Akt inactivation induces endoplasmic reticulum stress-independent autophagy in fibroblasts from patients with Pompe disease

Nishiyama, Yurika; Shimada, Yohta; Yokoi, Takayuki; Kobayashi, Hiroshi; Higuchi, Takashi; Eto, Yoshikatsu; Ida, Hiroyuki; Ohashi, Toya

doi:10.1016/j.ymgme.2012.09.011

Cited by 19 publications

(19 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this prediction, in two independent C2C12 GAA-KD cell lines and in two independent infantile Pompe patient fibroblasts, there was a significant reduction in the ability to simulate mTORC1 activation. These data are consistent with a recent report of reduced S6K1 phosphorylation in Pompe disease patient fibroblasts (14). Despite the reduction of mTORC1 activation, the combination of an amino acid mixture with leucine and insulin was able to activate mTORC1, although to a lower extent than in WT cells.…”

Section: Discussionsupporting

confidence: 93%

Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation

Shemesh

Wang

Yang

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Pompe disease is due to a deficiency in acid-α-glucosidase (GAA) and results in debilitating skeletal muscle wasting, characterized by the accumulation of glycogen and autophagic vesicles. Given the role of lysosomes as a platform for mTORC1 activation, we examined mTORC1 activity in models of Pompe disease. GAA-knockdown C2C12 myoblasts and GAA-deficient human skin fibroblasts of infantile Pompe patients were found to have decreased mTORC1 activation. Treatment with the cell-permeable leucine analog l-leucyl-l-leucine methyl ester restored mTORC1 activation. In vivo, Pompe mice also displayed reduced basal and leucine-stimulated mTORC1 activation in skeletal muscle, whereas treatment with a combination of insulin and leucine normalized mTORC1 activation. Chronic leucine feeding restored basal and leucine-stimulated mTORC1 activation, while partially protecting Pompe mice from developing kyphosis and the decline in muscle mass. Leucine-treated Pompe mice showed increased spontaneous activity and running capacity, with reduced muscle protein breakdown and glycogen accumulation. Together, these data demonstrate that GAA deficiency results in reduced mTORC1 activation that is partly responsible for the skeletal muscle wasting phenotype. Moreover, mTORC1 stimulation by dietary leucine supplementation prevented some of the detrimental skeletal muscle dysfunction that occurs in the Pompe disease mouse model.

show abstract

Section: Discussionsupporting

confidence: 93%

Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation

Shemesh

Wang

Yang

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

show abstract

“…Also, autophagy and apoptosis have been shown previously to be inversely related in hematopoietic stem cells 68. In another study in cultured Pompe patient fibroblasts, the inactivation of Akt can lead to autophagy, in a ER stress-independent manner, via the suppression of mTOR signaling 69. In the absence of ER stress in Pompe disease fibroblasts, the inactivated Akt signaling cascade drives the cells to autophagy, which can be reversed with insulin, which activates Akt signaling 69.…”

Section: Pathogenesismentioning

confidence: 89%

“…In another study in cultured Pompe patient fibroblasts, the inactivation of Akt can lead to autophagy, in a ER stress-independent manner, via the suppression of mTOR signaling 69. In the absence of ER stress in Pompe disease fibroblasts, the inactivated Akt signaling cascade drives the cells to autophagy, which can be reversed with insulin, which activates Akt signaling 69. In Niemann-Pick disease type C (NPC), sphingosine storage inhibits calcium uptake into the lysosomal acidic compartment, leading to insufficient calcium release for function of the endocytic pathway 70.…”

