Pharmacological Inhibition of Myostatin in a Mouse Model of Typical Nemaline Myopathy Increases Muscle Size and Force.
Pharmacological Inhibition of Myostatin in a Mouse Model of Typical Nemaline Myopathy Increases Muscle Size and Force.
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在典型的杀伤性肌病的小鼠模型中，肌生抑素的药理抑制会增加肌肉的大小和力。
DOI：
10.3390/ijms242015124
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发表时间：
2023-10-12
影响因子：
5.6
通讯作者：
Granzier, Henk
中科院分区：
文献类型：
--
作者：
Lindqvist, Johan;Granzier, Henk
线状体肌病是最常见的非营养不良性先天性肌病之一。受这种疾病影响的个体存在肌肉无力和肌肉萎缩的情况，往往需要诸如轮椅或呼吸支持等辅助措施。很大一部分患者（约三分之一）存在复合杂合的伴肌动蛋白基因突变，这通常会导致该疾病的典型形式。目前，线状体肌病尚无获批的治疗方法。我们的研究探索了肌抑素（一种肌肉质量的负调节因子）的调节在对抗与该疾病相关的肌肉萎缩方面的作用。为了研究肌抑素抑制的效果，我们使用了一种具有复合杂合伴肌动蛋白基因突变的小鼠模型，该模型模拟了该疾病的典型形式。从2周龄开始，每周通过腹腔注射10mg/kg的mRK35（一种肌抑素抗体）对小鼠进行治疗，一直持续到小鼠4个月龄。治疗导致体重增加，并且大多数骨骼肌的肌肉重量增加了约20%，对心脏没有影响。在复合杂合小鼠中，IIA和IIB型肌纤维的最小费雷特直径有所增加，而在野生型小鼠中只有IIB型肌纤维增加。对完整的趾长伸肌进行的体外力学实验表明，mRK35增加了野生型和复合杂合小鼠的肌纤维生理横截面积，并增强了绝对强直收缩力。此外，mRK35的使用提高了接受治疗小鼠的抓力。总之，这些发现表明抑制肌抑素可以减轻基于伴肌动蛋白的典型线状体肌病中的肌肉缺陷，有可能成为一种急需的治疗选择。
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.
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DOI：
10.1085/jgp.202012783
发表时间：
2021-03-01
期刊：
The Journal of general physiology
影响因子：
--
作者：
Gohlke J;Tonino P;Lindqvist J;Smith JE;Granzier H
通讯作者：
Granzier H
影响因子：
7.1
作者：
通讯作者：
--
影响因子：
15.9
作者：
de Winter，Josine M.;Molenaar，Joery P.;Ottenheijm，Coen A. C.
通讯作者：
Ottenheijm，Coen A. C.
影响因子：
1.5
作者：
BURKHOLDER, TJ;FINGADO, B;LIEBER, RL
通讯作者：
LIEBER, RL
DOI：
10.1097/nen.0b013e318293b1cc
发表时间：
2013-06-01
影响因子：
3.2
作者：
Lindqvist, Johan;Cheng, Arthur J.;Ochala, Julien
通讯作者：
Ochala, Julien