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TO investigate whether abnormally accumulated βAPP 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-βAPP-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 βAPP epitopes, whereas βAPP epitopes were greatly increased in cultured h-IBM muscle and in cultured normal muscle after βAPP-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 neuro-muscular junctions (NMJs). By contrast, both groups of βAPP-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 βAPP in cultured muscle fibers inhibits their innervation, and that the accumulation of βAPP 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.