autophagy in lysosomal myopathies

M I N I - S Y M P O S I U M : A u t o p h a g y D y s r e g u l a t i o n i n N e u r o p a t h o l o g y bpa_543 82..88

Autophagy in Lysosomal MyopathiesMay Christine V. Malicdan1,2; Ichizo Nishino1

1 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.2 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

AbstractLysosomal myopathies are hereditary myopathies characterized morphologically by thepresence of autophagic vacuoles. In mammals, autophagy plays an important role for theturnover of cellular components, particularly in response to starvation or glucagons. Innormal muscle, autolysosomes or autophagosomes are typically inconspicuous. In distinctneuromuscular disorders, however, lysosomes become structurally abnormal and function-ally impaired, leading to the accumulation of autophagic vacuoles in myofibers. In someinstances, the accumulation of autophagic vacuoles can be a prominent feature, implicatingautophagy as a contributor to disease pathomechanism and/or progression. At present, thereare two disorders in the muscle that are associated with a primary defect in lysosomalproteins, namely Pompe disease and Danon disease. This review will give a brief discussionon these disorders, highlighting the role of autophagy in disease progression.

Keywords

autophagy, Danon disease, LAMP-2,lysosome, myopathy, Pompe disease.

Corresponding author:

Ichizo Nishino, MD, PhD, 4-1-1Ogawahigashi-cho, Kodaira, Tokyo 187-8502,Japan (E-mail: [email protected])

Received 1 November 2011; accepted 1November 2011.

doi:10.1111/j.1750-3639.2011.00543.x

INTRODUCTIONMacroautophagy is a highly regulated process in the lysosomalpathway for the degradation of long-lived proteins and damaged orunneeded organelles in the cytoplasm, including mitochondria andendoplasmic reticulum (48). Autophagy is, in general, a mecha-nism by which cells respond to starvation, either because ofdecreased extracellular nutrients or intracellular metabolites (52).Macroautophagy provides the cells with additional energy or ATPsources by catabolizing macromolecules and organelles to generatemetabolic substrates, thereby allowing for adaptive protein synthe-sis. Macroautophagy also functions to maintain the overall qualityof the cytoplasm by getting rid of damaged organelles and proteinaggregates, and plays a central role in development, immuneresponse and cell differentiation. Although it has been establishedthat autophagy is induced by various factors, recent studies havedemonstrated that autophagy could also occur spontaneously forrenewal of the molecules and organelles (26).

Dysfunctional autophagy occurs in many primary lysosomal dis-orders (3, 39), as well as in neurodegenerative diseases, cancer andinflammatory diseases. As functional lysosomes are required todegrade cytoplasmic components, defects in lysosome functioncan lead to autophagic stress (5) characterized by accumulation ofautophagic intermediates (23). On the other end of the spectrum,pathogenic induction of autophagy that leads initially to the matu-ration of autophagosomes, but eventually to dysfunction in matura-tion, can occur in myopathies (1, 24).

Macroautophagy occurs both in physiologic conditions and indisease. In skeletal muscles and neuronal tissues, autophagy hasbeen found to be physiologically enhanced (27). Disorders in whichautophagic vacuoles are seen in the skeletal muscles are generallyreferred to as autophagic vacuolar myopathies (AVMs) (21, 24, 32,

33, 42, 51), which include two known primary lysosomal disorders:Pompe disease and Danon disease (30). Despite the observation thatthe generation of autophagic vacuoles can be remarkable in skeletaland/or cardiac muscles, their precise relevance in each disorder andthe mechanism by which they are formed remain to be clarified. Inthis review, we will focus on primary lysosomal protein deficienciesand related myopathies, highlighting the role of autophagy in thepathomechanism of the diseases.

POMPE DISEASE (ACID MALTASEDEFICIENCY)Pompe disease, also known as glycogen storage disease type II, is theprototypic autosomal recessive lysosomal storage disorder (36, 43)caused by a primary deficiency of acid alpha-1,4-glucosidase or acidmaltase. This lysosomal hydrolase, acid a-glucosidase (GAA; EC3.2.1.3), is an exo-1,4- and -1,6-a-glucosidase that specificallyhydrolyzes glycogen to glucose. Deficiency of GAA leads to accu-mulation of lysosomal glycogen in virtually all cells of the body, butthe pathological effects are most notable in cardiac and skeletalmuscles. Abnormal lysosomal glycogen accumulates in the myo-cytes of skeletal, cardiac and smooth muscle, and has been detectedin fetuses as early as 16–18 weeks gestation. Recently the estimatedprevalence is around 1 per 40 000 live births.

