Investigating the role of the primary cilium in muscle regeneration

研究初级纤毛在肌肉再生中的作用

• 批准号: MR/R000549/1
• 负责人: Andrea Munsterberg
• 金额: $ 72.86万
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR000549%2F1
• 关键词: Investigating; role; primary; cilium; muscle

Skeletal muscle is an important tissue, not only for athletes or young people, but for everyone during their everyday life. As we get older our muscle mass and strength tends to diminish and to support continued physical health and a good quality of life it is important to keep muscle healthy. This tissue has an amazing ability to repair itself after injury and muscle can rebuild itself, for example after long-term immobilization by doing exercise. This regenerative capacity depends on a population of stem cells that is present in muscle. These stem cells are called satellite cells (SC) and they reside in a specialised location, called a 'niche', within the muscle.The SC are normally quiescent (inactive), but in response to signals from the body they become activated and begin to multiply. The descendents of SCs will differentiate into more muscle, but also re-enter the niche in order to maintain the pool of stem cells throughout life. After SCs are activated they migrate along muscle fibres towards sites of injury, which they then repair. As we get older we lose some of our SCs and the remaining ones become less efficient at generating more muscle. So it is important to understand how to keep these cells healthy. We have found that SCs have a cellular protrusion called a primary cilium, which acts as an 'antenna' for important signals. One such signal is the Sonic hedgehog protein (Shh), which we know needs a primary cilium to be sensed by the cells. We have created a unique line of mice, engineered to carry mutant SCs, which lack a primary cilium. We showed that this leads to much less efficient muscle regeneration, with thinner muscle fibres, after injury. Our finding suggests that activating the Shh pathway may have potential therapeutic benefits for muscle diseases, or help sustain muscle function in the elderly.First we need to investigate in more detail how the primary cilium and Shh affect SC function - and this is what this project is about. We will examine the ability of the mutant SCs to become activated, to divide, to migrate, to differentiate, to re-enter their niche. It is also possible that SCs die if they don't have a cilium and we will test if muscle repair can be improved by injecting a drug that activates the Sonic hedgehog signalling pathway. All the methods we need to do these experiments are established in our laboratories. In addition to the detailed characterization of the repair mechanism we will examine the molecular changes that happen in SCs that do not have a primary cilium, specifically we will ask which genes are expressed differently as a result. This will give additional important insights and may reveal potential novel therapeutic targets in muscle disease, or help to maintain a healthy tissue in elderly and frail people.

骨骼肌是一种重要的组织，不仅对于运动员或年轻人来说，而且对于日常生活中的每个人来说都是如此。随着年龄的增长，我们的肌肉质量和力量往往会减少，为了支持持续的身体健康和良好的生活质量，保持肌肉健康非常重要。这种组织在受伤后具有惊人的自我修复能力，肌肉可以自我重建，例如在通过运动长期固定后。这种再生能力取决于肌肉中存在的干细胞群。这些干细胞被称为卫星细胞 (SC)，它们驻留在肌肉内一个称为“生态位”的特殊位置。SC 通常是静止的（不活跃），但为了响应来自身体的信号，它们被激活并开始繁殖。 SC 的后代将分化成更多的肌肉，但也会重新进入生态位，以便在整个生命过程中维持干细胞库。 SC 被激活后，它们会沿着肌肉纤维迁移到损伤部位，然后进行修复。随着年龄的增长，我们会失去一些 SC，而剩下的 SC 产生更多肌肉的效率就会降低。因此，了解如何保持这些细胞的健康非常重要。我们发现 SC 有一个称为初级纤毛的细胞突起，它充当重要信号的“天线”。其中一个信号是声波刺猬蛋白 (Shh)，我们知道细胞需要初级纤毛才能感知它。我们创造了一个独特的小鼠品系，经过基因改造，它们携带突变的 SC，但缺乏初级纤毛。我们发现，这会导致受伤后肌肉再生效率大大降低，肌肉纤维更薄。我们的发现表明，激活Shh通路可能对肌肉疾病有潜在的治疗作用，或者有助于维持老年人的肌肉功能。首先，我们需要更详细地研究初级纤毛和Shh如何影响SC功能——这就是这个项目的目的。我们将检查突变 SC 被激活、分裂、迁移、分化和重新进入其生态位的能力。如果 SC 没有纤毛，它们也有可能死亡，我们将测试是否可以通过注射激活 Sonic Hedgehog 信号通路的药物来改善肌肉修复。我们进行这些实验所需的所有方法都是在我们的实验室中建立的。除了修复机制的详细表征之外，我们还将检查没有初级纤毛的 SC 中发生的分子变化，特别是我们将询问哪些基因因此而表达不同。这将提供额外的重要见解，并可能揭示肌肉疾病的潜在新治疗靶点，或有助于维持老年人和体弱者的健康组织。

项目成果

Absence of the primary cilia formation gene Talpid3 impairs muscle stem cell function.

• DOI: 10.1038/s42003-023-05503-9
• 发表时间: 2023-11-04
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Martinez-Heredia, Victor;Blackwell, Danielle;Sebastian, Sujith;Pearson, Timothy;Mok, Gi Fay;Mincarelli, Laura;Utting, Charlotte;Folkes, Leighton;Poeschl, Ernst;Macaulay, Iain;Mayer, Ulrike;Munsterberg, Andrea
• 通讯作者: Munsterberg, Andrea

Characterising open chromatin in chick embryos identifies cis-regulatory elements important for paraxial mesoderm formation and axis extension.

• DOI: 10.1038/s41467-021-21426-7
• 发表时间: 2021-02-19
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Mok GF;Folkes L;Weldon SA;Maniou E;Martinez-Heredia V;Godden AM;Williams RM;Sauka-Spengler T;Wheeler GN;Moxon S;Münsterberg AE
• 通讯作者: Münsterberg AE

Muscle stem cell function is impaired in absence of Talpid3 - a gene required for primary cilia formation

如果缺乏 Talpid3（初级纤毛形成所需的基因），肌肉干细胞功能就会受损

• DOI: 10.1101/2022.10.14.512102
• 发表时间: 2022
• 作者: Martinez-Heredia V

Characterising open chromatin identifies novel cis-regulatory elements important for paraxial mesoderm formation and axis extension

表征开放染色质识别出对轴旁中胚层形成和轴延伸重要的新型顺式调控元件

• DOI: 10.1101/2020.01.20.912337
• 发表时间: 2020
• 作者: Mok G