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• W2022106349 abstract "1. Introduction and overviewThe 201st ENMC International Workshop on autophagy in muscular dystrophies (MD) was held in Bussum, The Netherlands, on 1–3 November 2013, and was attended by 20 participants from 10 countries (France, Finland, Germany, Italy, Japan, Sweden, The Netherlands, Turkey, United Kingdom, and USA). Participants included biochemists, biologists, pathologists, molecular geneticists, neurologists, and paediatricians.The first session of the workshop focused on the basic mechanism of autophagy in particular autophagosome formation and regulation, selective types of autophagy (chaperone-assisted and mitophagy), and the role of autophagy in muscle homeostasis. Further sessions concentrated on the current understanding of the role of autophagy in several muscle disorders including Pompe disease, Danon disease, X-linked myopathy with excessive autophagy (XMEA), laminopathies, GNE myopathy, centronuclear myopathies, myofibrillar myopathies, limb-girdle muscular dystrophies, oculopharyngeal muscular dystrophy (OPMD), distal myopathies, inclusion body myopathy associated with Paget’s disease of the bone and frontotemporal dementia (IBMPFD/VCP myopathy), Vici syndrome, collagen type VI related myopathies, congenital muscular dystrophies (MDC1A and megaconial type), and Duchenne muscular dystrophy (DMD). The preliminary results of sialic acid supplementation therapy in GNE myopathy and of a low protein diet in COL6-related myopathies were presented. A final topic was the presentation of novel methods to monitor autophagy in skeletal muscle using electron microscopy, in vivo flux assays, and the development of methodologies to ultimately monitor autophagic flux in vivo in patients. The last session was dedicated to the provision of guidelines on how to monitor autophagy in clinical trials.Macroautophagy (herein autophagy), or “self-eating”, is an evolutionarily conserved intracellular system by which macromolecules and organelles are delivered to lysosomes for degradation and recycling [[1]Yang Z. Klionsky D.J. Eaten alive: a history of macroautophagy.Nat Cell Biol. 2010; 12: 814-822Crossref PubMed Scopus (1602) Google Scholar]. This catabolic process is particularly relevant for skeletal muscle. Muscle represents 40% of whole-body lean mass, thereby providing a tissue source for amino acids that can be used in times of stress or starvation. In addition to nutrient regulation, autophagy is involved in cell differentiation and development, tumour suppression, innate and adaptive immunity, lifespan extension, and cell death [[2]Mehrpour M. Esclatine A. Beau I. Codogno P. Autophagy in health and disease 1. Regulation and significance of autophagy: an overview.Am J Physiol Cell Physiol. 2013; 298: C776-C785Crossref Scopus (168) Google Scholar]. In particular it functions as a quality control mechanism for the elimination of aggregated proteins and recycling of damaged organelles, such as mitochondria. Mitochondria, concomitant with energy production through oxidative phosphorylation, generate reactive oxygen species (ROS), causing protein, lipid, and DNA oxidation and often inducing cell death. Quality control of mitochondria is essential for cellular homeostasis, a process achieved through selective autophagy (mitophagy). Research during the last decade has made it clear that normal autophagy is fundamental for human health, aging and life span, and malfunctioning or failure of autophagy is associated with a wide range of human pathologies including muscular dystrophies. Regulated removal of proteins and organelles by autophagy-lysosome system is in fact 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. In particular alteration of autophagosome biogenesis has been found relevant for a number of muscular dystrophies including Ullrich congenital muscular dystrophy (UCMD), DMD, Emery–Dreifuss muscular dystrophy (EDMD) and congenital muscular dystrophy 1A (MDC1A). Alteration of autophagosome-lysosome fusion is instead involved in Vici syndrome, Danon disease and Pompe disease. Activation of autophagic flux has been proved beneficial in mice models of UCMD, DMD and EDMD, and inhibition of