Impaired innervation of cultured human muscle overexpressing betaAPP experimentally and genetically: relevance to inclusion-body myopathies.

Abstract

To investigate whether abnormally accumulated betaAPP may be responsible for denervation of muscle fibers that are present in hereditary inclusion-body myopathy (h-IBM) and sporadic inclusion-body myositis (s-IBM), we cultured five h-IBM and eight normal muscle biopsies. In eight other experiments, a 3 kb human 751-betaAPP-cDNA was transferred, using adenovirus vector, into cultured normal myotubes immediately after myoblast fusion. In all experiments, cultured muscle fibers were co-cultured with fetal rat spinal cord. Controls had no detectable betaAPP epitopes, whereas betaAPP epitopes were greatly increased in cultured h-IBM muscle and in cultured normal muscle after betaAPP-gene transfer. Innervated normal cultured muscle fibers were continuously contracting and fully cross-striated, and they had acetylcholine receptors (AChRs) and acetylcholinesterase (AChE) accumulated only at the neuromuscular junctions (NMJs). By contrast, both groups of betaAPP-overexpressing cultured muscle fibers were not contracting and not cross-striated; and did not have NJMs containing AChRs and AChE. Our results suggest that over-expression of betaAPP in cultured muscle fibers inhibits their innervation, and that the accumulation of betaAPP in muscle fibers of both h- and s-IBM patients may be responsible for their not becoming or remaining properly innervated or reinnervated, i.e. a 'myogenous-dysinnervation' mechanism.

• Authors: J McFerrin, W K Engel, V Askanas
• Journal: Neuroreport (Neuroreport) Vol. 9 Issue 14 Pg. 3201-5 (Oct 05 1998) ISSN: 0959-4965 [Print] England
• PMID: 9831451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amyloid beta-Peptides
• Epitopes

Topics

• Adult
• Amyloid beta-Peptides (analysis, genetics)
• Animals
• Cells, Cultured
• Epitopes (analysis)
• Fluorescent Antibody Technique
• Gene Expression (physiology)
• Humans
• Inclusion Bodies (chemistry)
• Middle Aged
• Muscle Fibers, Skeletal (chemistry, cytology, physiology)
• Muscle, Skeletal (innervation)
• Myositis (metabolism)
• Neuromuscular Junction (chemistry)
• Neurons (cytology)
• Rats
• Spinal Cord (cytology)