Inhibition of FasL sustains phagocytic cells and delays myogenesis in regenerating muscle fibers

Macrophage-muscle cell interactions are complex, and the majority is unknow n. The persistence of inflammatory cells in skeletal muscle could be critic al for myofiber viability. In the present paper, we show that FasL plays a role in the resolution of muscle inflammation. We analyzed inflamed muscles of normal mice treated from day 3 to day 8 with a FasL inhibitor (Fas-Ig) or with control Ig, Treated muscles were collected at 3, 5, and 10 days. Th e treatment with recombinant Fas-Ig protein induced a severe persistence of inflammatory cells at 5 days (115,000 +/- 22,838 vs. 41,661 +/- 6848, p < 0.01) and 10 days from injury (145,500 <plus/minus> 40,850 vs. 5000 +/- 100 0, p < 0.001). Myofiber regeneration was highly impaired (37 <plus/minus> 1 4 vs. 252 +/- 28, p < 0.01). Apoptosis of phagocytic cells was a,sent durin g Fas-Ig treatment (0.9 <plus/minus> 0.6 vs. 1300 +/- 150, p < 0.0001), but apoptotic, mononucleated cells appeared at day 10, 2 days after the suspen sion of Fas-Ig administration. The time course of FasL expression during mu scle inflammation, at mRNA and protein level, reveals a peak during myoblas t proliferation. The peak of FasL expression coincides with the peak of apo ptosis of phagocytic cells. In situ hybridization shows the co-expression o f FasL and MyoD mRNA in mononucleated cells, i.e., myoblasts. Experiments o n the myoblast cell culture confirmed the expression of FasL in myoblasts. The findings shown here indicate one of the pathways to control myoblast-ma crophage interaction and might be relevant for the control of inflammatory cells in muscle tissue. Perhaps altering FasL expression with recombinant p roteins could ameliorate inflammation in degenerative myopathies and up-reg ulate muscle regeneration.