autophagic flux in a mouse model of MDC1A. It is essential that investigators understand autophagy in skeletal muscle and its dysregulation in muscle disease so as to design therapeutic interventions aimed at correcting autophagy in these muscular dystrophies and myopathies.2. Autophagy and muscle2.1 Autophagosome formation and regulationNicolas Dupont gave an overview of the autophagosome formation. To date, three major types of autophagy have been described: autophagy/macroautophagy, microautophagy, and chaperone-mediated autophagy [[1]Yang Z. Klionsky D.J. Eaten alive: a history of macroautophagy.Nat Cell Biol. 2010; 12: 814-822Crossref PubMed Scopus (1602) Google Scholar]. Autophagy begins with the multi-step formation of double membrane-bound vacuoles named the autophagosome that sequesters the cytoplasmic material in bulk or in a selective manner. Once formed the autophagosome acquires acidic and degradative capacities by merging with endocytic compartments (to form a compartment called the amphisome). The final stage of autophagy is the fusion of autophagic vacuoles (amphisome or autophagosome) with lysosomes to form autolysosomes where autophagy cargo is totally degraded. About fifteen ATG (Autophagic-related genes) proteins constitute the core machinery of autophagosome formation [[2]Mehrpour M. Esclatine A. Beau I. Codogno P. Autophagy in health and disease 1. Regulation and significance of autophagy: an overview.Am J Physiol Cell Physiol. 2013; 298: C776-C785Crossref Scopus (168) Google Scholar]. These ATG proteins are hierarchically recruited to form a phagophore or isolation membrane that subsequently elongates to form the autophagosome. Recent studies have shown that ATG assembly takes place at the contact point between the endoplasmic reticulum membrane and the outer membranes of the mitochondrion [[3]Hamasaki M. Furuta N. Matsuda A. et al.Autophagosomes form at ER-mitochondria contact sites.Nature. 2013; 495: 389-393Crossref PubMed Scopus (1143) Google Scholar]. However other membranes, such as the endosomes, the Golgi apparatus, and the plasma membrane, also contribute to the biogenesis of the autophagosome [[4]Rubinsztein D.C. Shpilka T. Elazar Z. Mechanisms of autophagosome biogenesis.Curr Biol. 2012; 22: 29-34Abstract Full Text Full Text PDF Scopus (329) Google Scholar]. Autophagy is initiated by the activation of the ULK1 (the mammalian homolog of yeast Atg1) complex, which contains the serine/threonine kinase ULK-1 or -2, ATG13, a 200-kD focal adhesion kinase family interacting protein (FIP200), and ATG101. Once autophagy has been induced, this complex localizes at the site of phagophore formation to regulate the nucleation machinery [[5]Wirth M. Joachim J. Tooze S.A. Autophagosome formation – the role of ULK1 and Beclin1-PI3KC3 complexes in setting the stage.Semin Cancer Biol. 2013; 23: 301-309Crossref PubMed Scopus (191) Google Scholar]. Phagophore nucleation is highly dependent on the production of phosphatidylinositol 3-phosphate (PI3P) by class III phosphatidylinositol 3-kinase (PI3KC3 or VPS34). PI3KC3 forms the core PI3K complex I with its adaptors, p150/VPS15 Beclin 1 (the mammalian homolog of the yeast Atg6) and ATG14. Several proteins, such as AMBRA1 or Bcl-2, can either activate or inhibit the production of PI3P by PI3K complex I [[5]Wirth M. Joachim J. Tooze S.A. Autophagosome formation – the role of ULK1 and Beclin1-PI3KC3 complexes in setting the stage.Semin Cancer Biol. 2013; 23: 301-309Crossref PubMed Scopus (191) Google Scholar]. ULK1 activates PI3K complex I by phosphorylating Beclin 1 and AMBRA1. In turn, AMBRA1 interacts with the E3-ligase TRAF6 to induce the ubiquitination of ULK1, thus increasing its stability and functional efficiency. ULK1 can also modulate the activity of other modules of the ATG core machinery by controlling the vesicular transport of ATG9, and by interacting with ATG8 homologs via a LC3-interacting region (LIR motif). Another component of the ULK1 complex, FIP200, interacts with ATG16L1, which is an element in the ubiquitin-like cassette of the ATG core machinery. The production of PI3P in the phagophore membrane allows the recruitment of the WD repeat domain PI3P-interacting proteins WIPI1 and WIPI2 (homologs of yeast Atg18) at the phagophore and DFCP1 at the ER site of autophagosome formation known as the omegasome. WIPI proteins contribute to the expansion and the closure of the vesicle in concert with two ubiquitin-like conjugation systems, resulting in the ATG12–ATG5–ATG16L complex, and the formation of the phosphatidyl ethanolamine (PE) conjugate of microtubule-associated protein light chain 3 (LC3; the mammalian ortholog of Atg8 in yeast). The trans membrane protein ATG9 is also involved in the nucleation of the phagophore membrane by cycling between different compartments and the phagophore [[6]Orsi A. Razi M. Dooley H.C. et al.Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy.Mol Biol Cell. 2012; 23: 1860-1873Crossref PubMed Scopus (357) Google Scholar]. In mammalian cells, the trafficking of ATG9 to the phagophore is an early event that occurs soon after autophagy induction [[6]Orsi A. Razi M. Dooley H.C. et al.Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy.Mol Biol Cell. 2012; 23: 1860-1873Crossref PubMed Scopus (357) Google Scholar].2.2 Chaperone-assisted selective autophagy (CASA)Jan Daerr gave an overview over the dependence of cellular mechanotransduction on tension-induced and chaperone-assisted selective autophagy (CASA) [[7]Ulbricht A. Eppler F.J. Tapia V.E. et al.Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy.Curr Biol. 2013; 23: 430-435Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar]. Recent work in the Anna Ulbricht and Jörg Höhfeld lab identified CASA as a tension-induced autophagy pathway essential for mechanotransduction in mammalian cells. Tension-induced unfolding of cytoskeleton proteins and mechanosensors poses a constant threat to protein homeostasis in adherent cells and contracting muscles. This group has identified a mechanotransduction pathway that senses the tension-induced unfolding of the actin-crosslinking protein filamin, disposes of mechanically damaged forms of filamin, and induces a transcriptional response to compensate filamin degradation. A central component of this pathway is the cochaperone BAG3, which coordinates the activity of the chaperone proteins Hsc70 and HspB8 during mechanosensation at Z-disks in striated muscles and along actin stress fibres in non-muscle cells. In conjunction with its binding partner synaptopodin-2/myopodin, BAG3 facilitates the degradation of unfolded filamin by CASA. Furthermore, BAG3 is able to interact with components of the Hippo signalling network and thereby induces filamin transcription under mechanical tension. The central role of BAG3 for protein homeostasis in mechanically strained cells and tissues is illustrated by the fact that functional impairment of the cochaperone in mice and patients causes severe muscle dystrophy and cardiomyopathy.2.3 Autophagy in muscle homeostasisMarco Sandri described the involvement of autophagy in muscle homeostasis. Autophagy has been originally associated to protein breakdown and muscle atrophy. However, the interest on this pathway emerged after the discovery that FoxO transcription factors coordinate the activation of the ubiquitin proteasome and of autophagy-lysosome pathways in atrophying muscles [[8]Sandri M. Autophagy in skeletal muscle.FEBS Lett. 2010; 584: 1411-1416Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar]. However, the development of muscle specific autophagy-deficient mice unravelled an even more important physiological role of autophagy in maintenance of muscle homeostasis. In fact muscle specific Atg7 knockout mice showed a myopathic phenotype but, even more importantly, they were not protected from atrophy after denervation or fasting. Importantly, Atg7−/− showed different features of degeneration in denervated and fasted muscles suggesting that autophagy is required for myofiber survival in catabolic conditions. In atrophying muscle, the mitochondrial network is dramatically remodelled following fasting or denervation, and autophagy via Bnip3 contributes to mitochondrial changes [[9]Romanello V. Guadagnin E. Gomes L. et al.Mitochondrial fission and remodelling contributes to muscle atrophy.EMBO J. 2010; 29: 1774-1785Crossref PubMed Scopus (431) Google Scholar]. Another mechanism that regulates mitophagy involves Mul1. Mul1 is a mitochondrial ubiquitin ligase that plays an important role in mitochondrial network remodelling. Mul1 is up regulated in catabolic conditions, such as fasting or denervation, by the FoxO family of transcription factors and causes mitochondrial fragmentation and removal via autophagy [[10]Lokireddy S. Wijesoma I.W. Teng S. et al.The ubiquitin ligase mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli.Cell Metab. 