Division of Orthopaedic Surgery, and.
Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
JCI Insight. 2019 Dec 5;4(23):128454. doi: 10.1172/jci.insight.128454.
Muscle contractures are a prominent and disabling feature of many neuromuscular disorders, including the 2 most common forms of childhood neurologic dysfunction: neonatal brachial plexus injury (NBPI) and cerebral palsy. There are currently no treatment strategies to directly alter the contracture pathology, as the pathogenesis of these contractures is unknown. We previously showed in a mouse model of NBPI that contractures result from impaired longitudinal muscle growth. Current presumed explanations for growth impairment in contractures focus on the dysregulation of muscle stem cells, which differentiate and fuse to existing myofibers during growth, as this process has classically been thought to control muscle growth during the neonatal period. Here, we demonstrate in a mouse model of NBPI that denervation does not prevent myonuclear accretion and that reduction in myonuclear number has no effect on functional muscle length or contracture development, providing definitive evidence that altered myonuclear accretion is not a driver of neuromuscular contractures. In contrast, we observed elevated levels of protein degradation in NBPI muscle, and we demonstrate that contractures can be pharmacologically prevented with the proteasome inhibitor bortezomib. These studies provide what we believe is the first strategy to prevent neuromuscular contractures by correcting the underlying deficit in longitudinal muscle growth.
肌肉挛缩是许多神经肌肉疾病的一个突出且致残的特征，包括两种最常见的儿童神经功能障碍：新生儿臂丛神经损伤（NBPI）和脑瘫。目前尚无直接改变挛缩病理的治疗策略，因为这些挛缩的发病机制尚不清楚。我们之前在 NBPI 的小鼠模型中表明，挛缩是由于纵向肌肉生长受损所致。目前对于挛缩中生长受损的推测解释主要集中在肌肉干细胞的失调上，在生长过程中，这些干细胞会分化并融合到现有的肌纤维中，因为这一过程通常被认为可以控制新生儿期的肌肉生长。在这里，我们在 NBPI 的小鼠模型中证明，去神经支配并不能防止核内体的积累，而且核内体数量的减少对功能性肌肉长度或挛缩的发展没有影响，这提供了明确的证据表明，改变核内体的积累并不是神经肌肉挛缩的驱动因素。相比之下，我们观察到 NBPI 肌肉中的蛋白降解水平升高，并证明使用蛋白酶体抑制剂硼替佐米可以预防挛缩。这些研究提供了我们认为的第一个通过纠正纵向肌肉生长的潜在缺陷来预防神经肌肉挛缩的策略。
