Inducible depletion of adult skeletal muscle stem cells impairs the regeneration of neuromuscular junctions.
Inducible depletion of adult skeletal muscle stem cells impairs the regeneration of neuromuscular junctions.
复制标题
DOI：
10.7554/elife.09221
复制
发表时间：
2015-08-27
期刊：
影响因子：
7.7
通讯作者：
Chakkalakal JV
中科院分区：
文献类型：
--
作者：
Liu W;Wei-LaPierre L;Klose A;Dirksen RT;Chakkalakal JV
骨骼肌的维持依赖于神经肌肉接头（NMJ）的运动神经支配。多种机制有助于NMJ的修复和维持;然而，肌肉干细胞（卫星细胞，SC）被认为对这些过程几乎没有影响。因此，SC研究在减轻神经肌肉疾病和衰老中观察到的NMJ恶化引起的肌肉损失方面的适用性尚不明确。我们采用具有诱导型Cre的小鼠，并条件性表达DTA以耗尽或GFP以追踪SC。我们发现SC耗竭加剧了与神经肌肉破坏有关的肌肉萎缩和类型转换。此外，升高的纤维化和力产生的进一步下降是特定于SC消耗和神经肌肉破坏。命运分析显示SC活性附近再生NMJ。此外，SC耗竭加重再生NMJ的神经再支配和突触后形态缺陷。因此，我们的研究结果提出了一种机制，即进一步NMJ和骨骼肌下降后，SC耗尽和神经肌肉中断enadministration。新的肌肉纤维在我们的一生中不断产生，以取代那些因正常磨损而受损的肌肉纤维，并满足新的身体需求。这些新的肌肉纤维从肌肉干细胞库中发育而来。为了创造和维持完全工作的肌肉，称为运动神经元的神经细胞也必须正确地附着在肌肉纤维上。这些神经细胞传递来自大脑的信息，告诉肌肉该做什么。如果肌肉-神经连接没有正确形成，或者被切断，肌肉就会萎缩。这可能是神经肌肉疾病的一部分，也可能在某种程度上是衰老的正常部分。人们认为肌肉干细胞不会影响肌肉神经连接的形成。通过研究基因工程小鼠，刘等人现在表明情况并非如此。这些小鼠对它们的肌肉干细胞进行了修改，允许这些细胞的数量被人为地减少，并且一些细胞还产生了一种荧光蛋白，使它们能够被跟踪。通过手术切断小鼠的一些肌肉-神经连接引发了连接的重建，但也削弱了肌肉，并导致肌肉组织中一些与疾病相关的变化。在愈合过程中，肌肉干细胞在再生连接附近活跃。在这些断裂的连接愈合的同时减少小鼠肌肉干细胞的数量进一步削弱了肌肉。对肌肉-神经连接的更仔细的检查也显示了干细胞缺陷小鼠中形成的质量较差的连接。进一步研究干细胞如何帮助形成强大的神经-肌肉连接，可能会使科学家们开发出治疗与年龄或疾病相关的肌肉损失的新方法。DOI：www.example.com网站
Skeletal muscle maintenance depends on motor innervation at neuromuscular junctions (NMJs). Multiple mechanisms contribute to NMJ repair and maintenance; however muscle stem cells (satellite cells, SCs), are deemed to have little impact on these processes. Therefore, the applicability of SC studies to attenuate muscle loss due to NMJ deterioration as observed in neuromuscular diseases and aging is ambiguous. We employed mice with an inducible Cre, and conditionally expressed DTA to deplete or GFP to track SCs. We found SC depletion exacerbated muscle atrophy and type transitions connected to neuromuscular disruption. Also, elevated fibrosis and further declines in force generation were specific to SC depletion and neuromuscular disruption. Fate analysis revealed SC activity near regenerating NMJs. Moreover, SC depletion aggravated deficits in reinnervation and post-synaptic morphology at regenerating NMJs. Therefore, our results propose a mechanism whereby further NMJ and skeletal muscle decline ensues upon SC depletion and neuromuscular disruption. DOI: http://dx.doi.org/10.7554/eLife.09221.001 New muscle fibers are made throughout our lives to replace those that have been damaged by normal wear and tear, and to meet new physical demands. These new muscle fibers develop from a pool of muscle stem cells. To create and maintain fully working muscles, nerve cells called motor neurons must also properly attach to the muscle fibers. These nerve cells transmit messages from the brain that tell the muscles what to do. If the muscle-nerve connections do not form correctly, or are severed, muscles can waste away. This may occur as part of a neuromuscular disease, and also happens to some extent as a normal part of aging. It was thought that muscle stem cells do not affect how the muscle-nerve connections form. By studying genetically engineered mice, Liu et al. now show that this is not the case. These mice had modifications to their muscle stem cells that allowed the number of these cells to be artificially reduced, and some cells also produced a fluorescent protein that allowed them to be tracked. Surgically severing some of the muscle-nerve connections in the mice triggered the rebuilding of the connections, but also weakened the muscles and caused some disease-related changes in the muscle tissue. During the healing process, the muscle stem cells are active near the regenerating connections. Reducing the number of muscle stem cells in the mice while these broken connections were healing further weakened the muscles. Closer inspection of the muscle-nerve connections also revealed poorer quality connections were formed in the stem-cell deficient mice. Further study of how stem cells help to form strong nerve-muscle connections may allow scientists to develop new treatments for age- or disease-related muscle loss. DOI: http://dx.doi.org/10.7554/eLife.09221.002