2012; 16: 613-624Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar]. Importantly, knocking down Mul1 spares muscle mass during fasting. Mul1 ubiquitinates the mitochondrial pro-fusion protein mitofusin 2, causing its degradation via the proteasome system. The exact mechanism that triggers Mul1-dependent mitochondrial dysfunction and mitophagy is unclear, but it has been reported that mitofusin degradation is permissive for mitochondrial fission and mitophagy [[9]Romanello V. Guadagnin E. Gomes L. et al.Mitochondrial fission and remodelling contributes to muscle atrophy.EMBO J. 2010; 29: 1774-1785Crossref PubMed Scopus (431) Google Scholar]. Accordingly, expression of the fission machinery is sufficient to cause muscle wasting in mice, whereas inhibition of mitochondrial fission prevents muscle loss during denervation, indicating that disruption of the mitochondrial network via autophagy is a crucial amplificatory loop of the muscle atrophy program [[9]Romanello V. Guadagnin E. Gomes L. et al.Mitochondrial fission and remodelling contributes to muscle atrophy.EMBO J. 2010; 29: 1774-1785Crossref PubMed Scopus (431) Google Scholar]. However, whether other systems such as PINK1/Parkin, which have been described to regulate mitophagy in other cells, play a role in mitochondria quality control and muscle mass maintenance is unclear. Impairment of basal mitophagy leads to the accumulation of damaged and dysfunctional mitochondria that contribute to myofiber degeneration [[11]Grumati P. Coletto L. Sabatelli P. et al.Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration.Nat Med. 2010; 16: 1313-1320Crossref PubMed Scopus (394) Google Scholar]. Therefore autophagy is critical to maintain myofiber function by clearing abnormal organelles. Accordingly, the phenotype of mice with muscle-specific inactivation of various genes coding for autophagy-related proteins, such as Atg7, Atg5 or nutrient-deprivation autophagy factor-1 (NAF-1), a Bcl-2 associated autophagy regulator, results in atrophy, weakness and different myopathic features [[12]Kim K.H. Jeong Y.T. Oh H. et al.Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine.Nat Med. 2013; 19: 83-92Crossref PubMed Scopus (556) Google Scholar]. In addition, altered regulation of autophagy-related genes leads to muscle dysfunction. Histone deacetylases 1 and 2 (HDACs) were found to regulate muscle autophagy by controlling the expression of autophagy genes. Muscle-specific ablation of both HDAC1 and HDAC2 results in partial perinatal lethality, while those HDAC1/2 knockout mice that survive develop a progressive myopathy characterized by impaired autophagy [[13]Moresi V. Carrer M. Grueter C.E. et al.Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice.Proc Natl Acad Sci U S A. 2012; 109: 1649-1654Crossref PubMed Scopus (93) Google Scholar]. Recent reports underlined another physiological role of autophagy during muscle contraction. Autophagy is physiologically induced by exercise including both endurance and resistance exercise and mediates the metabolic beneficial effects of physical activity on glucose homeostasis. Autophagy is activated in collagen VI-deficient mice by endurance exercise [[14]Grumati P. Coletto L. Schiavinato A. et al.Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI-deficient muscles.Autophagy. 2011; 7: 1415-1423Crossref PubMed Scopus (185) Google Scholar] and this effect have been recently confirmed on humans [[15]Jamart C. Francaux M. Millet G.Y. Deldicque L. Frere D. Feasson L. Modulation of autophagy and ubiquitin-proteasome pathways during ultra-endurance running.J Appl Physiol. 