Clinical features of Pompe disease

Pompe disease encompasses a broad spectrum of clinical pheno-types, ranging from severe infantile-onset to a seemingly benign,less progressive late-onset form (8, 16). The late-onset form isfurther divided into childhood, juvenile and adult types. The variety

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© 2011 The Authors; Brain Pathology © 2011 International Society of Neuropathology

in clinical features is largely caused by the large variety of muta-tions in the GAA gene. More than 50 mutations have been reportedin the gene encoding GAA, leading to a total or partial deficiencyof lysosomal GAA.

The level of residual enzymatic activity has been correlated withthe location of mutations, age of disease onset and severity ofdisease, although a definite genotype-phenotype correlation cannotbe made. Importantly, among all enzymes responsible for glycogenstorage disease, GAA is the only enzyme that is localized in thelysosomes, whereas all other enzymes are present in the cytosol.Naturally, lysosomal abnormalities are seen only in Pompe diseaseamong the glycogen storage diseases.

In the most severe, infantile form of Pompe, disease may beapparent in utero but usually presents in the neonatal period withmacroglossia, cardiomyopathy, hypotonia and respiratory insuffi-ciency. In untreated infants, death occurs around the first year oflife because of cardiorespiratory failure. In the late-onset disease,skeletal muscle weakness predominates, mostly involving theproximal limb muscles and the diaphragm, but there is usually nocardiac involvement. These patients often show respiratory insuffi-ciency even when they are still ambulant. There are also adultpatients that present with very mild symptoms, often misdiagnosedas limb-girdle muscular dystrophy. Overall, there is an inversecorrelation between disease severity and the level of residual

enzyme activity, with the most severely affected infants having nodetectable enzyme activity. Complete deficiency (activity <1% ofnormal controls) is associated with classic infantile-onset Pompedisease. On the other hand, partial deficiency (activity that is2%–40% of normal controls) is associated with the non-classicinfantile-onset and the late-onset forms (18).

In terms of pathology, intracytoplasmic vacuoles are prominentin the infantile form of acid maltase deficiency more than in theadult form (Figure 1A, first column). Characteristically, thesevacuoles so extremely large that these can occupy most of thespace in many muscle fibers, resulting in a “lace-like” appearance(Figure 1A,B). This peculiar appearance is almost pathognomonicin terms of histological diagnosis. These vacuoles contain amor-phous materials that are presumably glycogen because of the strongreactivity with periodic acid Schiff stain. Acid phosphatase stain-ing also shows strong signals in these vacuoles, indicating highlysosomal content (Figure 1A). The findings on late-onset formsmay be more subtle, mostly consisting of a few acid-phosphataseinclusions (Figure 1A, last column).

Enzyme replacement therapy for Pompe

Enzyme replacement therapy (ERT), using recombinant humanGAA, is now available (2) and has been demonstrated to be effec-

Figure 1. Subtypes of Pompe diseases andfindings in pathology. Hematoxylin and eosinstaining (A) shows vacuolar structures(arrows) in myofibers pathognomonic for thedisease especially in infantile onset form. Inchildhood onset form, several vacuoles arescattered all throughout the sections. Thelate-onset form is characterized by milderchanges, namely scattered inclusion bodiesthat may appear like rimmed vacuoles. Thevacuolar structures are highly stained by acidphosphatase. Electron microscopy (B) showsthat the vacuoles (double arrows) occupy thewhole diameter of the fiber and disruptmyofibrillar structure.

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tive in infantile cases, although some, studies showed that ERT canalso benefit some patients with the late-onset form to some extent.It is generally believed, however, that ERT would be more effectivewhen it is given early in the course of symptom development andbefore irreversible muscular damage has occurred, where increasedcytoplasmic glycogen released from lysosomes is probably inac-cessible to the membrane receptor-dependent targeting mechanism(17).

It is peculiar that the ERT clears lysosomal storage disorder inthe heart but not efficiently in skeletal muscles, in both humans andin the GAA-/- mice, where glycogen accumulation persists evenwhen the enzyme activity reaches normal or near normal levels inmuscle (22, 28, 35). This has been attributed to the autophagicbuild-up in muscle, evidenced by the large pools of autophagicdebris in addition to the enlarged glycogen-filled lysosomes intherapy-resistant fast-twitch (type II) muscle fibers (37, 15). In theGAA -/- mice, in addition, the lack of response is also compli-cated by the fact that a large portion of the therapeutic enzyme isdiverted to the area of autophagic accumulation (13).

