Investigating the role of the primary cilium in muscle regeneration

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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.