2012; 112: 1529-1537Crossref PubMed Scopus (108) Google Scholar]. The rationale of exercise-dependent autophagy activation is still unclear but evidences suggest that autophagy is important for removal of proteins/organelles that are damaged by exercise itself or to provide energy for sustained contraction. These two hypotheses need to be better defined soon. For instance, the initial observation that autophagy is critical for glucose homeostasis has been recently challenged. In fact, opposite results have been recently published related to the role of autophagy on insulin sensitivity in skeletal muscle. Indeed both activation or inhibition of autophagy have been reported to ameliorate glucose uptake and lipids metabolism in diet-induced obesity [12Kim K.H. Jeong Y.T. Oh H. et al.Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine.Nat Med. 2013; 19: 83-92Crossref PubMed Scopus (556) Google Scholar, 16He C. Bassik M.C. Moresi V. et al.Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis.Nature. 2012; 481: 511-515Crossref PubMed Scopus (821) Google Scholar]. The two studies have used different transgenic mice that may account for the different results. One of the potential roles of autophagy involves the removal of structural proteins that are damaged by contraction. For instance it has been recently found that Filamin C is degraded by lysosomes. Filamin C is a protein of the Z-line that undergoes unfolding and refolding cycles during muscle contraction and is therefore prone to irreversible damage [[17]Arndt V. Dick N. Tawo R. et al.Chaperone-assisted selective autophagy is essential for muscle maintenance.Curr Biol. 2010; 20: 143-148Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar]. Alterations to filamin structure trigger the binding of the co-chaperone BAG3, which carries a complex made up of the chaperones Hsc70 and HspB8, as well as the ubiquitin ligase CHIP. CHIP ubiquitinates BAG3 and filamin, which are recognized and delivered to the autophagy system by p62 [[17]Arndt V. Dick N. Tawo R. et al.Chaperone-assisted selective autophagy is essential for muscle maintenance.Curr Biol. 2010; 20: 143-148Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar]. In conclusion, the recent findings underline an important role of autophagy in controlling several fundamental biological processes.2.4 Gene expressionMarco Sandri explained that in order to maintain autophagy flux for more than few hours it is mandatory to replenish the autophagy proteins that are consumed by the fusion with lysosomes and to rejuvenate the lysosome park. In autophagy-lysosome system, the proteins LC3, p62, Nbr1 and BNIP3 are critical for membrane commitment, cargo delivery and selective removal of damaged mitochondrial, respectively. To elicit their functions these proteins are entrapped into the autophagosome when the vesicle is formed and therefore, are destroyed upon fusion of autophagosome with lysosome. The transcriptional dependent upregulation of these genes is important to maintain their level during an enhancement of autophagy flux. In the case that their induction fails then autophagy cannot be sustained for a period longer than few hours and aborts. However, this transcriptional regulation should be always taken into account when autophagy is monitored on human muscle biopsies or in experimental/pathological conditions that last more than few hours. In fact p62 is a well-known autophagy substrate and therefore, is used as marker of autophagy flux. Accumulation of p62 suggests autophagy impairment while a decrease of p62 supports autophagy induction. However, it was recently shown that in some patients affected by glycogen storage disease the increase of p62 protein reflects an upregulation of p62 transcript and not autophagy impairment [[18]Nascimbeni A.C. Fanin M. Masiero E. Angelini C. Sandri M. Impaired autophagy contributes to muscle atrophy in glycogen storage disease type II patients.Autophagy. 