Abstract
The autophagy–lysosome system is critical for muscle homeostasis and defects in lysosomal function result in a number of inherited muscle diseases, generally referred to as autophagic vacuolar myopathies (AVMs). Among them, Danon Disease (DD) and glycogen storage disease type II (GSDII) are due to primary lysosomal protein defects. DD is characterized by mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. The DD mouse model suggests that inefficient lysosome biogenesis/maturation and impairment of autophagosome-lysosome fusion contribute to the pathogenesis of muscle wasting. To define the role of autophagy in human disease, we analyzed the muscle biopsies of DD patients and monitored autophagy and several autophagy regulators like transcription factor EB (TFEB), a master player in lysosomal biogenesis, and vacuolar protein sorting 15 (VPS15), a critical factor for autophagosome and endosome biogenesis and trafficking. Furthermore, to clarify whether the mechanisms involved are shared by other AVMs, we extended our mechanistic study to a group of adult GSDII patients. Our data show that, similar to GSDII, DD patients display an autophagy block that correlates with the severity of the disease. Both DD and GSDII show accumulation and altered localization of VPS15 in autophagy-incompetent fibers. However, TFEB displays a different pattern between these two lysosomal storage diseases. Although in DD TFEB and downstream targets are activated, in GSDII patients TFEB is inhibited. These findings suggest that these regulatory factors may have an active role in the pathogenesis of these diseases. Therapeutic approaches targeted to normalize these factors and restore the autophagic flux in these patients should therefore be considered.
Highlights
The autophagic pathway has a crucial role in skeletal muscle homeostasis, providing a finely tuned system for protein degradation and organelle removal.[1]
We extended our observation of autophagy impairment in glycogen storage disease type II (GSDII) to Danon disease (DD) and investigated the status of two important autophagy regulators: vacuolar protein sorting 15/phosphoinositide-3-kinase regulatory subunit 4 (VPS15/PIK3R4) and transcription factor EB (TFEB)
To investigate whether autophagy is involved in DD muscle pathology, we studied muscle biopsies of four DD patients (Supplementary Table S1), including three males and one female
Summary
The autophagic pathway has a crucial role in skeletal muscle homeostasis, providing a finely tuned system for protein degradation and organelle removal.[1]. The deficiency of LAMP2a-mediated CMA may trigger autophagy as a compensatory mechanism, the half-life of autophagosomes in LAMP2-deficient murine hepatocytes is Received 16.7.16; revised 05.12.16; accepted 07.12.16; Edited by GM Fimia prolonged, suggesting an impairment of autophagosome– lysosome fusion and degradation.[9] Muscles of DD patients have large vacuoles surrounded by lysosomes and delimited by membranes containing sarcolemmal proteins (such dystrophin-associated proteins, extracellular matrix molecules and acetylcholinesterase), and positive for the autophagosome marker LC3. These structures are described as ‘autophagic vacuoles with sarcolemmal features’ (AVSF).[10] AVSFs appear to be constituted by an accumulation of autophagosomes, lysosomes and autophagolysosomes. We compared the level of autophagy activation between DD with GSDII patients
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
