Glycogen autophagy in glucose homeostasis.
ABSTRACT Glycogen autophagy, the sequestration and degradation of cell glycogen in the autophagic vacuoles, is a selective, hormonally controlled and highly regulated process, representing a mechanism of glucose homeostasis under conditions of demand for the production of this sugar. In the newborn animals, this process is induced by glucagon secreted during the postnatal hypoglycemia and inhibited by insulin and parenteral glucose, which abolishes glucagon secretion. Hormonal action is mediated by the cAMP/protein kinase A (induction) and phosphoinositides/mTOR (inhibition) pathways that converge on common targets, such as the protein phosphatase 2A to regulate autophgosomal glycogen-hydrolyzing acid glucosidase and glycogen autophagy. Intralysosomal phosphate exchange reactions, which are affected by changes in the calcium levels and acid mannose 6- and acid glucose 6-phosphatase activities, can modify the intralysosomal composition in phosphorylated and nonphosphorylated glucose and promote the exit of free glucose through the lysosomal membrane. Glycogen autophagy-derived nonphosphorylated glucose assists the hyaloplasmic glycogen degradation-derived glucose 6-phosphate to combat postnatal hypoglycemia and participates in other metabolic pathways to secure the fine tuning of glucose homeostasis during the neonatal period.
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ABSTRACT: In this study, we tested the hypothesis that NAC administration leads to reduced oxidative stress and thus to decreased expression of autophagy markers in young mice. Our results reveal that NAC administration results in reduced muscle mRNA levels of several autophagy markers, including Beclin-1, Atg7, LC3, Atg9, and LAMP2. However, NAC supplement fails to block the activation of skeletal muscle autophagy in response to fasting, because fasting significantly increases the mRNA level of several autophagy markers and LC3 lipidation. We further examined the effects of NAC administration on mitochondrial antioxidant capacity in fed and 24-hour fasted mice. Our results clearly show that NAC administration depresses the expression of manganese superoxide dismutase (MnSOD) and TP53-induced glycolysis and apoptosis regulator (TIGAR), both of which play a predominant antioxidant role in mitochondria by reducing ROS level. In addition, we found no beneficial effect of NAC supplement on muscle mass but it can protect from muscle loss in response to fasting. Collectively, our findings indicate that ROS is required for skeletal muscle constitutive autophagy, rather than starvation-induced autophagy, and that antioxidant NAC inhibits constitutive autophagy by the regulation of mitochondrial ROS production and antioxidant capacity.Oxidative medicine and cellular longevity. 01/2014; 2014:315896.
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ABSTRACT: Pompe disease is a lysosomal storage disorder in which acid alpha-glucosidase (GAA) is deficient or absent. Deficiency of this lysosomal enzyme results in progressive expansion of glycogen-filled lysosomes in multiple tissues, with cardiac and skeletal muscle being the most severely affected. The clinical spectrum ranges from fatal hypertrophic cardiomyopathy and skeletal muscle myopathy in infants to relatively attenuated forms, which manifest as a progressive myopathy without cardiac involvement. The currently available enzyme replacement therapy (ERT) proved to be successful in reversing cardiac but not skeletal muscle abnormalities. Although the overall understanding of the disease has progressed, the pathophysiology of muscle damage remains poorly understood. Lysosomal enlargement/rupture has long been considered a mechanism of relentless muscle damage in Pompe disease. In past years, it became clear that this simple view of the pathology is inadequate; the pathological cascade involves dysfunctional autophagy, a major lysosome-dependent intracellular degradative pathway. The autophagic process in Pompe skeletal muscle is affected at the termination stage-impaired autophagosomal-lysosomal fusion. Yet another abnormality in the diseased muscle is the accelerated production of large, unrelated to ageing, lipofuscin deposits-a marker of cellular oxidative damage and a sign of mitochondrial dysfunction. The massive autophagic buildup and lipofuscin inclusions appear to cause a greater effect on muscle architecture than the enlarged lysosomes outside the autophagic regions. Furthermore, the dysfunctional autophagy affects the trafficking of the replacement enzyme and interferes with its delivery to the lysosomes. Several new therapeutic approaches have been tested in Pompe mouse models: substrate reduction therapy, lysosomal exocytosis following the overexpression of transcription factor EB and a closely related but distinct factor E3, and genetic manipulation of autophagy.Frontiers in Aging Neuroscience 01/2014; 6:177. · 5.20 Impact Factor
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ABSTRACT: Chaihu, prepared from the dried roots of Bupleurum Chinense DC (also known as bei Chaihu in Chinese) or Bupleurum scorzoneraefolium WILD (also known as nan Chaihu in Chinese), is a herbal medicine for harmonizing and soothing gan (liver) qi stagnation. Substantial pharmacological studies have been conducted on Chaihu and its active components (saikosaponins). One of the active components of Chaihu, saikosaponin-d, exhibited anticancer effects via autophagy induction. This article reviews the pharmacological findings for the roles of autophagy in the pharmacological actions of Chaihu and saikosaponins.Chinese Medicine 01/2014; 9:21. · 1.79 Impact Factor