2012; 8: 1697-1700Crossref PubMed Scopus (53) Google Scholar]. Similarly, a decrease of p62 protein may reflect a down regulation of its transcription and not an induction of autophagy system. Therefore, p62 and Nbr1 transcripts level should be always monitored when analyses are performed on human muscle biopsies, a condition that does not permit the proper analyses of autophagy flux. Other autophagy-related genes are transcriptionally regulated and several of these belong to the atrophy-related genes, genes that are always induced during muscle atrophy. Among these genes there are several whose induction is sufficient to activate autophagy such as Beclin1 and Bnip3 [9Romanello V. Guadagnin E. Gomes L. et al.Mitochondrial fission and remodelling contributes to muscle atrophy.EMBO J. 2010; 29: 1774-1785Crossref PubMed Scopus (431) Google Scholar, 19Bonaldo P. Sandri M. Cellular and molecular mechanisms of muscle atrophy.Dis Models Mech. 2013; 6: 25-39Crossref PubMed Scopus (736) Google Scholar]. Moreover a recent report identified a correlation between the time-dependent mRNA elevation of a specific set of ATG genes and autophagosome accumulation [[20]Tsuyuki S. Takabayashi M. Kawazu M. et al.Detection of mRNA as an indicator of autophagosome formation.Autophagy. 2013; 10: 497-513Crossref PubMed Scopus (41) Google Scholar]. Therefore, transcriptional-dependent upregulation is likely to be a convenient method of monitoring autophagosome formation [9Romanello V. Guadagnin E. Gomes L. et al.Mitochondrial fission and remodelling contributes to muscle atrophy.EMBO J. 2010; 29: 1774-1785Crossref PubMed Scopus (431) Google Scholar, 20Tsuyuki S. Takabayashi M. Kawazu M. et al.Detection of mRNA as an indicator of autophagosome formation.Autophagy. 2013; 10: 497-513Crossref PubMed Scopus (41) Google Scholar].The emerging master regulators of autophagy-lysosome gene network are two families of transcription factors, which are namely the FoxOs and TFEB. Both these transcription factors control each step of autophagy-lysosome system starting from phagophore formation to lysosome biogenesis and renewal [[21]Sandri M. Protein breakdown in muscle wasting: role of autophagy-lysosome and ubiquitin-proteasome.Int J Biochem Cell Biol. 2013; 45: 2121-2129Crossref PubMed Scopus (399) Google Scholar]. Importantly, the regulatory pathways that control FoxOs and TFEB activity are very similar and deeply interconnected. Indeed both these transcription factors are regulated by nutrient- and energy-sensitive signalling pathways. In conclusion, transcript levels of several autophagy-related genes is critical for interpretation of data of autophagy system while analysis of the implicated pathways and transcription factors is important for understanding the pathogenetic involvement/regulation of autophagy in muscle disorders.2.5 Proteomic characterization of aggregate components in degenerative hereditary myopathiesSabine Krause reported on quantitative proteomic analysis, a useful tool that may help to identify or to confine the number of causative candidate genes in hereditary myofibrillar myopathies as shown in FHL1-associated myopathy [[22]Feldkirchner S. Walter M.C. Muller S. et al.Proteomic characterization of aggregate components in an intrafamilial variable FHL1-associated myopathy.Neuromuscul Disord. 2013; 23: 418-426Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. In protein aggregates obtained by laser capture microdissection of skeletal muscle biopsies from two affected brothers, the most abundant protein was four and a half LIM domains 1 (FHL1) arising from the mutated gene. In addition, myofibrillar proteins and components of the autophagy pathway were among the most frequent proteins present in the analysed aggregates. In this study, p62 was the only abundant selective autophagic cargo receptor while NBR1 or LAMP2A were not identified. HSPA8 was significantly up regulated in aggregate-containing myofibers as compared to normal controls. Whether the presence of the identified proteins in myofibrillar aggregates is a bystander effect or implicates an active role in the pathogenesis of FHL1 and other myofibrillar myopathies remains to be determined. Primary mutant myoblasts from VCP-associated myopathy showed increased autophagy when cultured in the absence of nutrients, as well as defective cell fusion and increased apoptosis. The increased LC3-II form in mutant myoblasts cultured for a short starvation period suggests that mutant cells are prone to an elevated level of autophagy. Differential N-glycosylation of the lysosomal associated proteins LAMP1 and LAMP2 was also noted. LAMP2A alterations might interfere