Deconstructing Pompe Disease by Analyzing Single Muscle Fibers: “To See a World in a Grain of Sand…”

Raben, Nina; Takikita, Shoichi; Pittis, María Gabriela; Bembi, Bruno; Marie, Suely Kazue Nagahashi; Roberts, Ashley; Page, Laura; Kishnani, Priya S.; Schöser, Benedikt; Chien, Yin‐Hsiu; Ralston, Evelyn; Nagaraju, Kanneboyina; Plötz, Paul H.

doi:10.4161/auto.4591

Cited by 100 publications

(89 citation statements)

References 34 publications

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“…Older patients with the slowly progressive form develop severe skeletal muscle weakness and eventually respiratory failure without significant involvement of cardiac muscle. Recent studies have observed that GAA knockout (KO) mice display marked accumulation of autophagic vesicles with altered macroautophagy function (8,15,18). In addition, GAA deficiency causes lysosome enlargement concomitant with the lysosomal accumulation of glycogen (25).…”

mentioning

confidence: 99%

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

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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.

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mentioning

confidence: 99%

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

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“…In infantile Pompe patients, the enormous build-up of glycogen-filled lysosomes appears to cause the muscle damage (Raben et al 2007). Recent studies showed that autophagy impairment contributes to both disease progression and fibre atrophy (Nascimbeni et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Autophagy in Natural History and After ERT in Glycogenosis Type II

2014

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We studied the role of autophagy in a series of 10 infantile-, juvenile-, and adult-onset GSDII patients and investigated autophagy blockade in successive biopsies of adult cases during disease natural history. We also correlated the autophagosome accumulation and efficiency of enzyme replacement therapy (ERT) in four treated cases (two infantile and two juvenile-adult onsets).The autophagic flux was monitored by measuring the amount of p62-positive protein aggregates and compared, together with fibre vacuolisation, to fibre atrophy.A blocked autophagic flux resulted in p62 accumulation, increased vacuolisation, and progressive atrophy of muscle fibres in biopsies collected from patients during natural history. On the contrary, in the GSDII cases early treated with ERT, the autophagic flux improved and muscle fibre atrophy, fibre vacuolisation, and acid phosphatase activity decreased.The functionality of the autophagy-lysosome system is essential in GSDII muscle, which is characterised by the presence of swollen glycogen-filled lysosomes and autophagic build-up. Defining the role of autophagy and its relationship with muscle loss is critical for understanding the disease pathogenesis, for developing new therapies, and for improving ERT efficacy in GSDII.

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“…The reason for this discrepancy is still not clear, and one possible explanation is that the autophagy build-up in this disease [39][40][41][42] impairs the glycogen clearance in muscle fibers, because the circulating enzyme, which was endocytosed, became trapped in autophagosomes, late endosomes and intermediate autophagosomes, resulting in impaired targeting of the expressed enzyme to the lysosome, 43 leading to partial correction of glycogen storage. Another possibility is that, as in previous studies using AAV vector the glycogen clearance in the heart was complete and in our study it was only partial, 14,15,44 we speculated that maybe some cardiac cells are refractory to LV infection, although this statement needs further investigation.…”

Section: Neonatal Lentivirus Gene Transfer For Murine Gsdii So Kyosenmentioning

confidence: 98%

Neonatal gene transfer using lentiviral vector for murine Pompe disease: long-term expression and glycogen reduction

et al. 2009

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Pompe disease results from the deficiency of the lysosomal enzyme acid a-glucosidase (GAA), leading to accumulated glycogen in the heart and the skeletal muscles, which causes cardiomyopathy and muscle weakness. In this study, we tested the feasibility of gene therapy for Pompe disease using a lentivirus vector (LV). Newborn GAA knockout mice were treated with intravenous injection of LV encoding human GAA (hGAA) through the facial superficial temporal vein. The transgene expression in the tissues was analyzed up to 24 weeks after treatment. Our results showed that the recombinant LV was efficient not only in increasing the GAA activity in tissues but also in decreasing their glycogen content. The examination of histological sections showed clearence of the glycogen storage in skeletal and cardiac muscles 16 and 24 weeks after a single vector injection. Levels of expressed hGAA could be detected in serum of treated animals until 24 weeks. No significant immune reaction to transgene was detected in most treated animals. Therefore, we show that LV-mediated delivery system was effective in correcting the biochemical abnormalities and that this gene transfer system might be suitable for further studies on delivering GAA to Pompe disease mouse models.

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Deconstructing Pompe Disease by Analyzing Single Muscle Fibers: “To See a World in a Grain of Sand…”

Cited by 100 publications

References 34 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

Autophagy in Natural History and After ERT in Glycogenosis Type II

Neonatal gene transfer using lentiviral vector for murine Pompe disease: long-term expression and glycogen reduction

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