Impaired innervation of cultured human muscle overexpressing betaAPP experimentally and genetically: relevance to inclusion-body myopathies.
Impaired innervation of cultured human muscle overexpressing betaAPP experimentally and genetically: relevance to inclusion-body myopathies.
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实验和遗传上过度表达 betaAPP 的培养人类肌肉的神经支配受损：与包涵体肌病的相关性。
DOI：
10.1097/00001756-199810050-00013
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发表时间：
1998
期刊：
影响因子：
1.7
通讯作者：
Askanas,V
中科院分区：
文献类型：
--
作者：
McFerrin,J;Engel,WK;Askanas,V
为了探讨遗传性包涵体肌病(h-IBM)和散发性包涵体肌炎(S-IBM)中异常积聚的βAPP是否可能导致肌纤维的失神经，我们培养了5例h-IBM和8例正常肌肉组织。在其他8个实验中，在成肌细胞融合后，立即用腺病毒载体将3kb的人751-βAPP-cDNA腺病毒载体转移到培养的正常肌管中。在所有实验中，培养的肌纤维与胎鼠脊髓共培养。对照组未检测到βAPP表位，而转导βAPP基因后，培养的h-IBM肌和培养的正常肌肉中βAPP表位显著增加。神经支配的正常培养肌纤维连续收缩，完全横纹，乙酰胆碱受体(AChRs)和乙酰胆碱酯酶(AChE)仅聚集在神经肌肉接头(NMJ)。相比之下，两组过表达βAPP的培养肌纤维都没有收缩和交叉；也没有含有AChRs和AChE的NJMS。我们的结果表明，βAPP在培养的肌肉纤维中的过度表达抑制了它们的神经支配，而βAPP在h-和S-IBM患者的肌肉纤维中的积聚可能是导致他们没有成为或保持适当的神经支配或再神经支配的原因，即“肌源性神经紊乱”机制。
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, ie a ‘myogenous-dysinnervation’mechanism.