Abstract
Regulated removal of proteins and organelles by autophagy–lysosome system is critical for muscle homeostasis. Excessive activation of autophagy-dependent degradation contributes to muscle atrophy and cachexia. Conversely, inhibition of autophagy causes accumulation of protein aggregates and abnormal organelles, leading to myofiber degeneration and myopathy. Defects in lysosomal function result in severe muscle disorders such as Pompe (glycogen storage disease type II (GSDII)) disease, characterized by an accumulation of autophagosomes. However, whether autophagy is detrimental or not in muscle function of Pompe patients is unclear. We studied infantile and late-onset GSDII patients and correlated impairment of autophagy with muscle wasting. We also monitored autophagy in patients who received recombinant α-glucosidase. Our data show that infantile and late-onset patients have different levels of autophagic flux, accumulation of p62-positive protein aggregates and expression of atrophy-related genes. Although the infantile patients show impaired autophagic function, the late-onset patients display an interesting correlation among autophagy impairment, atrophy and disease progression. Moreover, reactivation of autophagy in vitro contributes to acid α-glucosidase maturation in both healthy and diseased myotubes. Together, our data suggest that autophagy protects myofibers from disease progression and atrophy in late-onset patients.
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Abbreviations
- GSDII:
-
glycogen storage disease type II
- GAA:
-
acid α-glucosidase
- p62/SQSTM1:
-
p62/sequestosome1
- FoxO:
-
forkhead box O
- Lamp2:
-
lysosomal-associated membrane protein 2
- XMEA:
-
X-linked myopathy with excessive autophagy
- V-ATPase:
-
vacuolar-type H+-ATPase
- GAA-KO:
-
acid α-glucosidase-knockout
- PGC1α:
-
peroxisome proliferator-activated receptor γ coactivator 1-α
- ERT:
-
enzyme replacement therapy
- LC3:
-
microtubule-associated protein 1 light chain 3
- LC3II:
-
microtubule-associated protein 1 light chain 3 β
- CSA:
-
cross-sectional area
- BECN1:
-
Beclin 1
- Bnip3:
-
Bcl-2/adenovirus E1B 19 kDa interacting protein 3
- MuRF1:
-
muscle-specific RING finger protein 1
- M6P:
-
mannose-6-phosphate
- mTOR:
-
mammalian target of rapamycin
- NFκB:
-
nuclear factor κ-light-chain-enhancer of activated B cells
- NRF2:
-
nuclear factor (erythroid-derived 2)-like 2
- PKC:
-
protein kinase C
- GAPDH:
-
glyceraldehyde 3-phosphate dehydrogenase
- H&E:
-
hematoxylin and eosin stain
- IF:
-
immunofluorescence
- PAS:
-
periodic acid-Schiff
- Cav3:
-
caveolin-3
- HBSS:
-
Hank’s-balanced salt solution
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Acknowledgements
We gratefully acknowledge B Dalle from Myosix for providing and culturing some of the myoblasts and Genzyme for the anti-GAA antibody. This work was supported by grants from AFM (14199) to AN, from Telethon-Italy (GTB07001-DR) and Eurobiobank network (QLRT2001-027769) to CA, from AFM (15504), from Telethon-Italy (TCP04009) and from ERC (MyoPHAGY, No: 282310) to MS.
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Nascimbeni, A., Fanin, M., Masiero, E. et al. The role of autophagy in the pathogenesis of glycogen storage disease type II (GSDII). Cell Death Differ 19, 1698–1708 (2012). https://doi.org/10.1038/cdd.2012.52
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DOI: https://doi.org/10.1038/cdd.2012.52
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