranes in muscle from patients with Danon disease and related AVMs, although reactivity levels of the proteins were variable (Table 1; Fig. 1). However, only collagens IV and VI showed less intense reactivity in the vacuolar membranes than that in the sarcolemma. Most of the AVSFs were scattered throughout the cytoplasm rather than clustered in the subsarcolemmal region. On serial transverse 5- m m sections, most of the AVSFs formed a closed space and the vacuolar membranes were not connected to the sarcolemma with only a few exceptions (Fig. 1Y). Longitudinal sections demonstrated the oval shape of the AVSF, confirming the closed structure of the vacuoles (Fig. 1Z). Vacuolar membranes connected to the sarcolemma were seen in only 2 patients; both were more than 20 years old. In muscle from patients with Danon disease, LIMP-1, a lysosomal membrane protein, showed accumulations scattered throughout the fibers in a distribution identical to that of the small basophilic granules on H&E-stained sections (Fig. 2; Table 2), indicating that most autophagic vacuoles in Danon disease are autolysosomes. These autolysosomal accumulations were surrounded by dystrophin-positive membranes in some fibers but not in others (Fig. 2). LAMP-1 and LIMP-2 showed slightly increased expression in fibers with LIMP-1-positive granules (data not shown). Muscle fibers with dystrophin- positive vacuoles accounted for 0.5% to 14.3%, increasing in proportion with age (y = 0.016 + 0.40x, r = 0.94; Fig. 3). Muscle fibers with autolysosomal accumulations, both with and without dystrophin-positive vacuolar membranes, accounted for 23.7% to 28.7%, showing a slight tendency to decrease with age (y = 28.6 - 0.15x, r = 0.71; Fig. 3). LDL-R, TfR, and Rab5 showed mild upregulation mainly in fibers with autolysosomal accumulations in Danon disease and related AVMs (Table 2). Cathepsin L was expressed weakly, mainly in fibers with autolysosomal accumulations. Only VAMP-7 was strongly expressed, mainly in the nonvacuolated fibers without autolysosomal accumulations. There were occasional intracytoplasmic vacuoles with sarcolemmal proteins in muscles from patients with other AVMs (i.e. DMRV/HIBM, SIBM, and AMD) but their presence was less consistent than in Danon disease and related AVMs. In addition, they never showed AChE or NSE activity. In DMRV/HIBM and SIBM, fibers with sarcolemmal protein-associated vacuoles accounted for approximately 5% to 15% of fibers with rimmed vacuoles (Fig. 4; Table 1). In AMD, sarcolemmal and extracellular matrix proteins were present in some vacuolar membranes. The frequency of fibers with sarcolemmal proteins-associated vacuoles was less than 5% of vacuolated fibers in infantile AMD, and 10% to 15% of vacuolated fibers in childhood and adult-onset AMD. In Danon disease and related AVMs, electron microscopy revealed scattered clusters of autophagic vacuoles containing cytoplasmic debris, electron dense materials, and myeloid bodies. Some of these autophagic vacuoles had basal lamina on the luminal side, while other clusters were not limited by a membrane (Fig. 5). Immunoelectron microscopy showed many autophagic vacuoles; however technical limitations posed by preparing samples from frozen tissue without prefixation prevented us from clearly defining vacuolar membranes. At higher magnifi- cation, dystrophin signals were detected on the cytoplasmic side of the vacuolar membrane and along the periphery of the vacuoles (Fig. 5). In contrast, the LIMP-1 antibody signals were associated with autophagic materials including glycogen particles and cytoplasmic debris within the vacuoles, suggesting that the vacuoles are limited by membranes with sarcolemmal features and contain multiple small autophagic vacuoles derived from autolysosomes. Muscles from LAMP-2-deficient mice at both 4 and 18 months of age showed features of AVSFs at both light and electron microscopic levels. There were slight variations in fiber size and small vacuoles with basophilic granules by H&E. The granules contained acid phosphatase-positive material. These AVSFs had AChE and NSE activities similarly to those in Danon disease. The frequency of muscle fibers with the AVSFs decorated by NSE and AChE activities was 0.4% at 4 months and 8% at 16 months (data not shown). On immunohistochemistry, the vacuolar membranes were stained with antibodies against dystrophin and other sarcolemmal proteins as well as extracellular matrix proteins, whereas LAMP-2 was completely absent in the