Recent studies have clarified why autophagic build-up is moreremarkable in type II muscle fibers (37). The cellular pathology inthis disease affects the pathways involved in both endocytic andautophagic processes. Raben et al have reported the dramaticexpansion of endocytic vesicles, decrease in mobility of lateendocytic vesicles and increase in luminal pH in a subset of lateendosomes/lysosomes in GAA knockout myoblasts. Using isolatedsingle fibers from these mice, they demonstrated that type 2 fiberscontain large regions of autophagic build-up spanning the entirelength of the fibers. In addition, they found out that type 2 fiberswere resistant to ERT, and this phenomenon is probably influencedby the low amount of proteins involved in endocytosis and traffick-ing of lysosomal enzymes, combined with increased autophagy inthese fibers. Furthermore, it was evident on electron microscopythat type 1 fibers contained only occasional double-membraneautophagosomes, whereas in type 2 fibers the autophagic regionscontained vesicles with morphological features representative ofvarious stages of the autophagic process. In addition, the intracel-lular microtubule network is disorganized in the area of thisautophagic build-up (15).

The pathologic mechanism by which glycogen accumulationeventually causes muscle malfunction is not fully understood, buthas been mainly considered secondary to the energy crisis in skel-etal muscles because of failure in digesting lysosomal glycogen toglucose; as a result, muscle cells should be deprived of a necessarysource of energy. But it is now becoming clear that in Pompedisease, failure of the lysosomal degradation of glycogen causesthe extensive accumulation of various kinds of autophagic vacuolesleading to dysfunction of cellular trafficking, continuous autoph-agic build-up, and marked abnormality of cytoskeleton organiza-tion in muscle fibers, which may enhance the autophagic process(14) and perturb muscle contractility.

Upregulation or dowregulation of macroautophagy in an attemptto strike a balance between the need to maintain some level ofautophagy and to inhibit it has been promising in some diseaseslike malignancy (4) and neurodegeneration. In Pompe disease,manipulation of macroautophagy has been shown to be effective inaddressing the inefficacy of ERT in muscles (40). When Atg5, a keygene in the autophagic process, was selectively inactivated in theskeletal muscle of the murine Pompe model, autophagic build-up

was indeed prevented but this exacerbated the clinical phenotype ofthe GAA-/- mice, despite a minimal decrease in muscle glycogen(38). In contrast, suppression of Atg7 specifically in fast skeletalmuscles led to the normalization of glycogen levels (39), indicatingthat suppression of autophagy alone can lead to a therapeuticbenefit in skeletal muscles. When combined with ERT, suppressionof either Atg5 or Atg7 enhanced the correction on muscle glycogenstorage, although there were biochemical and phenotypical differ-ences observed between the two genetic manipulation strategies.It is, however, important to note that suppressing autophagy inthe muscles can theoretically also have unwanted consequences,such as accumulation of dysfunctional mitochondria and oxidativestress (49), emphasizing the need to find that balance when consid-ering manipulating autophagy for treatment.

DANON DISEASE

Clinical features of Danon disease

Danon disease has been referred to as “glycogen storage diseaseIIb” (GSDIIb), but it is not actually a glycogen storage disease, as itis caused by the primary deficiency of a lysosomal membraneprotein, lysosome-associated membrane protein-2 (LAMP-2) (31).Danon disease is inherited as X-linked dominant; thus, males aremore severely affected than females, although females developsymptoms at a later onset (29). Patients with Danon diseasetypically show a triad of findings: hypertrophic cardiomyopathy;muscle weakness; and mental retardation (7). Muscle weaknessand atrophy predominantly affect neck and shoulder-girdlemuscles, but distal muscles can also be involved. Myopathy isusually mild and is evident in most male patients (90%), whereas itis seen only in only one third of female patients. All male patientshave elevated serum creatine kinase (CK) levels, even thosewithout apparent muscle symptoms. In contrast, serum CK iselevated in only 63% of female patients. Mental impairment isvariable, but is usually mild in men whereas it is often not seen inwomen. Other organs like the liver (45, 47) and retina (34, 41) canalso be involved.

LAMP-2 is a single spanned membranous protein with molecu-lar mass of 95–120 kDa. The large luminal-ectodomain is highlyglycosylated with some O-glycans and a large number ofN-glycans, constituting about 60% of the total mass of these pro-teins and divided into two homologous domains by a hinge region(11). The transmembrane region is followed by a short C-terminalcytoplasmic tail. This cytoplasmic region has a well-conservedtyrosine residue, which is thought to provide a crucial signal fortrafficking of LAMP-2 molecules to lysosomes. LAMP-2 has threeisoforms, LAMP-2a, LAMP-2b and LAMP-2c. LAMP-2a func-tions as a receptor for chaperone mediated autophagy by selec-tively targeting substrates that contain a sequence motif related tothe pentapeptide KFERQ for degradation in the lysosome (9, 25).LAMP-2b and LAMP-2c result from alternative splicing of exon 9.

