Myf6/MRF4 is a myogenic niche regulator required for the maintenance of the muscle stem cell pool. (13th October 2020) - Lazure, Felicia
Abstract: The function and maintenance of muscle stem cells (MuSCs) are tightly regulated by signals originating from their niche environment. Skeletal myofibers are a principle component of the MuSC niche and are in direct contact with the muscle stem cells. Here, we show that Myf6 establishes a ligand/receptor interaction between muscle stem cells and their associated muscle fibers. Our data show that Myf6 transcriptionally regulates a broad spectrum of myokines and muscle‐secreted proteins in skeletal myofibers, including EGF. EGFR signaling blocks p38 MAP kinase‐induced differentiation of muscle stem cells. Homozygous deletion of Myf6 causes a significant reduction in the ability of muscle to produce EGF, leading to a deregulation in EGFR signaling. Consequently, although Myf6‐knockout mice are born with a normal muscle stem cell compartment, they undergo a progressive reduction in their stem cell pool during postnatal life due to spontaneous exit from quiescence. Taken together, our data uncover a novel role for Myf6 in promoting the expression of key myokines, such as EGF, in the muscle fiber which prevents muscle stem cell exhaustion by blocking their premature differentiation. Synopsis: Skeletal muscle fibers are a key signaling component of the muscle stem cell niche. Myf6‐induced expression of myokines in skeletal muscle maintains myofiber‐associated muscle stem cell pools by blocking their premature differentiation in adult mice. Myf6 transcriptionally promotes the expression of a vast array of myokines such as Epidermal Growth Factor EGF and VEGFA in the myofibers of adult mice. Genetic deletion of Myf6 impairs the activation of the EGFR signaling pathway in satellite cells. Mice with a homozygous deletion of Myf6 are born normal. However, Muscle stem cells from Myf6‐knockout mice spontaneously break from quiescence, activate p38 MAPK and enter into myogenic differentiation in resting adult mouse muscle. Abstract : Skeletal muscle fibers are a key signaling component of the muscle stem cell niche. Myf6‐induced expression of myokines in skeletal muscle maintains myofiber‐associated muscle stem cell pools by blocking their premature differentiation in adult mice.