muscle. On electron microscopy, there were scattered intracytoplasmic autophagic vacuoles with glycogen particles and cytoplasmic debris (data not shown). In muscle from patients with Danon disease and related AVMs, the membranes of AVSF showed immunoreactivity for all of the sarcolemmal and extracellular matrix proteins tested. Dystrophin and dystrobrevin are cytoskeletal proteins localized along the cytoplasmic side of the sarcolemma (15). Sarcoglycans and b -dystroglycan are transmembranous proteins and are components of ‘‘dystrophin bolts’’ (16). Utrophin is a submembranous protein structurally similar to dystrophin and is widely expressed, albeit at low levels, in the sarcolemma (17). Integrin b 1 and a 7 are transmembranous proteins and form a complex with each other in the sarcolemma (18). Dysferlin and caveolin-3 are also sarcolemmal proteins and are responsible for limb-girdle muscular dystrophy (LGMD) 2B and LGMD 1C, respectively (19, 20). Extracellular proteins, collagen IV, perlecan, fibronectin, agrin, and laminin, are the main components of the basal lamina. Collagen VI is present in the interstitium but is associated directly with collagen IV (21). We observed very little staining of only collagens IV and VI in vacuolar membranes, indicating that the membranes hardly contain these collagens. Based on our findings, we deduce that the vacuolar membrane of AVSFs in Danon disease and related AVMs have most of the sarcolemmal proteins ranging from cytoplasmic dystrophin to the extracellular laminin. The vacuolar membranes of AVSF have abundant activities of AChE similar to neuromuscular junctions. Nevertheless, they are distinct from motor endplates because the membranes lacked AChRs. In the early stages of formation of the neuromuscular junction, AChE and AChRs are localized diffusely throughout the sarcolemma. When axon terminals make contact with muscle cells, postjunctional folds are quickly formed. In this process, AChE and ...
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The autophagy–lysosome system is critical for muscle homeostasis and defects in lysosomal function result in a number of inherited muscle diseases, generally referred to as autophagic vacuolar myopathies (AVMs). Among them, Danon Disease (DD) and glycogen storage disease type II (GSDII) are due to primary lysosomal protein defects. DD is characteri...
Citations
... XMEA is caused by pathogenic variants in the VMA21 gene at Xq28, resulting in a reduced expression of the vacuolar ATPase assembly factor 21 (VMA21) protein, a key proton pump for endo-lysosomal acidification, with consequent impairment of lysosomal function leading to autophagy failure [1]. From a pathological point of view, this leads to the accumulation of cytoplasmic vacuoles in muscle cells, described by Sugie et al. as autophagic vacuoles with sarcolemmal features (AVSF) [2]. ...
Objective
X-linked myopathy with excessive autophagy (XMEA) linked to the VMA21 gene leads to autophagy failure with progressive vacuolation and atrophy of skeletal muscles. Current knowledge of this rare disease is limited. Our objective was to define the clinical, radiological, and natural history of XMEA.
Methods
We conducted a retrospective study collecting clinical, genetic, muscle imaging, and biopsy data of XMEA patients followed in France and reviewed the literature for additional cases.
Results
Eighteen males had genetically confirmed XMEA in France, carrying four different VMA21 variants. Mean age at disease onset was 9.4 ± 9.9 (range 1–40) years. In 14/18 patients (77.8%), onset occurred during childhood (< 15 years); however in four patients, the disease started in adulthood. Patients had anterior and medial compartment thigh muscle weakness, distal contractures (56.3%), elevated CK levels (1287.9 ± 757.8 U/l) and autophagic vacuoles with sarcolemmal features on muscle histopathology. Muscle MRI (n = 10) showed a characteristic pattern of lower limb muscle involvement. In 11 patients, outcome measures were available for an average follow-up period of 10.6 ± 9.8 years and six of them show disease progression. Mean change of functional outcomes was 0.5 ± 1.2 points for Brooke and 2.2 ± 2.5 points for Vignos score, 7/16 patients (43.8%) needed a walking aid and 3/16 (18.8%) were wheelchair-bound (median age of 40 years old, range 39–48). The variant c.164-7 T > G was associated with a later onset of symptoms. Respiratory insufficiency was common (57.1%) but cardiac involvement rare (12.5%).
