Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA.
Int J Mol Sci. 2023 Oct 12;24(20):15124. doi: 10.3390/ijms242015124.
Nemaline myopathy is one of the most common non-dystrophic congenital myopathies. Individuals affected by this condition experience muscle weakness and muscle smallness, often requiring supportive measures like wheelchairs or respiratory support. A significant proportion of patients, approximately one-third, exhibit compound heterozygous nebulin mutations, which usually give rise to the typical form of the disease. Currently, there are no approved treatments available for nemaline myopathy. Our research explored the modulation of myostatin, a negative regulator of muscle mass, in combating the muscle smallness associated with the disease. To investigate the effect of myostatin inhibition, we employed a mouse model with compound heterozygous nebulin mutations that mimic the typical form of the disease. The mice were treated with mRK35, a myostatin antibody, through weekly intraperitoneal injections of 10 mg/kg mRK35, commencing at two weeks of age and continuing until the mice reached four months of age. The treatment resulted in an increase in body weight and an approximate 20% muscle weight gain across most skeletal muscles, without affecting the heart. The minimum Feret diameter of type IIA and IIB fibers exhibited an increase in compound heterozygous mice, while only type IIB fibers demonstrated an increase in wild-type mice. In vitro mechanical experiments conducted on intact extensor digitorum longus muscle revealed that mRK35 augmented the physiological cross-sectional area of muscle fibers and enhanced absolute tetanic force in both wild-type and compound heterozygous mice. Furthermore, mRK35 administration improved grip strength in treated mice. Collectively, these findings indicate that inhibiting myostatin can mitigate the muscle deficits in nebulin-based typical nemaline myopathy, potentially serving as a much-needed therapeutic option.
先天性肌无力是最常见的非营养不良性先天性肌病之一。患有这种疾病的个体表现为肌肉无力和肌肉萎缩，通常需要轮椅或呼吸支持等支持措施。大约三分之一的患者表现出复合杂合性 nebulin 突变，这通常会导致典型疾病形式。目前，尚无批准用于 nemaline 肌病的治疗方法。我们的研究探讨了肌生成抑制素（一种肌肉质量的负调节剂）的调节作用，以对抗与疾病相关的肌肉萎缩。为了研究肌生成抑制素抑制的效果，我们使用了一种具有复合杂合性 nebulin 突变的小鼠模型，该模型模拟了典型疾病形式。通过每周腹腔内注射 10mg/kg 的 mRK35 对小鼠进行治疗，从两周龄开始，持续到小鼠四个月大。治疗导致体重增加，大多数骨骼肌的肌肉重量增加约 20%，而不影响心脏。复合杂合子小鼠的 IIA 和 IIB 型纤维的最小 Feret 直径增加，而野生型小鼠仅 IIB 型纤维增加。对完整的趾长伸肌进行的体外机械实验表明，mRK35 增加了肌肉纤维的生理横截面积，并增强了野生型和复合杂合型小鼠的绝对强直力。此外，mRK35 给药改善了治疗小鼠的握力。总之，这些发现表明抑制肌生成抑制素可以减轻 nebulin 为基础的典型先天性肌无力中的肌肉缺陷，可能成为一种急需的治疗选择。
