• 2019-07
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  • Besides hearts hepatic energy balance also contributes


    Besides hearts, hepatic energy balance also contributes to dysregulation of autophagy and cardiac function. As a major organ for gluconeogenesis, liver is extremely sensitive to changes in glucogenic CY7-SE and accumulates fat (steatosis) in the face of obesity and type 2 diabetes, resulting in non-alcoholic fatty liver disease (NAFLD) [45]. Loss- and gain-of-function analysis has confirmed a key role of hepatic autophagy in metabolic disorders. For example, specific deletion of Atg7 in hepatocytes promotes dyslipidemia and hepatomegaly [46,47]. On the other hand, knockdown of Atg7 led to impaired insulin sensitivity and overt ER stress [48], consistent with downregulated hepatic Atg7 in genetic and diet-induced models of obesity. Loss of hepatic autophagy may be due to changes in autophagy genes in insulin resistance or hyperinsulinemia [49]. Impaired autophagy flux was reported in livers from patients with inflammatory hepatic steatosis [50]. Other than hearts and livers, autophagy regulation also contributes to adipogenesis and lipid storage [51]. In physiological setting, nutrient sensors mTORC1 and AMPK function as inhibitor and activator for autophagy, respectively. However, the balance becomes perturbed in metabolic stress [52], such that mTORC1 and AMPK are stimulated and inhibited, respectively, resulting in autophagy failure. Interestingly, elevated autophagosomes was noted in adipocytes derived from obese and diabetic human subjects [53]. Although further study is still warranted, elevated autophagy seems to function as a compensatory mechanism to preserve adipocyte homeostasis through ridding off damaged proteins and organelles under stress. It is noteworthy that excessive autophagy could promote energy storage and facilitate ‘self-digestion’, leading to autophagic cell death (a term commonly being referred to as “autosis”). Table 1 lists a few examples of changes of autophagy in metabolic active organs. Moreover, mitochondrial integrity also plays a key role in cardiac homeostasis as knockout of Mfn2 gene compromised Parkin-mediated mitophagy, promoted ROS production, leading to heart failure [54]. Loss of mitochondrial membrane potential ΔΨm and mitochondrial damage are common in cardiometabolic disease, which makes mitophagy a unique regulator for mitochondrial quality control through mitochondrial recruitment of dynamin related protein 1 (Drp1) and Parkin for mitochondrial fission and aggregate clearance [55].
    Autophagy and glycogen storage disease Massive buildup of autophagosomes is reported in muscle disorders denoting autophagy dysregulation. Autophagic buildup constitutes a main culprit component in cardiac or skeletal muscles, which may interfere with delivery of the therapeutic enzyme [14]. Pompe disease is a form of metabolic myopathy originated from genetic mutation in glycogen degrading lysosomal enzyme acid α-glucosidase (GAA) [56]. In Pompe disease (or glycogen storage disease type II), glycogen-filled lysosomes accumulate in skeletal muscles, due to impaired glycogen breakdown by GAA [14]. Moreover, disturbed intracellular Ca2+ homeostasis, mitochondrial Ca2+ overload, ROS production, loss in mitochondrial ΔΨm, decreased O2 consumption and ATP production were also evidence in mitochondria from cardiac and skeletal muscles in Pompe disease [57,58]. L-type Ca2+ channel blockers, mTOR regulators and lysosomal enzyme acid α-glucosidase replacement are effective for such lysosomal and neurodegenerative disorders [59,60]. mTOR is a known negative regulator of autophagy, forming two complexes, namely, mTOR complex 1 (TORC1) and mTOR complex 2 (TORC2). Rapamycin-sensitive mTORC1 complex has been well documented to respond to external stimuli (such as nutrient stress), leading to protein synthesis, cell growth and autophagy inhibition [61]. The impairment of autophagy in Pompe disease is likely due to dysregulation of mTOR signaling, in which case reactivation of mTOR signaling using arginine may serve as a target therapy for lysosomal and metabolic dysfunction in Pompe disease [60]. Recent evidence also revealed glycogen accumulation and autophagy failure in lymphocytes, containing PAS-positive vacuoles. Assessment of PAS-positive lymphocytes in the circulation may be indicative for early detection of autophagy vacuolar myopathies and Pompe disease [62]. Lysosomal-autophagosomal fusion is governed by transcription factor EB (TFEB), which functions to resolve autophagic buildup and remove glycogen-filled lysosomes, a hallmark for Pompe disease [63]. Feeney and colleagues found that delivery of TFEB is effective for the removal of enlarged lysosomes, alleviation of autophagic buildup and lysosomal exocytosis, leading to the reduced glycogen storage in Pompe disease. Interestingly, TFEB-offered benefit was negated in autophagy-deficient Pompe mice, denoting an unrecognized role for autophagy in TFEB-governed cellular clearance [15]. The utility of TFEB in Pompe disease received further confirmation from another lab where AAV-mediated TFEB gene delivery alleviated muscle anomalies [64]. Last but not least, TFEB also promotes lysosomal exocytosis in lysosomal storage disorders, including multiple sulfatase deficiency and mucopolysaccharidosis type IIIA. Recent evidence depicted a role for mTOR phosphorylation of TFEB nuclear export [65] although TFEB-related lysosomal and autophagy signaling regulation still remains elusive for inherited metabolic and endocrine disorders.