Impaired innervation of cultured human muscle overexpressing betaAPP experimentally and genetically: relevance to inclusion-body myopathies.
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.
McFerrin
J
J
USC Neuromuscular Center, Department of Neurology, University of Southern California School of Medicine, Good Samaritan Hospital, Los Angeles 90017-1912, USA.
Engel
W K
WK
Askanas
V
V
D000328:Adult; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D000939:Epitopes / Q000032:analysis; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry*; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000166:cytology* / Q000502:physiology; D018482:Muscle, Skeletal / Q000294:innervation*; D009220:Myositis / Q000378:metabolism; D009469:Neuromuscular Junction / Q000737:chemistry; D009474:Neurons / Q000166:cytology; D051381:Rats; D013116:Spinal Cord / Q000166:cytology
D016229:Amyloid beta-Peptides; D000939:Epitopes