Biology subjects

Kotsaris, G.

Publications and source records attributed to Kotsaris, G..

3 recordsLinked to original sources

bioRxiv2023

Reorganization of Septin structures regulates early myogenesis

Controlled myogenic differentiation is crucial for developmental formation, homeostatic maintenance and adult repair of skeletal muscle and relies on cell fate determinants in myogenic progenitors or resident stem cells. Proliferating muscle progenitors migrate, adopt spindle shape, align membranes and fuse into multinuclear syncytia. These processes are accompanied by cyto-architectural changes driven by rearranging of cytoskeletal components such as actin and microtubules. Here we highlight septins, the fourth component of the cytoskeleton, to represent an essential structural element of myoblasts. Specifically, Septin9 regulates myoblast differentiation during the early commitment process. Depletion of Septin9 in C2C12 cells and primary myoblasts led to a precocious switch from a proliferative towards a committed progenitor transcriptomic program. Additionally, we report Septin9 undergoing substantial reorganization and downregulation during myogenic differentiation. Together, we propose filamentous septin structures and their controlled reorganization in myoblasts to provide a key temporal regulation mechanism for the differentiation of myogenic progenitors.

cell biology↗

bioRxiv2022

Odd skipped-related 1 controls the pro-regenerative response of Fibro-Adipogenic Progenitors

Skeletal muscle regeneration requires the coordinated interplay of diverse tissue-resident- and infiltrating cells. Fibro-adipogenic progenitors (FAPs) are an interstitial cell population that provides a beneficial microenvironment for muscle stem cells (MuSCs) during muscle regeneration. Here we show that the transcription factor Osr1 is essential for FAPs to communicate with MuSCs and infiltrating macrophages, thus coordinating muscle regeneration. Conditional inactivation of Osr1 impaired muscle regeneration with reduced myofiber growth and formation of excessive fibrotic tissue with reduced stiffness. Osr1-deficient FAPs acquired a fibrogenic identity with altered matrix secretion and cytokine expression resulting in impaired MuSC viability, expansion and differentiation. Immune cell profiling suggested a novel role for Osr1-FAPs in macrophage polarization. In vitro analysis suggested that increased TGF{beta} signaling and altered matrix deposition by Osr1-deficient FAPs actively suppressed regenerative myogenesis. In conclusion, we show that Osr1 is central to FAP function orchestrating key regenerative events such as inflammation, matrix secretion and myogenesis.

developmental biology↗

bioRxiv2021

Neurofibromin 1 controls metabolic balance and Notch-dependent quiescence of juvenile myogenic progenitors

Patients affected by neurofibromatosis type 1 (NF1) frequently show muscle weakness with unknown etiology. Here we show that Neurofibromin-1 (Nf1) is not required in muscle fibers, but specifically in early postnatal myogenic progenitors (MPs), where Nf1 loss led to cell cycle exit and differentiation blockade, depleting the MP pool resulting in reduced myonuclear accrual as well as reduced muscle stem cell numbers. This was caused by precocious induction of stem cell quiescence coupled to metabolic reprogramming of MPs impinging on glycolytic shutdown, which was conserved in muscle fibers. We show that a Mek/Erk/NOS pathway hypersensitizes Nf1-deficient MPs to Notch signaling, consequently, early postnatal Notch pathway inhibition ameliorated premature quiescence, metabolic reprogramming and muscle growth. This reveals an unexpected role of Ras/Mek/Erk signaling supporting postnatal MP quiescence in concert with Notch signaling, which is controlled by Nf1 safeguarding coordinated muscle growth and muscle stem cell pool establishment. Furthermore, our data suggest transmission of metabolic reprogramming across cellular differentiation, affecting fiber metabolism and function in NF1.

cell biology↗