Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment.
Pascal LaforêtMichio InoueEvelyne GoillotClaire LefeuvreUmut CaginNathalie StreichenbergerSarah Leonard-LouisGuy BrochierAngeline MadelaineClemence LabasseCarola Hedberg-OldforsThomas KragLouisa JauzeJulien FabreguePhilippe LabruneJose MilisendaAleksandra Nadaj-PaklezaSabrina SacconiFederico MingozziGiuseppe RonzittiFrançois PetitBenedikt SchoserAnders OldforsJohn VissingNorma B RomeroIchizo NishinoEdoardo MalfattiPublished in: Acta neuropathologica communications (2019)
Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene.In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model.In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples.These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.
Keyphrases
- skeletal muscle
- end stage renal disease
- endothelial cells
- cell death
- mouse model
- ejection fraction
- newly diagnosed
- type iii
- chronic kidney disease
- insulin resistance
- gene therapy
- oxidative stress
- prognostic factors
- depressive symptoms
- endoplasmic reticulum stress
- gene expression
- peritoneal dialysis
- heart failure
- metabolic syndrome
- ultrasound guided
- high resolution
- induced pluripotent stem cells
- mass spectrometry
- type diabetes
- dna methylation
- physical activity
- left ventricular
- adipose tissue
- late onset
- patient reported outcomes
- sleep quality
- genome wide
- smoking cessation
- electron microscopy
- fine needle aspiration