Abstract
In Pompe disease, a lysosomal glycogen storage disorder, cardiac and skeletal muscle abnormalities are responsible for premature death and severe weakness. Swollen glycogen-filled lysosomes, the expected pathology, are accompanied in skeletal muscle by a secondary pathology-massive accumulation of autophagic debris-that appears to contribute greatly to the weakness. We have tried to reproduce these defects in murine, Pompe myotubes derived from either primary myoblasts or myoblasts with extended proliferative capacity. The cells accumulated large lysosomes filled with glycogen, but, to our disappointment, did not have autophagic buildup even though basal autophagy was intact. When we suppressed autophagy by knocking down Atg7, we found that glycogen uptake by lysosomes was not affected, suggesting that macroautophagy is not the major pathway for glycogen delivery to lysosomes. But two apparently incidental observations-a peculiar distribution of both microinjected dextran and of small acidic structures adjacent to the interior membrane of large alkalinized glycogencontaining lysosomes-raised the possibility that glycogen traffics to the lysosomes by microautophagy or/and by the engulfment of small lysosomes by large ones. The cultured myotubes, therefore, appear to be a useful model for studying the mechanisms involved in glycogen accumulation in Pompe disease and to test substrate deprivation approaches.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 729-731 |
| Number of pages | 3 |
| Journal | Autophagy |
| Volume | 5 |
| Issue number | 5 |
| DOIs | |
| State | Published - Jul 1 2009 |
| Externally published | Yes |
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Keywords
- Atg7
- Glycogen
- Lysosomal storage
- Myotubes
- Pompe disease
ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
Cite this
The values and limits of an in vitro model of Pompe disease : The best laid schemes o' mice an' men... / Takikita, Shoichi; Myerowitz, Rachel; Schreiner, Cynthia; Baum, Rebecca; Raben, Nina; Plotz, Paul H.
In: Autophagy, Vol. 5, No. 5, 01.07.2009, p. 729-731.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The values and limits of an in vitro model of Pompe disease
T2 - The best laid schemes o' mice an' men...
AU - Takikita, Shoichi
AU - Myerowitz, Rachel
AU - Schreiner, Cynthia
AU - Baum, Rebecca
AU - Raben, Nina
AU - Plotz, Paul H.
PY - 2009/7/1
Y1 - 2009/7/1
N2 - In Pompe disease, a lysosomal glycogen storage disorder, cardiac and skeletal muscle abnormalities are responsible for premature death and severe weakness. Swollen glycogen-filled lysosomes, the expected pathology, are accompanied in skeletal muscle by a secondary pathology-massive accumulation of autophagic debris-that appears to contribute greatly to the weakness. We have tried to reproduce these defects in murine, Pompe myotubes derived from either primary myoblasts or myoblasts with extended proliferative capacity. The cells accumulated large lysosomes filled with glycogen, but, to our disappointment, did not have autophagic buildup even though basal autophagy was intact. When we suppressed autophagy by knocking down Atg7, we found that glycogen uptake by lysosomes was not affected, suggesting that macroautophagy is not the major pathway for glycogen delivery to lysosomes. But two apparently incidental observations-a peculiar distribution of both microinjected dextran and of small acidic structures adjacent to the interior membrane of large alkalinized glycogencontaining lysosomes-raised the possibility that glycogen traffics to the lysosomes by microautophagy or/and by the engulfment of small lysosomes by large ones. The cultured myotubes, therefore, appear to be a useful model for studying the mechanisms involved in glycogen accumulation in Pompe disease and to test substrate deprivation approaches.
AB - In Pompe disease, a lysosomal glycogen storage disorder, cardiac and skeletal muscle abnormalities are responsible for premature death and severe weakness. Swollen glycogen-filled lysosomes, the expected pathology, are accompanied in skeletal muscle by a secondary pathology-massive accumulation of autophagic debris-that appears to contribute greatly to the weakness. We have tried to reproduce these defects in murine, Pompe myotubes derived from either primary myoblasts or myoblasts with extended proliferative capacity. The cells accumulated large lysosomes filled with glycogen, but, to our disappointment, did not have autophagic buildup even though basal autophagy was intact. When we suppressed autophagy by knocking down Atg7, we found that glycogen uptake by lysosomes was not affected, suggesting that macroautophagy is not the major pathway for glycogen delivery to lysosomes. But two apparently incidental observations-a peculiar distribution of both microinjected dextran and of small acidic structures adjacent to the interior membrane of large alkalinized glycogencontaining lysosomes-raised the possibility that glycogen traffics to the lysosomes by microautophagy or/and by the engulfment of small lysosomes by large ones. The cultured myotubes, therefore, appear to be a useful model for studying the mechanisms involved in glycogen accumulation in Pompe disease and to test substrate deprivation approaches.
KW - Atg7
KW - Glycogen
KW - Lysosomal storage
KW - Myotubes
KW - Pompe disease
UR - http://www.scopus.com/inward/record.url?scp=67650261893&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67650261893&partnerID=8YFLogxK
U2 - 10.4161/auto.5.5.8525
DO - 10.4161/auto.5.5.8525
M3 - Article
C2 - 19571661
AN - SCOPUS:67650261893
VL - 5
SP - 729
EP - 731
JO - Autophagy
JF - Autophagy
SN - 1554-8627
IS - 5
ER -