with chaperone-mediated autophagy.3. Autophagy and muscular dystrophies3.1 Glycogen storage disease type II – Pompe diseaseNina Raben discussed the role of autophagy in the pathogenesis of Pompe disease, an inherited neuromuscular disorder caused by a deficiency of acid alpha-glucosidase (GAA). The deficiency of this enzyme leads to accumulation of undigested glycogen within lysosomes in many tissues but is particularly harmful to cardiac, skeletal, and smooth muscle. The disease affects individuals with different degrees of severity and at varying ages of onset. The most severe infantile form manifests as fatal hypertrophic cardiomyopathy and skeletal muscle myopathy; milder late-onset forms are characterized by progressive muscle disease that can occur anytime from early childhood to late adulthood. The natural history of the disease changed following the implementation of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA; alglucosidase alfa; Myozyme® and Lumizyme®; Genzyme Corp., Cambridge, MA). The drug rescues cardiac abnormalities and enables much longer survival of infantile-onset patients but leaves them with skeletal muscle myopathy, often more severe than in late-onset cases. In late-onset patients, the therapy shows some benefits, but skeletal muscle weakness often persists after years on therapy. Several factors contribute to resistance of skeletal muscle to therapy; these include the sheer mass of muscle tissue, misdirection of the drug to non-muscle tissues, the low density of the mannose-6-phosphate receptor that is responsible for the uptake of the enzyme, inefficient trafficking of the internalized enzyme to lysosomes, and immune response. Although the overall understanding of the disease has progressed, the pathophysiology of muscle damage remains poorly understood. Lysosomal rupture and release of glycogen and lysosomal enzymes into the cytoplasm has long been considered a mechanism of relentless muscle damage in Pompe disease. In past years, Raben’s group gathered abundant evidence that this simple view of the pathology is incomplete. Electron microscopy and immunostaining of muscle biopsies from both Pompe patients and KO mice revealed large areas of autophagic accumulation in muscle fibres in addition to the enlargement of glycogen-laden lysosomes [[23]Raben N. Wong A. Ralston E. Myerowitz R. Autophagy and mitochondria in Pompe disease: nothing is so new as what has long been forgotten.Am J Med Genet C Semin Med Genet. 2012; 160: 13-21Crossref Scopus (80) Google Scholar]. In Pompe skeletal muscle, not only were the lysosomes filled with undigested glycogen, but other materials were also backed up outside – unable to reach the recycling place, the lysosome. The group developed yet another GAA knockout model, in which autophagosomes are labelled with GFP-LC3 (autophagosomal marker; GFP-LC3-GAA KO); in these mice autophagic build-up can be seen in live fibres without any staining [[24]Spampanato C. Feeney E. Li L. et al.Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease.EMBO Mol Med. 2013; 5: 691-706Crossref PubMed Scopus (229) Google Scholar]. The autophagic process in Pompe skeletal muscle is affected at both the initiation of autophagosomal formation (an increase) and at the termination stage (impaired autophagosomal-lysosomal fusion, a condition known as autophagic block). The autophagic block was shown by time-lapse microscopy of live muscle fibres (transfected with mCherry-LAMP, a lysosomal marker), which were derived from GFP-LC3-GAA KO. The dysfunctional autophagy contributes significantly to the pathogenesis of the disease and interferes with delivery of the drug to the lysosomes [[24]Spampanato C. Feeney E. Li L. et al.Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease.EMBO Mo" @default.
• W2022106349 created "2016-06-24" @default.
• W2022106349 creator A5030945081 @default.
• W2022106349 creator A5069310256 @default.
• W2022106349 date "2014-06-01" @default.
• W2022106349 modified "2023-10-16" @default.
• W2022106349 title "201st ENMC International Workshop: Autophagy in muscular dystrophies – Translational approach, 1–3 November 2013, Bussum, The Netherlands" @default.
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