Lack of robust satellite cell activation and muscle regeneration during the progression of Pompe disease
© Schaaf et al. 2015
Received: 3 September 2015
Accepted: 8 October 2015
Published: 28 October 2015
Muscle stem cells termed satellite cells are essential for muscle regeneration. A central question in many neuromuscular disorders is why satellite cells are unable to prevent progressive muscle wasting. We have analyzed muscle fiber pathology and the satellite cell response in Pompe disease, a metabolic myopathy caused by acid alpha-glucosidase deficiency and lysosomal glycogen accumulation. Pathology included muscle fiber vacuolization, loss of cross striation, and immune cell infiltration.
The total number of Pax7-positive satellite cells in muscle biopsies from infantile, childhood onset and adult patients (with different ages and disease severities) were indistinguishable from controls, indicating that the satellite cell pool is not exhausted in Pompe disease. Pax7/Ki67 double stainings showed low levels of satellite cell proliferation similar to controls, while MyoD and Myogenin stainings showed undetectable satellite cell differentiation. Muscle regenerative activity monitored with expression of embryonic Myosin Heavy Chain was weak in the rapidly progressing classic infantile form and undetectable in the more slowly progressive childhood and adult onset disease including in severely affected patients.
These results imply that ongoing muscle wasting in Pompe disease may be explained by insufficient satellite cell activation and muscle regeneration. The preservation of the satellite cell pool may offer a venue for the development of novel treatment strategies directed towards the activation of endogenous satellite cells.
Healthy skeletal muscle has a remarkable capacity to repair both minor and severe damage. Extensive muscle damage, such as caused by exercise or in muscular disease, requires a stem cell-mediated response. The muscle stem cells or muscle satellite cells are located at the myofiber periphery underneath the basal lamina . Satellite cells are normally quiescent, but become rapidly activated after damage and proliferate to generate a large set of progeny that is capable of regenerating damaged myofibers by fusion. Recent elegant studies using mouse models that allow conditional depletion of the muscle stem cell pool showed that satellite cells are indispensible for muscle regeneration [2–5].
Genetic diseases affecting skeletal muscle pose a continuous challenge to the muscle regenerative system. More than 700 neuromuscular disorders are known . While the molecular pathological processes behind the muscle diseases are diverse, in all cases the balance between muscle injury and regeneration is disturbed resulting in progression of muscle wasting. The central question is why the muscle regenerative program is incapable of efficiently repairing disease-induced muscle damage.
One hypothesis to explain this is depletion of the satellite cell pool due to continuous regeneration attempts. This idea has been derived from in vitro characterization of myoblasts from Duchenne Muscular Dystrophy (DMD) patients, which showed reduced proliferative capacity . In agreement, studies using a mouse model for DMD (termed mdx) suggested the existence of a subpopulation of satellite cells that is exhausted in mdx mice . However, electron microscopy and immunofluorescent analysis of skeletal muscle biopsies have shown that the number of satellite cells can be increased rather than exhausted in muscular dystrophies (including DMD, myotonic dystrophy, Limb Girdle Muscular Dystrophy type 2A (LGMD2A)) and inflammatory myopathies (including polymyositis, sporadic inclusion body myositis, and dermatomyositis) [9–13]. Besides increased proliferation, also increased satellite cell differentiation was observed in the above diseases as indicated by increased expression of myogenic lineage (MyoD, Myogenin) and muscle regenerative (embryonic Myosin Heavy Chain (eMyHC)) markers. The chronic satellite cell activation and inflammation may result in Transforming Growth Factor (TGF-β) signaling-mediated fibrosis at the cost of muscle repair .
A different group of neuromuscular disorders are the metabolic myopathies . Recent findings suggest that metabolic changes can affect satellite cell function and skeletal muscle regeneration . Here we have investigated the muscle regenerative response in Pompe disease (OMIM 232300). Pompe disease is caused by acid-alpha glucosidase (GAA) deficiency resulting in lysosomal glycogen accumulation in a variety of tissues, but its effect is most damaging in skeletal muscle (reviewed in ). The clinical spectrum of Pompe disease ranges from severely affected infants (the classic infantile form) to children and adults with a slower progressive form of Pompe disease (the non-classic or late onset form) [17–21]. The muscle pathology in Pompe disease is distinct from that in muscular dystrophies as fibrosis is not a prominent feature and immune responses are considered to be low. The pathological changes in skeletal muscle of Pompe patients are progressive and range from enlarged lysosomes in between myofibrils to completely vacuolized myofibers.
We have analyzed skeletal muscle biopsies from classic infantile patients and from patients with childhood and adult onset Pompe disease and compared the extent of muscle damage, satellite cell activation, immune cell infiltration, and muscle regenerative activity.
