β-Amyloid Peptide Expression Is Sufficient for Myotube Death: Implications for Human Inclusion Body Myopathy

Abstract

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 β-amyloid peptide (Aβ) and C′-terminal βAPP epitopes. However, the etiology of myofiber loss and the role of intracellular Aβ in IBM is unknown. Here we report correlative evidence for apoptotic cell death in myofibers of IBM patients that exhibit pronounced Aβ deposition. HSV-1-mediated gene transfer of Aβ42 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 βAPP domain C99 also induced myotube apoptosis, but to a significantly lesser extent than Aβ. Apoptosis specific to Aβ-expressing myotubes was also demonstrated through DNA fragmentation, decreased mitochondrial function and the loss of membrane phospholipid polarity. Myotubes laden with Aβ42, but not other transgene products, developed cytoplasmic inclusions consisting of fibrillar material. Furthermore, injection of normal mouse gastrocnemius muscle with HSV-encoding Aβ cDNA resulted in TUNEL-positive myofibers with pyknotic nuclei. We conclude that Aβ 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.