Section: Pathogenesismentioning

confidence: 97%

Developing therapeutic approaches for metachromatic leukodystrophy

Patil¹,

Maegawa²

2013

DDDT

View full text Add to dashboard Cite

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disorder caused by the deficiency of arylsulfatase A (ASA), resulting in impaired degradation of sulfatide, an essential sphingolipid of myelin. The clinical manifestations of MLD are characterized by progressive demyelination and subsequent neurological symptoms resulting in severe debilitation. The availability of therapeutic options for treating MLD is limited but expanding with a number of early stage clinical trials already in progress. In the development of therapeutic approaches for MLD, scientists have been facing a number of challenges including blood–brain barrier (BBB) penetration, safety issues concerning therapies targeting the central nervous system, uncertainty regarding the ideal timing for intervention in the disease course, and the lack of more in-depth understanding of the molecular pathogenesis of MLD. Here, we discuss the current status of the different approaches to developing therapies for MLD. Hematopoietic stem cell transplantation has been used to treat MLD patients, utilizing both umbilical cord blood and bone marrow sources. Intrathecal enzyme replacement therapy and gene therapies, administered locally into the brain or by generating genetically modified hematopoietic stem cells, are emerging as novel strategies. In pre-clinical studies, different cell delivery systems including microencapsulated cells or selectively neural cells have shown encouraging results. Small molecules that are more likely to cross the BBB can be used as enzyme enhancers of diverse ASA mutants, either as pharmacological chaperones, or proteostasis regulators. Specific small molecules may also be used to reduce the biosynthesis of sulfatides, or target different affected downstream pathways secondary to the primary ASA deficiency. Given the progressive neurodegenerative aspects of MLD, also seen in other lysosomal diseases, current and future therapeutic strategies will be complementary, whether used in combination or separately at specific stages of the disease course, to produce better outcomes for patients afflicted with this devastating inherited disorder.

show abstract

“…Although we initially predicted that AKT levels should be higher in the treated mice, secondary to increased muscle mass and IGF-1 signaling (22), the opposite trend was observed. Only one previous study has investigated the role of AKT/mTOR in Pompe's disease, when Nishiyama et al (23) found AKT signaling to be reduced in the fibroblasts of affected patients, with improvement in lysosomal delivery of GAA following activation of this pathway by insulin. Although the results from our study seem to contradict these previous findings, it is important to note that fibroblasts and skeletal muscle may respond differently to the loss of GAA, and AKT may play different roles in different tissues.…”

Section: Discussionmentioning

confidence: 99%

Adjunctive β ₂ ‐agonist treatment reduces glycogen independently of receptor‐mediated acid α‐glucosidase uptake in the limb muscles of mice with Pompe disease

Farah

Madden²,

et al. 2014

FASEB j.

View full text Add to dashboard Cite

Enzyme or gene replacement therapy with acid α-glucosidase (GAA) has achieved only partial efficacy in Pompe disease. We evaluated the effect of adjunctive clenbuterol treatment on cation-independent mannose-6-phosphate receptor (CI-MPR)-mediated uptake and intracellular trafficking of GAA during muscle-specific GAA expression with an adeno-associated virus (AAV) vector in GAA-knockout (KO) mice. Clenbuterol, which increases expression of CI-MPR in muscle, was administered with the AAV vector. This combination therapy increased latency during rotarod and wirehang testing at 12 wk, in comparison with vector alone. The mean urinary glucose tetrasaccharide (Glc4), a urinary biomarker, was lower in GAA-KO mice following combination therapy, compared with vector alone. Similarly, glycogen content was lower in cardiac and skeletal muscle following 12 wk of combination therapy in heart, quadriceps, diaphragm, and soleus, compared with vector alone. These data suggested that clenbuterol treatment enhanced trafficking of GAA to lysosomes, given that GAA was expressed within myofibers. The integral role of CI-MPR was demonstrated by the lack of effectiveness from clenbuterol in GAA-KO mice that lacked CI-MPR in muscle, where it failed to reverse the high glycogen content of the heart and diaphragm or impaired wirehang performance. However, the glycogen content of skeletal muscle was reduced by the addition of clenbuterol in the absence of CI-MPR, as was lysosomal vacuolation, which correlated with increased AKT signaling. In summary, β2-agonist treatment enhanced CI-MPR-mediated uptake and trafficking of GAA in mice with Pompe disease, and a similarly enhanced benefit might be expected in other lysosomal storage disorders.

show abstract

Akt inactivation induces endoplasmic reticulum stress-independent autophagy in fibroblasts from patients with Pompe disease

Cited by 19 publications

References 21 publications

Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation

Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation

Developing therapeutic approaches for metachromatic leukodystrophy

Adjunctive β ₂ ‐agonist treatment reduces glycogen independently of receptor‐mediated acid α‐glucosidase uptake in the limb muscles of mice with Pompe disease

Contact Info

Product

Resources

About

Akt inactivation induces endoplasmic reticulum stress-independent autophagy in fibroblasts from patients with Pompe disease

Cited by 19 publications

References 21 publications

Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation

Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation

Developing therapeutic approaches for metachromatic leukodystrophy

Adjunctive β 2 ‐agonist treatment reduces glycogen independently of receptor‐mediated acid α‐glucosidase uptake in the limb muscles of mice with Pompe disease

Contact Info

Product

Resources

About

Adjunctive β ₂ ‐agonist treatment reduces glycogen independently of receptor‐mediated acid α‐glucosidase uptake in the limb muscles of mice with Pompe disease