Adult skeletal muscle has the ability to repair and regenerate following exercise, trauma or disease-induced damage despite being comprised of multinucleated muscle fibers whose nuclei cannot divide. This property is primarily attributable to adult myogenic precursor cells (satellite cells). When activated in response to local muscle damage, satellite cells proliferate extensively, either self-renew to reconstitute the reserve muscle progenitor pool or differentiate into new skeletal muscle fibers by fusing with each other or into the existing muscle fiber. Because satellite cells display lineage-specific differentiation (muscle cell) and self-renewal, two characteristics of stem cells, they are considered the primary resident adult stem cells of skeletal muscle. While intensive research efforts have advanced our understanding of satellite cell biology since their discovery in 1961, the regulatory mechanism(s) controlling satellite cell number remain unknown. Here we provide evidence implicating FGF6 signaling, which can be modulated by the Hippo pathway mediator TEAD1 in skeletal muscle fibers, in the regulation of adult mouse satellite cell number. We previously investigated a mouse model with transgenic TEAD1 overexpression in the muscle fiber and discovered a remarkable up to 6-fold increase in the number of satellite cells without any changes in overall muscle size. We further determined that paracrine signal(s) from the TEAD1-expressing myofiber signal for the satellite cell pool expansion in this mouse model. Applying transcriptomics to this mouse model, we have identified FGF signaling, i.e. FGF6, as a physiologically relevant pathway regulating satellite cell pool size. Indeed, our preliminary analysis of skeletal muscle from Fgf6 mutant mice reveals a significant reduction in the number of satellite cells. This reduction is further exacerbated in mice, in which the two FGF receptors predominantly expressed by satellite cells are inactivated specifically in the myogenic lineage. Our goal is to determine the role of FGF signaling from the myofiber to the satellite cell in achieving a particular pool size of adult muscle progenitor cells for effective repair of muscle tissue throughout life, and how myofiber-specific TEAD1 is regulating paracrine signaling from the myofiber to contribute to regulate this process.
Specific Aims : 1) Determine the role of FGF6 and FGF2 in perinatal SC scaling and adult muscle regeneration, 2) Determine the role of Fgfr1 and Fgfr4 in the SC perinatally and in adulthood, 3) Determine how TEAD-mediated transcriptional regulation within the myofiber governs SC pool scaling. We expect new fundamental findings into how the size of the satellite cell population in muscle is specified during development and adaptively maintained during adult life. Insight into how the number of regenerative cells (stem cells) in muscle is controlled provides an entry into the development of new cell-based therapies against muscle wasting diseases, sport/combat injury, and age-related sarcopenia.
The question of resident stem cell specification, maintenance, and homeostasis is both broad and important: In addition to furthering our basic understanding of how adult stem cells interact with their host tissues for optimum performance throughout life, this research may suggest interventions that would lessen the age- related decline in stem cell efficiency and number that occurs upon aging in many critical tissues, including muscle. The impairment of aged skeletal muscle regeneration leads to structural (fibrosis), biochemical and physiological deficits in muscle function that culminate in reduced physical activity, frailty, and the progressive decline in the health of the aged. Importantly, the proposed research has the potential to identify extrinsic and intrinsic factors that stimulate muscle SC proliferation and/or fate decision, which is both consistent with current theories on age-related decline in muscle regeneration, and a feasible avenue for potential therapy development against muscle degenerative disease, and to restore muscle after sport and/or combat injury.
