Metabolomic Profiling of Pompe Disease-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveals That Oxidative Stress Is Associated with Cardiac and Skeletal Muscle Pathology.
Pompe disease (PD) is a lysosomal storage disease that is caused by a deficiency of the acid α-glucosidase, which results in glycogen accumulation in the lysosome. The major clinical symptoms of PD include skeletal muscle weakness, respiratory failure, and cardiac hypertrophy. Based on its severity and symptom onset, PD is classified into infantile and late-onset forms. Lysosomal accumulation of glycogen can promote many types of cellular dysfunction, such as autophagic dysfunction, endoplasmic reticulum stress, and abnormal calcium signaling within skeletal muscle. However, the disease mechanism underlying PD cardiomyopathy is not fully understood. Several researchers have shown that PD induced pluripotent stem cell (iPSC)-derived cardiomyocytes successfully replicate the disease phenotype and are useful disease models. We have analyzed the metabolomic profile of late-onset PD iPSC-derived cardiomyocytes and found that oxidative stress and mitochondrial dysfunction are likely associated with cardiac complications. Furthermore, we have validated that these disease-specific changes were also observed in the cardiomyocytes and skeletal muscle of a genetically engineered murine PD model. Oxidative stress may contribute to skeletal muscle and cardiomyocyte dysfunction in PD mice; however, NF-E2-related factor 2 was downregulated in cardiomyocytes and skeletal muscle, despite evidence of oxidative stress. We hypothesized that oxidative stress and an impaired antioxidative stress response mechanism may underlie the molecular pathology of late-onset PD. Stem Cells Translational Medicine 2017;6:31-39.
Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan.|Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
Yohei
Y
Sato
Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan.|Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
Hiroshi
H
Kobayashi
Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
Takashi
T
Higuchi
Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
Yohta
Y
Shimada
Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan.|Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
Hiroyuki
H
Ida
Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan.|Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan.
Toya
T
Ohashi
D000818:Animals; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D019075:Electrophoresis, Capillary; D006009:Glycogen Storage Disease Type II / Q000473:pathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods*; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress
Metabolomic profiling; Mitochondrial dysfunction; Oxidative stress; Pluripotent stem cell; Pompe disease