• 2019-07
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  • 2020-03
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  • 2020-08
  • To elucidate the role of autopha


    To elucidate the role of autophagy in Pifithrin-α (PFTα) storage diseases, autophagy was evaluated in muscle biopsies and myotubes of early and late-onset glycogen storage disease type II patients with or without enzyme replacement therapy. It is possible that autophagy flux is essential to reconciling maturation of and uptake of GAA, while defect in autophagy contributes to the progression of glycogen storage disease [15]. Enzyme replacement therapy removes lysosomal glycogen readily away from the heart although to a lesser extent in skeletal muscle [66]. Along the same line, report from Nascimbeni and colleagues confirmed the role of autophagy failure in glycogen storage disease and that autophagy flux is important for maturation and uptake of GAA [67,68]. These findings favored the notion of drug development to restore autophagic flux in order to improve enzyme replacement efficacy. In patients, autophagic buildup may damage skeletal muscles with overt autophagosome formation and autophagic buildup in myofibers, in a manner reminiscent of murine models. Further study revealed that poor muscle responsiveness to enzyme replacement therapy may be related to the presence of autophagic debris in Pompe disease. Using an Atg5 muscle-specific inactivation model, autophagy inhibition alone was able to alleviate the glycogen level by 50–60%. More intriguingly, enzyme replacement therapy in the face of Atg7 knockout lowered muscle glycogen levels to normal levels, something absent in Pompe murine models without autophagy deficiency [66]. To this end, alleviating autophagic buildup or suppression of autophagy may represent a promising target for Pompe disease therapy as well as other diseases with disturbed autophagy.
    Autophagy and inherited myopathies/endocrine disorders Autophagy removes aged or injured organelles and protein aggregates, whereas UPS system is essential for protein quality control. Both autophagy and UPS contribute to etiology of muscle wasting in inherited myopathies and muscular dystrophies [69]. Deranged autophagy or UPS function produces detrimental sequelae on muscle integrity. For example, loss of Dysferlin, a transmembrane protein, serves as the causative factor of limb girdle muscular dystrophy type 2B and Miyoshi myopathy (LGMD2B/MM). Intriguingly, autophagy induction using rapamycin suppressed the ER-stimulated autophagosome formation-mediated mutant dysferlin aggregation in the ER [22], contributing to muscular dystrophy as the post-mitotic skeletal muscles are susceptible to aged or injured organelles and aggregation-prone proteins. A clinical trial recently examined the benefit of low-protein nutritional diet (1 year) in skeletal autophagy induction in patients afflicted with COL6/collagen VI-related myopathies (e.g., Ullrich congenital muscular dystrophy and Bethlem myopathy due to COL6 gene mutation). Their findings confirmed utility of the low-protein diet in autophagy induction to benefit patients with COL6 myopathies [70]. These observations support a key role of autophagy induction as a therapeutic target for muscular disorders such as simvastatin-improved skeletal muscle function in muscular dystrophy [71]. It is noteworthy that autophagy also contributes to inherited muscular dystrophy such as Duchenne muscular dystrophy (DMD) and Golden retriever muscular dystrophy (both X-linked disorders triggered by mutation in DMD gene) and inherited neurological disorders such as those caused by repeat expansion mutations (which are tied to at least 22 inherited neurological diseases) [24,72]. As depicted in Fig. 1, more recent data suggested that faulty mitophagy due to defects in the PINK1/Parkin pathway may contribute to dystrophic cardiac defects in DMD [23]. Although the underlying pathophysiology and genetics can be rather complex for these genetic anomalies, autophagy dysregulation, along with the degradation of misfolded proteins, appears to a common mechanistic theme identified among these diseases [73] (also depicted in Fig. 1). Therefore, a thorough mechanistic description of autophagy or mitophagy degradative machinery should offer novel therapeutic targets and remedies for inherited muscle (or perhaps neurological) disorders.