Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis

Abstract

Efficient tissue regeneration is dependent on the coordinated responses of multiple cell types. Here, we describe a new subpopulation of fibro/adipogenic progenitors (FAPs) resident in muscle tissue but arising from a distinct developmental lineage. Transplantation of purified FAPs results in the generation of ectopic white fat when delivered subcutaneously or intramuscularly in a model of fatty infiltration, but not in healthy muscle, suggesting that the environment controls their engraftment. These cells are quiescent in intact muscle but proliferate efficiently in response to damage. FAPs do not generate myofibres, but enhance the rate of differentiation of primary myogenic progenitors in co-cultivation experiments. In summary, FAPs expand upon damage to provide a transient source of pro-differentiation signals for proliferating myogenic progenitors.

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

“…Analysing both polyclonal and monoclonal cell cultures, we could not identify any MP subpopulation with adipogenic potential. Our results further support previous work showing that MPs are committed to the myogenic fate30, 31, 49, 51 and that FAPs are the adipocyte precursor population residing in murine30, 31, 32, 52 and human24, 51, 53, 54 adult skeletal muscle. Although we cannot reject the hypothesis that a small subpopulation of satellite cells could form brown adipocytes—as shown by Yin et al 27.…”

“…This could explain the low Ucp1 expression in protocols that do not include the PPARg agonist rosiglitazone in the differentiation medium 29, 31, 32. Moreover, we show that the thyroid hormone T 3 is critical for UCP1 expression in differentiated FAPs, and this hormone was not always included in the differentiation medium 30, 31. Lastly, studies using cells that have been passaged or frozen thawed prior to differentiation report low Ucp1 levels in FAP‐derived adipocytes 24.…”

“…Infiltration by neutrophils, macrophages, and eosinophils and inflammation are hallmarks of muscle regeneration 34, 44. Moreover, FAPs have been shown to be an inducible source of IL‐6, increasing IL‐6 expression for at least 5 days following muscle damage 30. To understand the role of IL‐6 in Ucp1 expression upon experimental fatty infiltration, we examined IL‐6 knockout mice 4 weeks following intramuscular GLY injections (followed or not by CL316 treatment).…”

“…To induce the proliferation and differentiation of FAPs in vivo , mice were anaesthetized with isoflurane (Forane, Abbott, Wiesbaden, Germany), and one of the tibialis anterior (TA) muscles was injected with cardiotoxin (CTX, Sigma, Buchs, Switzerland, , 50 μL, 10 mM in phosphate buffered saline) or glycerol [GLY, Sigma, 50 μL, 50% v/v in Hank's balanced salt solution (HBSS)]. Injections of HBSS into TA muscles were previously shown to not elicit skeletal muscle regeneration or intramuscular adipocyte deposition33; therefore, we used the uninjected contralateral muscles as control as described before 30, 31, 34. To promote Ucp1 expression in GLY‐induced intramuscular adipocytes, mice received intraperitoneal injections of CL316,243 hydrate (CL316, 0.5 mg/kg body mass in saline) for five consecutive days 4 weeks after intramuscular injection of GLY.…”

“…A lineage tracing study reported that most adipocytes in skeletal muscle derive from a Pax3 − lineage and that adipocytes formed in aged mice during muscle regeneration derive from Myf5 − cells 29. Moreover, it has been shown that Sca1 + /PDGFRα + fibro/adipogenic progenitors (FAPs) from skeletal muscle, but not alpha 7‐integrin + myogenic progenitors, are able to differentiate into adipocytes 30, 31. Interestingly, FAPs isolated from skeletal muscle of adult 129S6/SvEvTac (Sv/129) mice are able to differentiate into UCP1‐expressing adipocytes when pre‐treated with bone morphogenetic protein 7 (BMP7) before differentiation in vitro 32…”