Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder--murine Pompe disease.
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 alphaglucosidase, 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.
Raben
Nina
N
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. rabenn@mail.nih.gov
Schreiner
Cynthia
C
Baum
Rebecca
R
Takikita
Shoichi
S
Xu
Sengen
S
Xie
Tao
T
Myerowitz
Rachel
R
Komatsu
Masaaki
M
Van der Meulen
Jack H
JH
Nagaraju
Kanneboyina
K
Ralston
Evelyn
E
Plotz
Paul H
PH
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000473:pathology / Q000628:therapy*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D019426:Integrases / Q000378:metabolism; D051379:Mice; D018656:Muscle Fibers, Fast-Twitch / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D025801:Ubiquitin / Q000378:metabolism; D000520:alpha-Glucosidases / Q000172:deficiency / Q000378:metabolism / Q000627:therapeutic use*
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D018994:Myosin Light Chains; D025801:Ubiquitin; D006003:Glycogen; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C045073:Cre recombinase; D019426:Integrases; D000520:alpha-Glucosidases