Abstract
We studied the role of autophagy in a series of 10 infantile-, juvenile-, and adult-onset GSDII patients and investigated autophagy blockade in successive biopsies of adult cases during disease natural history. We also correlated the autophagosome accumulation and efficiency of enzyme replacement therapy (ERT) in four treated cases (two infantile and two juvenile-adult onsets).
The autophagic flux was monitored by measuring the amount of p62-positive protein aggregates and compared, together with fibre vacuolisation, to fibre atrophy.
A blocked autophagic flux resulted in p62 accumulation, increased vacuolisation, and progressive atrophy of muscle fibres in biopsies collected from patients during natural history. On the contrary, in the GSDII cases early treated with ERT, the autophagic flux improved and muscle fibre atrophy, fibre vacuolisation, and acid phosphatase activity decreased.
The functionality of the autophagy-lysosome system is essential in GSDII muscle, which is characterised by the presence of swollen glycogen-filled lysosomes and autophagic build-up. Defining the role of autophagy and its relationship with muscle loss is critical for understanding the disease pathogenesis, for developing new therapies, and for improving ERT efficacy in GSDII.
Competing interests: None declared
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Acknowledgments
This paper was supported by grants from Telethon (GUP13013), Association Francaise contre les Myopathies (AFM), the Eurobiobank Network, and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI).
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Communicated by: Robin Lachmann, PhD, FRCP
Appendices
Synopsis
Muscle fibre atrophy and autophagy are linked in the progression of glycogenosis type 2; ERT might reverse such features.
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Conflict of Interest
Dr. Corrado Angelini has received compensation from Genzyme European Registry.
Dr. Anna C. Nascimbeni declares that she has no conflict of interest.
Dr. Marina Fanin declares that she has no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (University of Padova, Italy) and with the Helsinki Declaration of 1975 and revised in 2000.
Informed consent was obtained from all patients (or their parents) for being included in the study.
Contribution of Individual Authors
Drs. Angelini, Nascimbeni, and Fanin have contributed pertinent aspects of the planning, conduct, and reporting of the work described in the article.
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Angelini, C., Nascimbeni, A.C., Fanin, M. (2014). Autophagy in Natural History and After ERT in Glycogenosis Type II. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 21. JIMD Reports, vol 21. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_389
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DOI: https://doi.org/10.1007/8904_2014_389
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