title: Adenosine A3 receptor stimulation reduces muscle injury following physical trauma and is associated with alterations in the MMP/TIMP response.
abstract: We have previously demonstrated that in response to traumatic injury in skeletal muscle, there is a dysregulation of the matrix metalloproteases (MMPs) and their inhibitors (TIMPs), a response hypothesized to interfere with proper skeletal muscle regeneration. Moreover, we have shown that pharmacological activation of the adenosine A(3) receptor by Cl-IBMECA in skeletal muscle can protect against ischemia-reperfusion and eccentric exercise injury. However, the mechanism by which Cl-IBMECA protects muscle tissue is poorly defined. This study evaluated the effects of Cl-IBMECA on MMP/TIMP expression in skeletal muscle and tested the hypothesis that adenosine A(3) receptor-stimulated protection of skeletal muscle following traumatic injury is associated with a blunting of MMPs involved in inflammatory processes and collagen degradation, and an increase in MMPs associated with extracellular matrix remodeling. Sixty C57BL/6J male mice were injected with Cl-IBMECA (n = 30) or a vehicle (n = 30), and Evans blue dye. Injury was induced by applying a cold steel probe (-79°C) to the tibialis anterior (TA) muscle for 10 s. TA muscles from uninjured and injured legs were collected 3, 10, and 24 h postinjury for analysis of muscle injury and MMP/TIMP mRNA and protein levels. Twenty-four hours postinjury, 56.8% of the fibers were damaged in vehicle-treated mice vs. 35.4% in Cl-IBMECA-treated mice (P = 0.02). Cl-IBMECA treatment reduced membrane type 1 (MT1)-MMP, MMP-3, MMP-9, and TIMP-1 mRNA expression 2- to 20-fold compared with vehicle-treated mice (P < 0.05). Cl-IBMECA decreased protein levels of latent/shed MT1-MMP 23-2,000%, respectively, 3-10 h postinjury. In Cl-IBMECA-treated mice, latent MMP-2 was decreased 20% 3 h postinjury, active MMP-3 was decreased 64% 3 h postinjury, and latent/active MMP-9 was decreased 417,631% 3 h postinjury and 20% 10 h postinjury. Protein levels of active MMP-2 and latent MMP-3 were increased 25% and 74% 3 h postinjury, respectively. The present study elucidates a new protective role of adenosine A(3) receptor stimulation in posttraumatic skeletal muscle injury.
authors: U.S. Army Research Institute of Environmental Medicine, Military Performance Division, Natick, MA 01760, USA. maria.urso@us.army.mil
authors: Maria L
authors: ML
authors: Urso
authors: Ruibo
authors: R
authors: Wang
authors: Edward J
authors: EJ
authors: Zambraski
authors: Bruce T
authors: BT
authors: Liang
mesh_terms: D058909:Adenosine A3 Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005615:Freezing; D007249:Inflammation / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D014947:Wounds and Injuries / Q000188:drug therapy* / Q000201:enzymology
chemical_list: D058909:Adenosine A3 Receptor Agonists; D012333:RNA, Messenger; D043684:Receptor, Adenosine A3; D019714:Tissue Inhibitor of Metalloproteinases; D003094:Collagen; D020782:Matrix Metalloproteinases