Interpretation
XMEA has variable age of onset, but a characteristic clinical, histopathological, and muscle imaging presentation, guiding the diagnosis. Although slowly, motor disability progresses with time, and relevant genotype–phenotype correlations will help design future clinical trials.
... Danon disease has been classified as a lysosomal glycogen storage disease with normal acid maltase activity. It is characterized by the accumulation of intracytoplasmic autophagic vacuoles in cardiac and skeletal muscle fibers [2,5,6]. ...
Background and Objectives: Danon disease is a multisystemic disorder associated with variants in the LAMP2 gene, mainly affecting the cardiac muscle. Here, we report a multigenerational family from Latvia with two male patients, hemizygous for a novel splice-affecting variant c.928+3A>G. Affected patients exhibit a cardiac phenotype, moderate mental disability, and mild retinal changes. Materials and Methods: Both patients underwent either exome or hypertrophic cardiomyopathy gene panel next-generation sequencing. The pathogenic variant effect was determined using reverse transcription, Sanger sequencing, and high-resolution electrophoresis. Results: Evaluation of the splicing process revealed that approximately 80% of the transcripts exhibited a lack of the entire exon 7. This alteration was predicted to cause a shift of the reading frame, consequently introducing a premature stop codon downstream in the sequence. Conclusions: Based on our data, we propose that c.928+3A>G is a pathogenic variant associated with Danon disease.
... Danon disease (DD) is a rare, hereditary, X-linked, and dominant lysosomal glycogen storage disease, caused by a deficiency in lysosome-associated membrane protein-2 (LAMP-2) [1]. The disease predominantly affects men, who usually exhibit more severe clinical manifestations and present at an earlier age than women. ...
... This condition usually involves the skeletal muscle and myocardium and can be definitively diagnosed through a biopsy. The characteristic pathological features of DD include intracytoplasmic vacuoles harboring autophagic components and glycogen [1]. The classic "trifecta," which includes cardiac enlargement, skeletal myopathy, and abnormal liver function, is used to definitively diagnose patients with suspected DD [5]. ...
BACKGROUND
Danon disease (DD), in which mutations in the X-linked lysosome-associated membrane protein-2 (LAMP-2) gene result in hypertrophic cardiomyopathy, is a rare disease, reported primarily in small samples or cases. However, with the development of cardiac magnetic resonance imaging and genetic technology in recent years, the number of reports has increased.
CASE SUMMARY
We report a case of DD in an adolescent male patient, confirmed by genetic testing. The patient was admitted to our hospital with complaints of a three-year history of chest tightness and shortness of breath. His preliminary clinical diagnosis is hypertrophic cardiomyopathy. Our report includes the patient’s clinical course from hospital admission to death, step-by-step diagnosis, treatment course, and noninvasive imaging features. We highlight how a noninvasive diagnostic approach, based solely on clinical and imaging “red flags” for DD, can be used to achieve a diagnosis of DD with a high degree of confidence.
CONCLUSION
DD is a very dangerous cardiomyopathy, and it is necessary to achieve early diagnosis and treatment.
... (2023) 23:397 https://doi.org/10.1186/s12872-023-03356-y Background Danon disease (DD) is a rare X-linked dominant lysosomal glycogen storage disease that manifests as severe ventricular hypertrophy and heart failure [1]. Currently, detection of mutations in the lysosomal-associated membrane protein-2 (LAMP-2) gene is the gold standard for DD diagnosis [2], and endocardial biopsy is also a critical method for diagnosing it. ...
