Impaired innervation of cultured human muscle overexpressing βAPP experimentally and genetically

Publisher Website
Google Scholar
Abstract
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.