Center for Cell-Matrix Research, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014 Oulu, Finland.
A.I. Virtanen Institute, University of Eastern Finland, 70211 Kuopio, Finland.
J Neurosci. 2018 Apr 25;38(17):4243-4258. doi: 10.1523/JNEUROSCI.3119-17.2018. Epub 2018 Apr 6.
Collagen XIII occurs as both a transmembrane-bound and a shed extracellular protein and is able to regulate the formation and function of neuromuscular synapses. Its absence results in myasthenia: presynaptic and postsynaptic defects at the neuromuscular junction (NMJ), leading to destabilization of the motor nerves, muscle regeneration and atrophy. Mutations in have recently been found to cause congenital myasthenic syndrome, characterized by fatigue and chronic muscle weakness, which may be lethal. We show here that muscle defects in collagen XIII-deficient mice stabilize in adulthood, so that the disease is not progressive until very late. Sciatic nerve crush was performed to examine how the lack of collagen XIII or forced expression of its transmembrane form affects the neuromuscular synapse regeneration and functional recovery following injury. We show that collagen XIII-deficient male mice are unable to achieve complete NMJ regeneration and functional recovery. This is mainly attributable to presynaptic defects that already existed in the absence of collagen XIII before injury. Shedding of the ectodomain is not required, as the transmembrane form of collagen XIII alone fully rescues the phenotype. Thus, collagen XIII could serve as a therapeutic agent in cases of injury-induced PNS regeneration and functional recovery. We conclude that intrinsic alterations at the NMJ in mice contribute to impaired and incomplete NMJ regeneration and functional recovery after peripheral nerve injury. However, such alterations do not progress once they have stabilized in early adulthood, emphasizing the role of collagen XIII in NMJ maturation. Collagen XIII is required for gaining and maintaining the normal size, complexity, and functional capacity of neuromuscular synapses. Loss-of-function mutations in cause congenital myasthenic syndrome 19, characterized by postnatally progressive muscle fatigue, which compromises patients' functional capacity. We show here in collagen XIII-deficient mice that the disease stabilizes in adulthood once the NMJs have matured. This study also describes a relevant contribution of the altered NMJ morphology and function to neuromuscular synapses, and PNS regeneration and functional recovery in collagen XIII-deficient mice after peripheral nerve injury. Correlating the animal model data on collagen XIII-associated congenital myasthenic syndrome, it can be speculated that neuromuscular connections in congenital myasthenic syndrome patients are not able to fully regenerate and restore normal functionality if exposed to peripheral nerve injury.
胶原 XIII 既可以作为跨膜结合蛋白，也可以作为脱落的细胞外蛋白，能够调节神经肌肉突触的形成和功能。其缺失会导致重症肌无力：神经肌肉连接处（NMJ）的突触前和突触后缺陷，导致运动神经不稳定、肌肉再生和萎缩。最近发现， 中的突变会导致先天性肌无力综合征，其特征是疲劳和慢性肌肉无力，这可能是致命的。我们在这里表明，胶原 XIII 缺乏的小鼠的肌肉缺陷在成年后稳定下来，因此疾病直到很晚才会进展。坐骨神经挤压用于检查胶原 XIII 缺乏或其跨膜形式的强制表达如何影响神经肌肉突触的再生和损伤后的功能恢复。我们表明，胶原 XIII 缺乏的雄性小鼠无法实现完全的 NMJ 再生和功能恢复。这主要归因于在受伤前胶原 XIII 缺失时已经存在的突触前缺陷。细胞外结构域的脱落不是必需的，因为胶原 XIII 的跨膜形式可以完全挽救表型。因此，胶原 XIII 可以作为治疗剂用于损伤诱导的周围神经再生和功能恢复。我们得出结论， 小鼠 NMJ 中的内在改变导致周围神经损伤后 NMJ 再生和功能恢复受损和不完全。然而，一旦在成年早期稳定下来，这些改变就不会进展，这强调了胶原 XIII 在 NMJ 成熟中的作用。胶原 XIII 是获得和维持神经肌肉突触正常大小、复杂性和功能能力所必需的。 中的功能丧失突变导致先天性肌无力综合征 19，其特征是出生后进行性肌肉疲劳，这会损害患者的功能能力。我们在这里表明，在胶原 XIII 缺乏的小鼠中，一旦 NMJ 成熟，疾病就会稳定下来。这项研究还描述了 NMJ 形态和功能改变对胶原 XIII 缺乏的小鼠周围神经损伤后神经肌肉突触和周围神经再生和功能恢复的相关贡献。将胶原 XIII 相关先天性肌无力综合征的动物模型数据进行关联，可以推测，如果先天性肌无力综合征患者的神经肌肉连接暴露于周围神经损伤，它们将无法完全再生并恢复正常功能。