Background
Danon disease (DD) is an exceptionally uncommon X-linked dominant lysosomal glycogen storage disorder characterized by pronounced ventricular hypertrophy and cardiac insufficiency. The timely identification of cardiac impairment in individuals with DD holds significant clinical importance.
Case presentation
We present a case of Danon Disease in a three-generation pedigree from Anhui Province, China. Clinical features and laboratory data were collected and analyzed for a 16-year-old male proband (III-1) and two affected female family members (II-2 and II-3). The proband exhibited Wolf-Parkinson-White syndrome, hypertrophic cardiomyopathy, abnormal cognitive function, and muscle weakness. Gene sequencing confirmed a mutation (c.963G > A) in the LAMP-2 gene.
Conclusion
Patients with DD may present both dilated and hypertrophic cardiomyopathy. Comprehensive myocardial tissue characterization by MRI plays a key role in the diagnosis of the disease.
... 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. ...
... Since this subtype is characterized by the presence of specific autophagic vacuoles known as AVSF, it is referred to as AVSF myopathy. 4 AVSF expresses virtually all sarcolemmal proteins, in addition to acetylcholinesterase (AChE), on their vacuolar membranes in muscle cells. ...
Autophagic vacuolar myopathy is a subgroup of muscle diseases defined as a condition in which autophagic vacuoles are present as a muscle pathological feature and is caused by abnormality of autophagy in skeletal muscles. There is an autophagic vacuolar myopathy characterized by the presence of specific autophagic vacuoles known as autophagic vacuoles with sarcolemmal features (AVSF). It is referred to as AVSF myopathy and includes Danon disease and related myopathies. Danon disease is an X‐linked dominant disease associated with a primary deficiency of lysosomal‐associated membrane protein 2 in which severe hypertrophic cardiomyopathy and myopathy develop. Cardiomyopathy is a determinant prognostic factor of this disease, and heart transplantation is still the sole radical treatment. The pathomechanism of AVSF myopathy is considered to be caused by abnormality of autophagy resulting from primary lysosomal dysfunction.
... For example, loss of the acidic hydrolase, GAA or a reduction in VMA21, the chaperone necessary for the assembly of the vacuolar-type ATPase both lead to lysosomes with reduced degradative capacity 278,279 . The pathology in these myopathies termed Pompe's disease and X-linked myopathy with excessive autophagy (XMEA) is distinctive with the sarcoplasmic accumulation of vacuoles surrounded by sarcolemmal proteins such dystrophin and caveolin-3 280 . ...
Neuromuscular disorders comprise a diverse group of human inborn diseases that arise from defects in the structure and/or function of the muscle tissue — encompassing the muscle cells (myofibres) themselves and their extracellular matrix — or muscle fibre innervation. Since the identification in 1987 of the first genetic lesion associated with a neuromuscular disorder — mutations in dystrophin as an underlying cause of Duchenne muscular dystrophy — the field has made tremendous progress in understanding the genetic basis of these diseases, with pathogenic variants in more than 500 genes now identified as underlying causes of neuromuscular disorders. The subset of neuromuscular disorders that affect skeletal muscle are referred to as myopathies or muscular dystrophies, and are due to variants in genes encoding muscle proteins. Many of these proteins provide structural stability to the myofibres or function in regulating sarcolemmal integrity, whereas others are involved in protein turnover, intracellular trafficking, calcium handling and electrical excitability — processes that ensure myofibre resistance to stress and their primary activity in muscle contraction. In this Review, we discuss how defects in muscle proteins give rise to muscle dysfunction, and ultimately to disease, with a focus on pathologies that are most common, best understood and that provide the most insight into muscle biology.
... Yet, the value of these organelles in muscle is clear when viewed in the context of Lysosomal Storage Diseases (LSDs). For example, Pompe [5,[221][222][223][224][225][226] and Danon Disease [227][228][229][230][231][232] are both associated with an accumulation of non-digested autophagosomes and enlarged lysosomes, manifesting in diminished muscle mass and function. ...