LAMP-2 is mainly localized in the limiting membranes of lyso-somes and late endosomes and is also found in small amounts inearly endosomal membranes and the plasma membrane. LAMP-2is also spans the limiting membrane of late autophagic vacuoles.LAMP-2 is also detected in the lysosomal/endosomal lumen. It hasbeen suggested that the luminal LAMP molecules are soluble, but

Lysosomal Myopathies Malicdan & Nishino



it is also possible that these are associated with the internalmembranes of lysosomes or endosomes (11).

LAMP-2 is required for the maturation of early autophagicvacuoles by fusion with endosomes and lysosomes. Deficiency ofLAMP-2 leads to a failure in the normal progression of autophagicmaturation, as the LAMP-2-deficient hepatocytes exhibit accumu-lation of early autophagic vacuoles, intracellular mistargeting oflysosomal enzymes and LAMP-1, improper cathepsin D process-ing, abnormal retention of mannose-6-phosphate receptors inautophagic vacuoles, reduction of degradation of long-lived pro-teins, and resistance to induction of autophagic protein degradationafter starvation (47). Although deficiency in LAMP-2a-mediatedchaperone mediated autophagy induces macroautophagy, the halflife of autophagic vacuoles in complete LAMP-2-deficient hepato-cytes was prolonged, suggesting that retarded consumption was thecause of their accumulation (10).

Skeletal muscles from the patients with Danon disease showscattered small basophilic granules in myofibers, in addition tomild to moderate variation in fiber size without necrotic or regen-erative changes (46) (Figure 2A). Lysosomal acid phosphataseactivity is enriched in these granules (Figure 2B), showing accu-mulation of lysosomal organelles in myofibers. Autophagy-relatedproteins were also accumulated together with lysosomal proteins.Sarcolemmal proteins, like dystrophin and its associated proteins,extracellular matrix proteins and acetylcholine esterase, arerecruited into large vacuolar structures surrounding those lysoso-mal granules. These structures are known as autophagic vacuoleswith sarcolemmal features (AVSF) (Figure 3). On electron micros-copy (Figure 2C), these larger AVSF vacuoles are lined with a layerof basal lamina and contain small autophagic vacuoles, multilamel-lar bodies, and electron-dense materials inside. Furthermore, vacu-olar membranes with sarcolemmal features formed a closed spaceon serial sections (46). Therefore, the AVSF must be independentfrom the sarcolemma and the inner portion of AVSF should betopologically equivalent to the extracellular space. The mechanismby which this membrane is generated remains to be clarified; sar-colemmal membrane indentation is unlikely, and de novo genera-tion is most probable, especially in cases where mistransport ofsarcolemmal proteins to intracellular vacuoles occurs. Anotherfeature of this AVSF is an increase in its frequency with aging, andthis is correlated with the progression of muscle weakness (46).Thus, AVSF may be a hallmark for progression of disease, at leastin the skeletal muscle of Danon disease patients.

A significant number of patients with hypertrophic cardiomy-opathy are associated with LAMP-2 mutation, emphasizing theimportance of screening for mutations in this gene among patientswith non-established etiology of cardiomyopathy (32). All Danondisease patients present with severe cardiac symptoms, whichinclude cardiomyopathy with or without dysrhythmia, and some-times patients succumb to cardiac failure. On histological observa-tion, cardiomyocytes show severe vacuolation and degeneration,including myofibrillar disruption and lipofuscin accumulation.

The association of myopathy and LAMP-2 deficiency has notbeen fully elucidated. The affectation of skeletal muscle issomehow deduced from findings in the analysis of the heart inLAMP-2-deficient mice (44), where cardiomyopathy was seen. Invitro force measurement of isolated cardiac trabeculae in LAMP-2-deficient mice showed significantly lower twitch forces to halfof those in wild type. Neuropathologic changes include variation

in fiber size and fibrosis, progressing as the mice age, in additionto the presence of increased lysosomal granules in most fibers.Large clusters of small autophagic vacuoles are seen in theyounger age, whereas large autophagic vacuoles are observed inolder mice.

