Abstract 198: Myd88 Signaling Promotes Il6 Release and Slows Muscle Regeneration After Limb Ischemia
Introduction MyD88 is an adapter protein involved in sensing tissue damage by innate immune receptors. We have previously shown that the absence of MyD88 protected against ischemia induced muscle injury in mice. This dramatic finding could be due to resistance to ischemia and/or accelerated regeneration. We hypothesize that MyD88 promotes ischemic muscle injury through increased inflammation and cell necrosis.
Methods MyD88KO (KO) and WT littermates underwent femoral artery ligation (FAL) on the right hindlimb. Serum TNFα and IL6 were measured by ELISA at 24 hrs. After 1 wk, hindlimb muscle was examined for inflammatory cell infiltration, muscle necrosis, fat replacement, regenerating myocytes, and myofiber area (1 wk).
Results After 24 h, serum TNFα levels were increased in mice undergoing FAL but were similar in KO and WT mice. Serum IL6, a myokine that inhibits muscle growth, was higher in WT than KO mice (79.3 ± 18.4 vs. 22.9 ± 11.8 pg/ml; p<0.05). One wk after FAL, inflammatory infiltration, fat replacement and muscle necrosis were extensive in both WT and KO mice. Regenerating myofibers, represented by multinucleated cells, were more numerous and larger in size in KO mice (148.7 ± 14.4 μm2 vs. 77.3 ± 23.5 μm2, N=4-6 each; p=0.03; Fig 1).
Discussion Ischemia promotes muscle inflammation and necrosis independent of MyD88. Instead, the absence of MyD88 enhanced regeneration, potentially through a reduction in IL6 production. Thus, contrary to our hypothesis, MyD88 appears to increase muscle injury following ischemia by inhibiting muscle regeneration and not through increased inflammation and necrosis.
- © 2013 by American Heart Association, Inc.