TY - JOUR
T1 - Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder - Murine Pompe disease
AU - Raben, Nina
AU - Schreiner, Cynthia
AU - Baum, Rebecca
AU - Takikita, Shoichi
AU - Xu, Sengen
AU - Xie, Tao
AU - Myerowitz, Rachel
AU - Komatsu, Masaaki
AU - Van Der Meulen, Jack H.
AU - Nagaraju, Kanneboyina
AU - Ralston, Evelyn
AU - Plotz, Paul H.
PY - 2010/11/16
Y1 - 2010/11/16
N2 - Autophagy, an intracellular system for delivering portions of cytoplasm and damaged organelles to lysosomes for degradation/recycling, plays a role in many physiological processes and is disturbed in many diseases. We recently provided evidence for the role of autophagy in Pompe disease, a lysosomal storage disorder in which acid alpha-glucosidase, the enzyme involved in the breakdown of glycogen, is deficient or absent. Clinically the disease manifests as a cardiac and skeletal muscle myopathy. The current enzyme replacement therapy (ERT) clears lysosomal glycogen effectively from the heart but less so from skeletal muscle. In our Pompe model, the poor muscle response to therapy is associated with the presence of pools of autophagic debris. To clear the fibers of the autophagic debris, we have generated a Pompe model in which an autophagy gene, Atg7, is inactivated in muscle. Suppression of autophagy alone reduced the glycogen level by 50-60%. Following ERT, muscle glycogen was reduced to normal levels, an outcome not observed in Pompe mice with genetically intact autophagy. The suppression of autophagy, which has proven successful in the Pompe model, is a novel therapeutic approach that may be useful in other diseases with disturbed autophagy.
AB - Autophagy, an intracellular system for delivering portions of cytoplasm and damaged organelles to lysosomes for degradation/recycling, plays a role in many physiological processes and is disturbed in many diseases. We recently provided evidence for the role of autophagy in Pompe disease, a lysosomal storage disorder in which acid alpha-glucosidase, the enzyme involved in the breakdown of glycogen, is deficient or absent. Clinically the disease manifests as a cardiac and skeletal muscle myopathy. The current enzyme replacement therapy (ERT) clears lysosomal glycogen effectively from the heart but less so from skeletal muscle. In our Pompe model, the poor muscle response to therapy is associated with the presence of pools of autophagic debris. To clear the fibers of the autophagic debris, we have generated a Pompe model in which an autophagy gene, Atg7, is inactivated in muscle. Suppression of autophagy alone reduced the glycogen level by 50-60%. Following ERT, muscle glycogen was reduced to normal levels, an outcome not observed in Pompe mice with genetically intact autophagy. The suppression of autophagy, which has proven successful in the Pompe model, is a novel therapeutic approach that may be useful in other diseases with disturbed autophagy.
KW - Atg7
KW - Enzyme replacement therapy
KW - Lysosomal glycogen storage
KW - Myopathy
KW - Pompe disease
UR - http://www.scopus.com/inward/record.url?scp=78649288882&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78649288882&partnerID=8YFLogxK
U2 - 10.4161/auto.6.8.13378
DO - 10.4161/auto.6.8.13378
M3 - Article
C2 - 20861693
AN - SCOPUS:78649288882
SN - 1554-8627
VL - 6
SP - 1078
EP - 1089
JO - Autophagy
JF - Autophagy
IS - 8
ER -