Beta-amyloid peptide expression is sufficient for myotube death: implications for human inclusion body myopathy.
Inclusion body myositis (sIBM) is the most common disorder of skeletal muscle in aged humans. It shares biochemical features with Alzheimer's disease, including congophilic deposits, which are immunoreactive for beta-amyloid peptide (Abeta) and C'-terminal betaAPP epitopes. However, the etiology of myofiber loss and the role of intracellular Abeta in IBM is unknown. Here we report correlative evidence for apoptotic cell death in myofibers of IBM patients that exhibit pronounced Abeta deposition. HSV-1-mediated gene transfer of Abeta(42) into cultured C2C12 myotubes resulted in a 12.6-fold increase in dUTP-labeled and condensed nuclei over nonexpressing myotubes (P < 0.05). The C'-terminal betaAPP domain C99 also induced myotube apoptosis, but to a significantly lesser extent than Abeta. Apoptosis specific to Abeta-expressing myotubes was also demonstrated through DNA fragmentation, decreased mitochondrial function and the loss of membrane phospholipid polarity. Myotubes laden with Abeta(42), but not other transgene products, developed cytoplasmic inclusions consisting of fibrillar material. Furthermore, injection of normal mouse gastrocnemius muscle with HSV-encoding Abeta cDNA resulted in TUNEL-positive myofibers with pyknotic nuclei. We conclude that Abeta is sufficient to induce apoptosis in myofibers both in vivo and in vitro and suggest it may contribute to myofiber loss and muscle dysfunction in patients with IBM.
Querfurth
H W
HW
Division of Neurology, St. Elizabeth's Medical Center, Boston, MA 02135, USA. hquerfur@opal.tufts.edu
Suhara
T
T
Rosen
K M
KM
McPhie
D L
DL
Fujio
Y
Y
Tejada
G
G
Neve
R L
RL
Adelman
L S
LS
Walsh
K
K
D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D053938:DNA Fragmentation / Q000235:genetics; D018076:DNA, Complementary / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008854:Microscopy, Electron; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018979:Myositis, Inclusion Body / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D018139:Simplexvirus / Q000235:genetics
D016229:Amyloid beta-Peptides; D018076:DNA, Complementary; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)