Muscle-derived cytokines: novel regulators of skeletal myogenesis

skeletal muscle;cytokine;differentiation;regeneration

Waldemer-Streyer, Rachel Jean

关键词: skeletal muscle;    cytokine;    differentiation;    regeneration;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/92918/WALDEMER-STREYER-DISSERTATION-2016.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Mature skeletal muscle has a uniquely robust capacity for regeneration. This ability is due in large part to the resident population of muscle stem cells in the tissue, known as satellite cells. These adult stem cells reside in a quiescent state near the basal lamina of skeletal myofibers, but are rapidly activated by myofiber injury from trauma, strenuous exercise, or disease. Upon activation, satellite cells proliferate to produce many daughter myoblasts at the injury site. These daughter myoblasts subsequently undergo an ordered series of steps to remake functional syncytial myofibers, including migration, cell cycle withdrawal, expression of pro-differentiation genetic programs, and cell-cell fusion. However, the molecular cues that regulate these steps are still incompletely understood.Over the past decade, there have been various reports demonstrating that skeletal muscle cells are prolific secretors of cytokines and other soluble factors. In fact, myoblasts express and secrete different cytokines at distinct points during proliferation and the stages of differentiation. These observations gave rise to the idea that perhaps muscle cells could influence their own differentiation in an autocrine or paracrine manner by regulating cytokine production. This was intriguing, as it was long assumed that the immune cells that infiltrate the muscle tissue in high numbers after injury—largely neutrophils and macrophages—were the source of any secreted factors observed during skeletal muscle regeneration. Still, the functions and underlying molecular mechanisms of these cytokines are mostly unexplored.We performed a functional RNAi screen in order to better understand the roles of these muscle-derived cytokines in myogenesis, which is described in chapter II of this thesis. After screening 134 cytokine genes, we were able to categorize the resulting 29 positive hits into four functional groups (Table II.3). Class I and II cytokines represent potential positive regulators of myogenesis, while Class III and IV cytokines are potential myogenic inhibitors. Curious about the functions of these cytokines, we set about characterizing in detail the molecular mechanisms they use to affect myoblast differentiation and fusion. Tumor necrosis factor superfamily member 14 (Tnfsf14) emerged from our screen as a potential positive regulator of myogenesis, though no function for Tnfsf14 in muscle tissue had been reported. Through the studies described in chapter III of this thesis, we found that Tnfsf14 promotes myogenesis through cell survival, by maintaining a sufficient number of myoblasts available to fuse into myotubes. This action is dependent upon the Akt signaling pathway, and can be modulated in vivo to enhance muscle regeneration after injury.In chapter IV, we describe chemokine (C-X-C motif) ligand 14 (Cxcl14) as a negative regulator of myogenesis. We found that Cxcl14 expression in myoblasts prevents cell cycle withdrawal, thereby preventing subsequent differentiation. Interestingly, Cxcl14 inhibition during skeletal muscle injury sped up the regenerative process in vivo. We observed this rapid regeneration even in aging animals, which generally have decreased regenerative ability.Lastly, chemokine (C-C motif) ligand 8 (Ccl8) is described as a positive regulator of myogenesis in chapter V of this thesis. Ccl8 may be multifunctional: it appears to promote sufficient myoblast number by enhancing proliferation and survival in proliferating cells, and possibly functions in differentiating cells through a distinct pro-myogenic mechanism. We also observed that Ccl8 expression can be blunted by inhibition of the protein kinase mTOR. Further work will be necessary to fully characterize the function of Ccl8 in myogenesis, and to better understand how Ccl8 is regulated by the cell.There are still many cytokines from our RNAi screen that remain to be investigated. More complete characterization of these secreted factors and the signaling pathways they fit into can help us to better understand how skeletal muscle is developed, maintained, and regenerated. Indeed, these cytokines may represent novel therapeutic targets for managing muscular diseases or age-related muscle wasting.