Materials and methods
Patients and control biopsies
Muscle biopsies were taken from the Vastus Lateralis using a standard open surgery or needle biopsy procedure as described previously  from Pompe patients, two DMD patients and control subjects. Control subjects were selected for which a progressive neuromuscular disorder was ruled out by medical history and muscle tissue sections showed normal histology on haematoxylin and eosin staining. The Ethical Committee of the Erasmus MC University Medical Center approved the use of the biopsies (MEC 2007–103). Written informed consent was obtained from all patients and control subjects or their legal guardians. All samples were frozen in N2-chilled isopentane and cryosectioned (5–10 μm). Medical Research Council (MRC) sumscores were calculated from the assessment of the strength of 26 muscle groups essentially as described .
Scoring of muscle damage
Scoring of muscle damage based on pathology in muscle fibers
>75 % normal
Little in most and/or all
Little in all and/or significant in some
25–75 % normal
Significant in all and strong in some; significant and/or strong in most
Significant in all and/or many in some
<25 % normal
Very strong in all
Many in all
5–10 μm cryosections of patient and control biopsies were stored until analysis at −80 °C. Sections were thawed before staining. Primary antibodies were directed against CD68, clone KP1 (M0814; DAKO; 1:800), eMyHC (F1.652; DSHB; 1:150), Ki67 (Ab15580; Abcam; 1:50), Laminin (L9393; Sigma; 1:500 or LS-C96142; LS Bio; 1:500), MyoD (SC304; Santa Cruz; 1:200), Myogenin (M-225 ; Santa Cruz; 1:200), Pax7 (DSHB; 1:50), CD3 (2GV6; Ventana; ready to use), CD20Cy; clone L26; Dako, 1:400). Following the primary antibody incubation, sections were rinsed and incubated with biotin-conjugated anti-mouse antibody (BA-2000; Vector labs,1:50) and then with Alexafluor594-conjugated streptavidin (S11227; Life Technologies, 1:500). Sections incubated with rabbit primary antibodies were subsequently incubated with Alexafluor 488-conjugated goat-anti rabbit antibodies (A11307; Life Technologies,1:500). Finally chicken anti-Laminin was detected with Alexafluor647-conjugated goat anti-chicken antibodies (A21449; Life Technologies, 1:500). All sections were counterstained with Hoechst33258 (H3569; Life Technologies, 1:15000). The slides were mounted with Mowiol (475904; Calbiochem). For some biopsies, limited amounts of sections of sufficient quality were available for immunofluorescent analysis, and not all stainings could be performed for all patients.
Image acquisition and analysis
For digital imaging complete histological sections were scanned on a Hamamatsu NanoZoomer 2.0 (Hamamatsu Photonics). Images were analyzed using NDP view software (NDP View 1.2.31 ENG, Hamamatsu Photonics). Sections for immunofluorescence were scanned on a Zeiss LSM700 (Carl Zeiss B. V., Sliedrecht, The Netherlands) using tile-scan modality. Image analysis was performed using Fiji (fiji.sc/Fiji).
All data are expressed as means ± SD. Multiple groups were compared using a one way non-parametric ANOVA. Bonferroni correction was applied as Post-hoc test to adjust for multiple testing. Statistical significance was set at P <0.05. All calculations were performed using Graphpad 5.0 (Graphpad software, USA).
Study design and skeletal muscle pathology
The satellite cell pool remains intact during disease progression
Compromised activation of satellite cells
Satellite cell numbers are neither increased nor exhausted in Pompe disease
We have shown that the numbers of satellite cells in skeletal muscle biopsies from Pompe patients are similar to controls. The number of satellite cells is known to be age-dependent with a ratio of 12 % (satellite cells/myonuclei) at 1–2 years of age, followed by a decline to about 2 % in adults . Pompe patients and controls followed a similar age-dependent pattern. This finding is surprising given the extensive muscle pathology, especially in classic infantile patients. These patients showed strongly disrupted myofiber organization with loss of cross striation, widespread glycogen accumulation, and numerous vacuoles, as described previously [22, 26, 34, 35]. Distinct pathology was seen in muscle biopsies from clinically severely affected adult patients and in some of the childhood onset patients. A priori, a satellite cell response to Pompe disease was anticipated. Based on the level of muscle damage, a possible scenario was exhaustion of the satellite cell population as a result of continuous cycles of regeneration, as has been proposed for DMD patients. Another scenario would be an increase in satellite cell numbers due to satellite cell activation resulting in increased proliferation, as seen in a number of neuromuscular disorders including dystrophies and inflammatory myopathies [9–13]. These possible scenarios are not necessary mutually exclusive and may be dependent on the disease severity and age at which the satellite status is examined. Here, we analyzed the satellite cell response for Pompe patients with various degrees of disease severity and different ages in order to cover these possible scenarios. This showed that during all disease stages including in classic infantile patients and in severely affected adult patients at advanced age (around 70 years), the satellite cell population remained intact, arguing against satellite cell exhaustion in Pompe disease.