Sarcopenia is the loss of both muscle mass and function with age. Although the molecular underpinnings of sarcopenia are not fully understood, numerous pathways are implicated, including autophagy, in which defective cargo is selectively identified and degraded at the lysosome. The specific tagging and degradation of mitochondria is termed mitophagy, a process important for the maintenance of an organelle pool that functions efficiently in energy production and with relatively low reactive oxygen species production. Emerging data, yet insufficient, have implicated various steps in this pathway as potential contributors to the aging muscle atrophy phenotype. Included in this is the lysosome, the end-stage organelle possessing a host of proteolytic and degradative enzymes, and a function devoted to the hydrolysis and breakdown of defective molecular complexes and organelles. This review provides a summary of our current understanding of how the autophagy-lysosome system is regulated in aging muscle, highlighting specific areas where knowledge gaps exist. Characterization of the autophagy pathway with a particular focus on the lysosome will undoubtedly pave the way for the development of novel therapeutic strategies to combat age-related muscle loss.
... Alternative splicing of the terminal exon 9 produces three isoforms: LAMP2A, LAMP2B, and LAMP2C, varying in the sequence of the transmembrane and cytosolic tail and in their roles in autophagy [127]. Danon disease is classified as a form of autophagic vacuolar myopathy with intracytoplasmic autophagic vacuoles with sarcolemmal features [128]. ...
... LAMP2 expression analysis was performed in different tissue samples from females related to boys with Danon disease. Sugie et al. [128] analyzed muscle biopsy from a woman with cardiomyopathy but without clinically apparent skeletal myopathy whose mentally retarded son developed progressive cardiomyopathy and mild skeletal muscle weakness. Immunohistochemical and Western blot analyses revealed a small amount of LAMP2 in her muscle despite a null mutation identified in the LAMP2 gene (ten-base deletion at the junction of intron 5 and exon 6). ...
Through the use of new genomic and metabolomic technologies, our comprehension of the molecular and biochemical etiologies of genetic disorders is rapidly expanding, and so are insights into their varying phenotypes. Dosage compensation (lyonization) is an epigenetic mechanism that balances the expression of genes on heteromorphic sex chromosomes. Many studies in the literature have suggested a profound influence of this phenomenon on the manifestation of X-linked disorders in females. In this review, we summarize the clinical and genetic findings in female heterozygotic carriers of a pathogenic variant in one of ten selected X-linked genes whose defects result in metabolic disorders.
... Danon disease is an X-linked dominant multisystem disorder affecting predominantly cardiac and skeletal muscles [2,4,8]. The HCM is a representing clinical feature, which rapidly progresses to heart failure leading to cardiac death [5,9,10]. ...
... Loss of autophagy also results in an exacerbation of muscle wasting in response to atrophic stimuli such as starvation and denervation. Moreover, deficient autophagy is implicated in a myriad of myopathies and muscular dystrophies[99, [104][105][106][107], which can be rescued by the reactivation of this process[99, [104][105][106]. Thus, autophagy is required for muscle mass maintenance, and is critical for the quality control of skeletal muscle organelles; however, over-active autophagy can result in excessive catabolism and atrophy. ...
The loss of skeletal muscle mass under a wide range of acute and chronic maladies is associated with poor prognosis, reduced quality of life, and increased mortality. Decades of research indicate the importance of skeletal muscle for whole body metabolism, glucose homeostasis, as well as overall health and wellbeing. This tissue’s remarkable ability to rapidly and effectively adapt to changing environmental cues is a double-edged sword. Physiological adaptations that are beneficial throughout life become maladaptive during atrophic conditions. The atrophic program can be activated by mechanical, oxidative, and energetic distress, and is influenced by the availability of nutrients, growth factors, and cytokines. Largely governed by a transcription-dependent mechanism, this program impinges on multiple protein networks including various organelles as well as biosynthetic and quality control systems. Although modulating muscle function to prevent and treat disease is an enticing concept that has intrigued research teams for decades, a lack of thorough understanding of the molecular mechanisms and signaling pathways that control muscle mass, in addition to poor transferability of findings from rodents to humans, has obstructed efforts to develop effective treatments. Here, we review the progress made in unraveling the molecular mechanisms responsible for the regulation of muscle mass, as this continues to be an intensive area of research.
