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

We investigated the role of matrix metalloproteinase-10 (MMP-10) in skeletal muscle repair after ischemia using a femoral artery excision model in wild-type (WT) and MMP-10–deficient (Mmp10–/–) mice. Functional recovery was assessed by small-animal positron emission tomography, and tissue morphology was evaluated by immunohistochemistry. Gene expression and protein analyses were performed to examine MMP-10–dependent molecular mechanisms under hypoxic conditions. Early after ischemia, MMP-10 deficiency resulted in delayed tissue reperfusion (10%, P < 0.01) and increased necrosis (twofold, P < 0.01), as well as enhanced neutrophil (fourfold, P < 0.01) and macrophage (1.5-fold, P < 0.01) infiltration. These early alterations led to impaired myotube regeneration in the Mmp10–/– soleus muscle at later stages (regenerating myofibers: 30 ± 9% in WT vs. 68 ± 10% in Mmp10–/– mice, P < 0.01). Importantly, intramuscular injection of MMP-10 in Mmp10–/– mice rescued this phenotype. Molecular analyses revealed increased Cxcl1 expression in ischemic Mmp10–/– muscle at both the mRNA (tenfold, P < 0.05) and protein (30%) levels, consistent with the loss of transcriptional repression by MMP-10. These findings were further confirmed by in vivo silencing of MMP-10 using siRNA. Together, our results demonstrate that MMP-10 plays a critical role in effective muscle repair after ischemia and suggest that regulation of chemokines such as Cxcl1 contributes to MMP-10–mediated control of muscle regeneration.