Impaired activation of satellite cells in Pompe patients
Both satellite cell proliferation, monitored from the percentage of Ki67-positive satellite cells, and differentiation, indicated by the number of MyoD- and Myogenin-positive cells, were similar to controls for all Pompe patient groups. This indicated a failure of a robust satellite cell response in Pompe disease irrespective of disease severity. A previous report described low levels of satellite cell activation in classic infantile Pompe patients monitored 1 year after enzyme replacement therapy . Two patients that showed a good histological response to enzyme replacement therapy showed the lowest activation levels. It would be interesting to compare the effect of enzyme replacement therapy by comparing baseline and treated samples in future studies.
An important question is whether the failure of satellite cell activation in Pompe disease is caused by the absence of an activating signal or the presence of an inhibitory factor. In muscle injury induced experimentally or by exercise, sarcolemmal damage triggers satellite cell activation by disturbing the niche of the satellite cell in between the sarcolemma and basal lamina. In Pompe disease, no gross disruption of the sarcolemma can be observed even in classic infantile patients, as shown using electron microscopy  and light microscopy (provided glutaraldehyde-based fixation of biopsies). This would argue for reduced presence of a satellite cell-activating signal in Pompe disease. However we cannot rule out more subtle damage to the sarcolemma that has not been detected using these methods.
Subsequent signals involved in both activation and inhibition of muscle regeneration are derived from the immune system. Following injury, a transient immune response triggers satellite cell activation and muscle regeneration. However, chronic immune responses can potently inhibit muscle regeneration and induce TGFβ-signaling-mediated muscle fibrosis as is the case for the muscular dystrophies. An immune response in Pompe patients is a hereto understudied factor considering the paucity of published reports on this aspect. One previous report has also detected inflammatory cells in skeletal muscle of an adult Pompe patient , but the cells have not been further characterized. At the molecular level, microarray analysis of genome wide mRNA expression patterns indicate elevated expression levels of several genes involved in immune regulation in skeletal muscle biopsies from classic infantile patients . In the current study, infiltration of skeletal muscle with CD68-positive cells was observed in severely affected Pompe patients and suggested the presence of macrophages involved in phagocytosis of degenerating muscle fibers. It remains to be determined how these macrophages affect satellite cell activation or inhibition, and to what extent glycogen accumulation in macrophages from Pompe patients [38, 39] plays a role in this process.
Another factor that may contribute to the deregulation of satellite cell activation is impaired autophagy. It has been suggested that hematopoietic stem cells depend on autophagy as energy source for proper activation , and recent results also indicate a similar role for autophagy in satellite cell activation . Interestingly, autophagy in skeletal muscle is impaired in Pompe disease [41, 42], warranting further investigation on its role in modulating satellite cell activation.
A venue for the development of novel treatment strategies
The positive news for Pompe patients is that their satellite cell pool is intact and not exhausted. This may open novel treatment options targeted at enhancement of satellite cell activation and improved muscle regeneration. A prerequisite for successful implementation of such an approach is that the intrinsic properties of satellite cells in Pompe patients are intact. Electron microscopy studies of satellite cells from Pompe patients showed normal morphology . Studies focused on the functional characteristics of satellite cells in muscle of Pompe patients are required to fully address this subject. Several factors have been shown to be capable of enhancing satellite cell activation, including growth factors, small molecules that modulate signaling pathways, immune modulation, and physical exercise. In recent studies we and others have shown that controlled exercise is well tolerated by Pompe patients [43–47].
In conclusion, despite the extensive muscle damage satellite cells do not become robustly activated during Pompe disease progression. In line with this, the regenerative response in skeletal muscle of classic infantile Pompe patients was weak and absent in childhood- and adult-onset Pompe patients. The preservation of the satellite cell pool may offer a venue for the development of novel treatment strategies directed towards the activation of endogenous satellite cells.
The authors wish to acknowledge Dr. Lex Verdijk (Maastricht University Medical Centre, The Netherlands) for advice on satellite cell stainings, Dr. Linda E. M. van den Berg (Erasmus MC, The Netherlands) for advice on experimental design and data analysis, Binha Autar and Riadi Suryadhiningrat for their help with the sections and histological stainings. This study was financially supported by the Prinses Beatrix Spierfonds/Stichting Spieren voor Spieren (project numbers W.OR13-21 and OP07-08).
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