Lysosomal myopathies: An excessive build-up in autophagosomes is too much to handle

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.
Neuromuscular Disorders (Impact Factor: 2.64). 08/2008; 18(7):521-9. DOI: 10.1016/j.nmd.2008.04.010
Source: PubMed


Lysosomes are membrane-bound acidic organelles that contain hydrolases used for intracellular digestion of various macromolecules in a process generally referred to as autophagy. In normal skeletal and cardiac muscles, lysosomes usually appear morphologically unremarkable and thus are not readily visible on light microscopy. In distinct neuromuscular disorders, however, lysosomes have been shown to be structurally abnormal and functionally impaired, leading to the accumulation of autophagic vacuoles in myofibers. More specifically, there are myopathies in which buildup of these autophagic vacuoles seem to predominate the pathological picture. In such conditions, autophagy is considered not merely a secondary event, but a phenomenon that actually contributes to disease pathomechanism and/or progression. At present, there are two disorders in the muscle which are associated with primary defect in lysosomal proteins, namely Danon disease and Pompe disease. Other myopathies which have prominent autophagy in the skeletal muscle include X-linked myopathy with excessive autophagy (XMEA). In this review, these disorders are briefly characterized, and the role of autophagy in the context of the pathomechanism of these disorders is highlighted.

Download full-text


Available from: Paul Saftig
  • Source
    • "A similar trend was seen in our de novo treated patients. The presence of excessive autophagy in smooth muscle associated with abnormal glycogen accumulation is particularly interesting since autophagy is thought to have a direct role in the pathomechanism of Pompe disease [18,19] and its negative effect to ERT efficiency has been demonstrated in animal models [20]. Because the morphological alterations of skeletal and smooth muscle are remarkably similar, the arrector pili muscle appears to be suitable for the study of these pathomechanisms in human patients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glycogenosis type II or Pompe disease is an autosomal-recessive lysosomal storage disease due to mutations in the gene encoding acid alpha-glucosidase (GAA), an enzyme required for lysosomal glycogen degradation. The disease predominantly affects the skeletal and respiratory muscles but there is growing evidence of the involvement of smooth muscle cells in blood vessel walls, suggesting a multi-system disorder. Moreover, the failure of autophagy in Pompe disease could contribute to muscular atrophy and disease progression and is thought to compromise the efficacy of enzyme replacement therapy (ERT). We investigated the light microscopical and ultrastructural pathology of the arrector pili muscle from punch skin biopsies from the calf of 6 adult Pompe disease patients and 6 age and gender matched healthy controls. Two patients had a follow-up biopsy after 19 and 20 month of ERT. The electron microscopic investigation of patient biopsies revealed the widespread occurrence of glycogenosomes, membrane bound accumulations of granular glycogen, associated with autophagic vacuoles. In the controls we detected only muscle cells with non-membrane bound forms of glycogen. These morphological changes in smooth muscle cells are similar to those seen in skeletal muscle and smooth muscle cells of arterioles of Pompe patients. Furthermore, two patients with pre- and post-ERT skin biopsies showed a decrease in the number of cells with extensive autophagy after treatment. Electron microscopic examination of the arrector pili muscles appears to be a surrogate marker for the involvement of smooth muscles reflecting disease severity. These findings suggest that the standardized and widely used skin biopsy could offer a minimally invasive way to screen for smooth muscle involvement and warrant further studies in larger cohorts of patients.
    Full-text · Article · Feb 2014 · Orphanet Journal of Rare Diseases
  • Source
    • "Autophagy is intricately implicated in health and disease. Autophagy defects play a role in the pathogenesis of numerous diseases, including myopathy, neuronal degeneration, microbial infection, inflammatory bowel disease, aging and cancer (6–11). Studies have demonstrated the functional role of autophagy in various cellular processes and the potential of autophagy modulation as a novel therapeutic strategy for a number of pathological conditions, including cancer (12–14). "
    [Show abstract] [Hide abstract]
    ABSTRACT: It has been well documented that the inhibition of the mammalian target of rapamycin (mTOR) induces autophagy in proliferative cells. Therefore, mTOR inhibitors have been proposed for the treatment of cancer. As autophagy plays significant roles in tumor cell survival, the present study aimed to investigate the contribution of autophagy activation to the antitumor effects of cis-diamminedichloroplatinum (CDDP). An MTT assay was used to determine the cytotoxic effects of rapamycin on MG63 osteosarcoma cells. The cell cycle was assessed using a flow cytometry analysis subsequent to staining the DNA with propidium iodide. The mitochondrial membrane potential (Δψ) was measured using the fluorescent probe, JC-1. Western blot analysis was used to determine the expression of the proteins that are involved in apoptosis and autophagy, including p53, p62, light chain 3 (LC3) and Beclin-1. The viability of the MG63 cells was inhibited following rapamycin or CDDP treatment. The mitochondrial Δψ collapsed following treatment with rapamycin or CDDP. Rapamycin induced cell death and enhanced the effects of the induction of MG63 cell death by CDDP. Western blot analysis detected the induced expression of the p53 and Beclin-1 proteins and the autophagic proteins, LC3 and p62. Rapamycin was observed to induce the death of cancer cells through apoptotic and autophagic mechanisms. Rapamycin may enhance the effects of the activation of autophagy and the induction of apoptosis by CDDP.
    Full-text · Article · Nov 2013 · Oncology letters
  • Source
    • "Autophagy is intricately implicated in both health and disease. Autophagy defects play a role in the pathogenesis of diverse diseases, including myopathy, neuronal degeneration, microbial infection, inflammatory bowel disease, aging, and cancer (Cadwell et al., 2008; Malicdan et al., 2008; Saitoh et al., 2008; Winslow and Rubinsztein, 2008; Yen and Klionsky, 2008; Orvedahl and Levine, 2009). Recent studies have elucidated the functional role of autophagy in different cellular processes and the potential of autophagy modulation as a novel therapeutic strategy for different pathologic conditions, including cancer (Carew et al., 2007; Mathew et al., 2007; Chen and Karantza-Wadsworth, 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Apoptosis may be induced after Bcl-2 expression is inhibited in proliferative cancer cells. This study focused on the effect of autophagy activation by ABT737 on anti-tumor effects of epirubicin. Methods: Cytotoxic effects of ABT737 on the HepG2 liver cancer cell line were assessed by MTT assay and cell apoptosis through flow cytometry. Mitochondrial membrane potential was measured by fluorescence microscopy. Monodansylcadaverin (MDC) staining was used to detect activation of autophagy. Expression of p53, p62, LC3, and Beclin1, apoptotic or autophagy related proteins, was detected by Western blotting. Results: ABT737 and epirubicin induced growth inhibition in HepG2 cells in a dose- and time-dependent manner. Both ABT737 and epirubicin alone could induce cell apoptosis with a reduction in mitochondrial membrane potential as well as increased apoptotic protein expression. Further increase of apoptosis was detected when HepG2 cells were co- treated with ABT373 and epirubicin. Furthermore, our results demonstrated that ABT373 or epirubicin ccould activate cell autophagy with elevated autophagosome formation, increased expression of autophagy related proteins and LC3 fluorescent puncta. Conclusions: ABT737 influences cancer cells through both apoptotic and autophagic mechanisms, and ABT737 may enhance the effects of epirubicin on HepG2 cells by activating autophagy and inducing apoptosis.
    Preview · Article · Oct 2013 · Asian Pacific journal of cancer prevention: APJCP
Show more