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Matrix Metalloprotease Inhibition Negatively Affects Signaling Required for Muscle Regeneration Post‐traumatic Injury
Author(s) -
Urso Maria L,
Carrigan Christopher T,
Warren Gordon L
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.939.18
Subject(s) - myod , myf5 , matrix metalloproteinase , myogenin , endocrinology , regeneration (biology) , medicine , chemistry , skeletal muscle , microbiology and biotechnology , biology , myogenesis
Matrix metalloproteases (MMPs) are required for extracellular matrix turnover. We previously reported that an unfavorable ratio develops between MMPs and their inhibitors in response to traumatic muscle injury. The MMP inhibitor Batimastat (BB94) improves recovery in dystrophic muscle. We hypothesized that BB94 would promote favorable MMP and myogenic signaling, expediting functional recovery post‐injury. Injury was induced by applying a steel probe (−79ºC) to the tibialis anterior (TA) for 10s. Mice were injected with BB94 or Placebo post‐injury. TA muscles were collected after muscle function testing 48h, 5d, 10d, 18d and 30d post‐injury. In BB‐94 treated mice, protein levels of active MT‐1(−71.4%), MMP‐2 (−77.9%), MMP‐3 (−63.8%) and MMP‐9 (−86.8%) decreased (p<0.05) post‐injury compared to Placebo mice. There were no differences in TA strength loss or recovery between BB‐94 and Placebo mice (strength loss: 63.5%). mRNA for myogenic and satellite cell activation factors (Myf5, Myf6, mCadherin, SCA‐1, Notch‐1) increased in injured muscle by 2.6‐ to 4.5‐fold in Placebo mice (p<0.05), but not in BB‐94 mice. MyoD was 3.5‐fold lower in BB‐94 mice. Despite decreased MMP activity, BB‐94 did not improve functional recovery. This might be explained by the changes in myogenic gene expression. MMP‐inhibition immediately post‐injury may impair signaling required for regeneration.