Basic Biology V
Skeletal muscle has a robust ability to heal after wounds. Muscle repair depends on two distinct stem cells found within the muscle, the satellite cells, which give rise to new myofibers, and the fibro/adipogenic progenitors (FAPs), which coordinate satellite cell behavior. In investigating how FAPs help muscles repair injuries, we discovered that FAPs are the only cells in the muscle that possess primary cilia. Primary cilia are structurally similar to the cilia that propel paramecia through water, but do not move. Instead primary cilia act much like antennas to transmit signals from other cells. The ability of muscle to recover from wounds is compromised with old age and in certain chronic diseases, such as Duchenne muscular dystrophy (DMD). In these conditions, stem cells fail to restore muscle function after injury and the muscle is replaced with fibroblasts and fat. We found that interfering with FAP cilia in mice inhibits the replacement of muscle with fat. This project builds off of these findings to elucidate how cilia control FAP function during muscle injury repair, what signals these cilia sense, and whether we can use drugs to manipulate FAP ciliary signaling to prevent fibrosis and fatty infiltration. This work will illuminate how cilia control stem cell behavior and how ciliary signaling controls FAP function in muscle regeneration. We will use this understanding to assess whether modulating ciliary signaling in FAPs may provide a novel therapy for DMD.
Statement of Benefit to California:
Adult stem cells repair injured tissues, but their ability to heal injuries diminishes with age or disease. For example, skeletal muscle has a robust ability to recover from wounds, but in certain diseases, such as Duchenne muscular dystrophy (DMD), stem cells within the muscle fail, causing muscle to be replaced with other cell types, including fibroblasts and fat. DMD affects 1 in 4,000 males and those with DMD have a life expectancy of approximately 25. Fibroblasts and fat also replace muscle with age. People gradually lose muscle mass after the age of 25 eventually causing sarcopenia, the loss of skeletal muscle and strength. Sarcopenia, an important component of frailty, affects almost half of people over 75 years old. California, as the most populous state, has the greatest number of people over 75 and the elderly are an increasing proportion of our population. By elucidating how muscle stem cells communicate with each other to coordinate injury repair and how this communication breaks down in diseases such as DMD and sarcopenia, we will help reveal the origins of these diseases. As no specific therapies currently exist for either DMD or sarcopenia, we will test whether pharmacological manipulation of stem cell signaling blocks progression in a mouse model of DMD. Together, these experiments may provide novel therapeutic approaches for DMD, a currently untreatable disease, and sarcopenia, a deepening public health problem.
Fibro/adipogenic progenitor (FAP) cells found in skeletal muscle are required for normal muscle regeneration upon acute injury to coordinate the behavior of muscle satellite cells that give rise to new myofibrils. In old age and in certain chronic muscle diseases, such as Duchene Muscular Dystrophy, repair of muscle is compromised, and FAPs differentiate causing replacement of muscle cells with fibroblasts and fat. The applicant has previously found that FAPs are the only cells in muscle that have primary cilia that can sense signals. Here, the applicant proposes to investigate: 1) the role of the FAP cilia in muscle regeneration upon injury; 2) whether specific signaling pathways are transduced by the FAP cilia to coordinate muscle repair and 3) whether pharmacologic modulation of the signaling pathway(s) can influence muscle repair. Novelty and Transformative Potential - The observation that FAP cells are the only cell in muscle that have primary cilia and the hypothesis that the cilia of FAP cells play an important role in muscle regeneration are novel. - The proposed experiments do not adequately address the objective of the proposal - the role cilia play in muscle repair. Therefore, the transformative potential of the proposed research is limited. Feasibility and Experimental Design - Reviewers questioned the interpretation of preliminary data, noting that it did not differentiate between disappearance of cilia from the cells and loss of ciliated cells due to cell death. This concern also applies to Aim 1. Reviewers considered this to be a fatal flaw. - Reviewers questioned Aims 2 and 3 noting that they would not specifically address the goal of the proposal, which appears to be the role and mechanism of cilia on FAP cells in muscle regeneration. For example, whereas the proposed signaling studies may address the role of the signaling pathway in FAP cells in muscle repair, they do not address the role of FAP cilia in FAP cell-mediated muscle repair. - Reviewers noted that the proposed drug-induced modification of the signaling pathway in vivo would lead to systemic effects, which could confound interpretation of any observed potential phenotype. Principal Investigator (PI) and Research Team - The PI has extensive expertise in developmental biology and has publications on the signaling pathway(s) to be investigated and on cilia. - The PI and the research team are fully capable of conducting the proposed research. Responsiveness to the RFA - The proposed research uses a vertebrate model system that is justifiable on the basis of the genetic models required to address the hypotheses to be tested - The proposal is responsive to the RFA as it seeks to understand the regulation of fibro/ adipogenic progenitors in the context of their function in muscle regeneration.