Lack of robust satellite cell activation and muscle regeneration during the progression of Pompe disease.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Molecular Stem Cell Biology, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands. g.schaaf@erasmusmc.nl.|Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, The Netherlands. g.schaaf@erasmusmc.nl.|Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands. g.schaaf@erasmusmc.nl.
Gerben J
GJ
Schaaf
Molecular Stem Cell Biology, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.|Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.|Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Tom J M
TJ
van Gestel
Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands.|Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Esther
E
Brusse
Department of Pathology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Robert M
RM
Verdijk
Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands.|Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Irenaeus F M
IF
de Coo
Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands.|Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Pieter A
PA
van Doorn
Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.|Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Ans T
AT
van der Ploeg
Molecular Stem Cell Biology, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands. w.pijnappel@erasmusmc.nl.|Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, The Netherlands. w.pijnappel@erasmusmc.nl.|Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands. w.pijnappel@erasmusmc.nl.
W W M Pim
WW
Pijnappel
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D015703:Antigens, CD / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006009:Glycogen Storage Disease Type II / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D007223:Infant; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology / Q000502:physiology*; D051763:PAX7 Transcription Factor / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology*; D055815:Young Adult
D015703:Antigens, CD; D019394:Ki-67 Antigen; D009124:Muscle Proteins; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human