Abstract
Recent literature reports changes in resident stem cells fate/behaviour during muscle wasting. One of the most represented stem cells in muscle is Fibro-adipogenic progenitors (FAPs). FAPs are a very responsive cell population involved in maintaining muscle homeostasis. During muscle wasting, FAPs are known to preferentiallydifferentiate into adipocyte/fibrosis, responsible for ectopic fibro/fatty accumulation. Furthermore, physical activity is considered as an efficient countermeasure. So far, little is known about the impact of physical activity on resident muscle stem cells, especially FAPs. Therefore, our objective is to understand how different levels of muscle activity could act on FAPs dynamics. We first collected vastus lateralis biopsies before and after 5 days ofsevere human muscle disuse (Dry immersion (DI) model), and we reported a rapid remodelling of the extracellular matrix, as well as a rapid alteration of the dynamic of resident muscle stem cells. Then, to understand the role of physical activity in the prevention of muscle ectopic adiposity accumulation, we developed an in vitro protocol ofprimary mice muscle cell contraction to mimick muscle secretory activity. Additionally, FAPs dynamic/phenotypes from exercised mice, were questioned after chronic and acute exercise. We showed that FAPs challenged with exercise’s conditioned medium significantly decrease their proliferation and differentiation into adipocyte. Among all the factors found in exercise conditioned medium, we highlighted lactate, a metaboliteproduced during exercise, as a major modulator of FAPs dynamic. We showed that lactate drastically reduced FAPs proliferation. We also showed that exercise could modify FAPs phenotype inducing a shift toward Sca1low phenotype leading to a lower proliferation state. Together, these results showed that muscle microenvironment is highly involved in the FAPs behaviour during muscle wasting, and could contribute to the rapid alteration of muscle function. Physical activity is able to modulate this dynamic, and prevent FAPs engagement into fibro/adipocyte lineage through the ability of muscle to secrete several exerkines, including lactate, but also by a direct impact on the FAPs phenotype, preventing their differentiation and pathological fate.