Further attempts to analyze the whole function of LAMPs weredone by using LAMP-1 and LAMP-2 double-deficient cells fromdouble gene knocked out embryos (12). The double-deficient cellsand, to a lesser extent, LAMP-2 single-deficient cells, showed an

Figure 2. Pathology changes in Danon disease. Hematoxylin and eosin(A) staining shows moderate variation in fiber size with small basophilicgranules within the scattered myofibers (arrows). These granules arehighlighted with acid phosphatase (B). In electron microscopy, theautophagic vacuoles with sarcolemmal features (AVSF) appear to belined with a layer of basal lamina (red arrows) and contain small autoph-agic vacuoles, multilamellar bodies and electron dense material (C).




Figure 3. Histochemistry and immunohistochemistry. Transverse sec-tions of skeletal muscle biopsies from Danon disease patients. Severalfibers contain scattered tiny basophilic intracytoplasmic vacuoles (A):H&E. The vacuolar membrane has high nonspecific esterase (B)

and acetylcholinesterase (C) activities. None of the vacuoles bind toa-bungarotoxin (D). Sections were stained with antibody againstthe C-terminus of dystrophin (E), the rod domain of dystrophin (F),the N-terminus of dystrophin (G), laminin a2 (H), a-sarcoglycan (I),b-sarcoglycan (J), g-sarcoglycan (K), d-sarcoglycan (L), dystrobrevin (M),a-dystroglycan (N), utrophin (O), dysferlin (P), b-dystroglycan (Q), perle-can (R), caveolin-E (S), collagen IV (T), fibronectin (U), collagen VI (V),integrin b1 (W), and agrin (X). The vacuolar membranes were immuno-

positive with most of the primary antibodies, although reactivity of theseproteins was variable. The results are summarized in Table 1. Transverse5-mm serial sections (Y1–Y5) and longitudinal section (Z) of muscle fromDanon disease patient showing immunoreaction for dystrophin. Vacu-olar membrane in muscle fiber (*) is not connected to the sarcolemmabut is closed. Longitudinal section shows that the vacuoles are sphericalor oval. (D–W, Y1–Y5, Z): FIT C-labeled staining; (X): DAB staining, (C–S,

U, V, Y1–Y5): serial sections. Scale bars: (A–W, Y1–Y5) = 20 mm; (Z) =30 mm. Reproduced with permission from Kazuma S et al (2005) Autoph-agic vacuoles with sarcolemmal features delineate Danon disease andrelated myopathies. 64: 513–522.




accumulation of unesterified cholesterol in endo/lysosomal com-partments as well as reduced amounts of lipid droplets. The choles-terol accumulation in LAMP-1 and LAMP-2 double-deficient cellscould be rescued by overexpression of murine LAMP-2a, but notby LAMP-1 (20), implying the role of chaperone-mediated autoph-agy. In LAMP-1 and LAMP-2 double-deficient cells, the recruit-ment of RAB7 to phagosomes (19) is delayed, indicating that theprogression of autophagic process does not occur smoothly. RAB7has been localized to late endosomes and shown to be important inthe late endocytic pathway.

Considering all these results, the pathomechanism in Danondisease may not be entirely caused by the failure of lysosomaldegradation systems. Rather, the structures created during theautophagic process or the autophagic vacuole formation mayplay a more active contribution to the cardiac dysfunction andmuscle pathology. Similarly, macroautophagy induced in responseto defects in chaperone mediated autophagy or mitochondrial toxic-ity appear to play detrimental roles in neurons (6, 50). This notioncan be supported by the fact that there are more autophagic vacuolesin the cardiac muscles compared with skeletal myofibers inthe LAMP-2-deficient mice, whose cardiac symptoms are moresevere than the muscle weakness. Moreover, not only the numerousnumbers of autophagic vacuoles but also the surroundingAVSF thatoccupy the center of myofibers may disturb the function of muscles,and could lead to the ultimate destruction of myofibrillar structures.

CONCLUSIONIt is now becoming clear that neither the onset of symptoms nor theprogression of disease in lysosomal autophagic myopathies resultdirectly from the primary lysosomal enzymatic defect. Pompedisease can no longer be viewed simply as a glycogen storagedisease. Increasing evidence now highlights that the functionalpathology in Pompe disease is not entirely attributed to the accu-mulation of glycogen in lysosomes, but instead result from themassive accumulation of autophagic vacuoles, which has a pro-found effect on the myofibrillar organization. These unwanted andundigested intracellular debris, as a downstream phenomenon tolysosomal dysfunction, can affect endocytic trafficking and preventproper delivery of enzyme for therapy. In Danon disease, lysosomaldysfunction does not provide an adequate explanation for develop-ment of muscle weakness. Rather, the increase in autophagic vacu-oles within the myofibers disrupt myofibrillar structures, ultimatelyleading to myofiber breakdown and loss of function.

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