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  • Phosphatase Inhibitor Cocktail II br Autophagy and metabolic


    Autophagy and metabolic myopathies in lysosomal storage disorders Lysosome controls catabolic and anabolic processes in response to a cadre of environmental factors including nutrient/energy availability and cell stress [74]. Lysosomal storage disorders denote to a cluster of inherited metabolic anomalies elicited by deficiencies in lysosomal proteins, leading to accumulation of undegraded metabolites, disruption of lysosomal proteostasis and metabolic myopathies [[74], [75], [76]]. Recent findings have revealed an important role for lysosomes in nutrient-dependent biological events such as nutrient sensing, metabolic adaptation, and protein quality control [77]. Small vessel vasculopathy (medial thickening with luminal stenosis due to vascular smooth muscle cell proliferation) may develop in response to aberrant autophagy with deficiency of lysosomal associated membrane protein 2 (LAMP-2) [78]. Central nervous system is afflicted with neuroinflammation resulting from heightened neuronal vulnerability based on post-mitotic state [79]. For example, lysosomal storage of heparan sulfate triggers mitochondrial defects, altered autophagy, and neuronal death in a mouse model of mucopolysaccharidosis III type C [80]. Danon disease is an X-linked disorder that leads to mitochondrial injury, impaired mitophagy, skeletal muscle weakness and severe cardiomyopathy (such as skeletal myopathy and LAMP2 cardiomyopathy) due to deficiency in LAMP2 [81]. In female patients, a more delayed onset and less severe phenotype may be resulted from random inactivation of the X chromosome housing mutant alleles. LAMP-2 deficiency leads to compromised autophagic flux, leading to oxidative stress, and subsequently, cardiomyocyte apoptosis. Removal of free radicals exhibited benefits for patients with Danon disease [82]. A unique Danon disease model based on induced pluripotent stem Phosphatase Inhibitor Cocktail II (iPSCs) was produced to evaluate the therapeutic potential of Xi-chromosome reactivation using a DNA methylation inhibitor. This type of iPSC platform is expected to provide new tools for not only mechanistic but also therapeutic insights for X-linked Danon disease [83]. Autophagy condition may be applied to differentiate Danon disease from other forms of inherited myopathies. For example, Sugimoto reported a case (46-year-old man) of the late-onset myopathy and dilated cardiomyopathy with clinical features distinct from the X-linked myopathy (Danon disease). This investigator noted excessive autophagy and autophagic vacuolar myopathy [84]. Autopsy and microscopic analyses also revealed existence of extensive intra-lysosomal degradation of mitochondria and other organelles, and distended lysosomes in cardiomyocytes, hepatocytes and smooth muscle cells in a patient with non-Danon disease albeit with a clinical history of cardiac hypertrophy and hypertension. Distended lysosomes suggested ubiquitination in the absence of immuno-detectable p62 (autophagy) formation [85]. Therefore, autophagy status may serve as a relevant marker for differential diagnosis for Danon disease and other forms of myopathies. Other than inherited lysosomal diseases mentioned above, autophagy may play a role in other comorbidities. X-linked myopathy with excessive autophagy (XMEA) is a rare hereditary childhood-onset disease with compromised proton pump vacuolar ATPase (V-ATPase), as a result of hypomorphic mutation in VMA21 [86]. In consequence, lysosomal pH is elevated, leading to loss of acidic lysosomal hydrolase digestive function and accumulation of autophagic vacuoles with sarcolemmal features (AVSF) [87]. Nonetheless, cardiac structure and function seem to be spared in patients with symptomatic XMEA [88]. Several aspects may be considered. VMA21 is responsible for assembly of V-ATPase, whereas LAMP-2 is associated with multiple functions including endosomal cholesterol transport [89]. Given the ample of clinical and epidemiological evidence denoting a role for autophagy in the maintenance of metabolic homeostasis [3,25], pharmacotherapies on modulation of autophagy have shown some promises in the clinical management of metabolic derangements [25,90] although many drugs suffer from off-target or autophagy-independent effects. For a better review of drugs with autophagy regulating potential in metabolic diseases, please see our recent review [25] for a better and more detailed discussion.