Functional MMP‐10 is required for efficient tissue repair after experimental hind limb ischemia

We studied the role of matrix metallo proteinase-10 (MMP-10) during skeletal muscle repair after ischemia using a model of femoral artery excision in wild-type (WT) and MMP-10 deficient (Mmp10–/–) mice. Functional changes were analyzed by small animal positron emission tomography and tissue morphology by immunohistochemistry. Gene expression and protein analysis were used to study the molecular mechanisms governed by MMP-10 in hypoxia. Early after ischemia, MMP-10 deficiency resulted in delayed tissue reperfusion (10%, P < 0.01) and in increased necrosis (2-fold, P < 0.01), neutrophil (4-fold, P < 0.01), and macrophage (1.5-fold, P < 0.01) infiltration. These differences at early time points resulted in delayed myotube regeneration in Mmp10–/– soleus at later stages (regenerating myofibers: 30 ± 9% WT vs. 68 ± 10% Mmp10–/–, P < 0.01). The injection of MMP-10 into Mmp10–/– mice rescued the observed phenotype. A molecular analysis revealed higher levels of Cxcl1 mRNA (10-fold, P < 0.05) and protein (30%) in the ischemic Mmp10–/– muscle resulting from a lack of transcriptional inhibition by MMP-10. This was further confirmed using siRNA against MMP-10 in vivo. Our results demonstrate an important role of MMP-10 for proper muscle repair after ischemia, and suggest that chemokine regulation such as Cxcl1 by MMP-10 is involved in muscle regeneration.—Gomez-Rodriguez, V., Orbe, J., Martinez-Aguilar, E., Rodriguez, J. A., Fernandez-Alonso, L., Serneels, J., Bobadilla, M., Perez-Ruiz, A., Collantes, M., Mazzone, M., Paramo, J. A., Roncal, C., Functional MMP-10 is required for efficient tissue repair after experimental hind limb ischemia. FASEB J. 29, 960–972 (2015). www.fasebj.org