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.

骨骼肌是重要的组织，不仅适合运动员或年轻人，而且对于每个人的日常生活。随着年龄的增长，我们的肌肉质量和力量往往会减少并支持持续的身体健康，并且生活质量良好，保持肌肉健康很重要。该组织具有惊人的伤害后修复的能力，肌肉可以重建自身，例如在长期固定后进行运动。这种再生能力取决于肌肉中存在的干细胞群。这些干细胞称为卫星细胞（SC），它们位于肌肉内的专门位置，称为“小众”。SC通常是静止的（不活动），但是对于从体内的信号响应，它们被激活并开始繁殖。 SC的后代将分化为更多的肌肉，但也可以重新进入利基市场，以维持整个生命的干细胞池。激活SC后，它们将沿着肌肉纤维迁移到受伤部位，然后修复。随着年龄的增长，我们将失去一些SC，其余的SC在产生更多肌肉方面的效率降低了。因此，重要的是要了解如何保持这些细胞健康。我们发现SC的细胞突出称为原代纤毛，它是重要信号的“天线”。一个这样的信号是声音刺猬蛋白（SHH），我们知道它需要由细胞感测的原代纤毛。我们创建了一条独特的小鼠系，设计用于携带缺乏原发性纤毛的突变体SC。我们表明，这会导致受伤后效率较低的肌肉再生，肌肉纤维较薄。我们的发现表明，激活SHH途径可能对肌肉疾病具有潜在的治疗益处，或者有助于在老年人中维持肌肉功能。首先，我们需要更详细地研究主要的纤毛和SHH如何影响SC功能 - 这就是该项目的意义。我们将研究突变体SC被激活，分裂，迁移，区分，重新进入其利基市场的能力。如果SCS没有纤毛，也可能会死亡，我们将通过注射激活声音刺猬信号通路的药物来测试是否可以改善肌肉修复。我们需要进行这些实验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外，我们还将检查没有主要纤毛的SC中发生的分子变化，具体来说，我们将询问哪些基因的表达方式有所不同。这将提供其他重要的见解，并可能揭示肌肉疾病中潜在的新型治疗靶标，或者有助于维持老年人和体弱的人的健康组织。

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

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

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