Acute
ischemia-reperfusion injury in skeletal muscle is a significant clinical concern in the
trauma setting. The mitochondrial permeability transition inhibitor
NIM-811 has previously been shown to reduce ischemic injury in the liver and kidney. The effects of this treatment on skeletal muscle are, however, not well understood. We first used an in vitro model of muscle cell
ischemia in which primary human skeletal myoblasts were exposed to hypoxic conditions (1% O2 and 5% CO2) for 6 h. Cells were treated with
NIM-811 (0-20 µM). MTS assay was used to quantify cell survival and LDH assay to quantify cytotoxicity 2 h
after treatment. Results indicate that
NIM-811 treatment of ischemic myotubes significantly increased cell survival and decreased LDH in a dose-dependent manner. We then examined
NIM-811 effects in vivo using orthodontic rubber bands (ORBs) for 90 min of single hindlimb
ischemia. Mice received vehicle or
NIM-811 (10 mg/kg BW) 10 min before reperfusion and 3 h later.
Ischemia and reperfusion were monitored using
laser speckle imaging. In vivo data demonstrate that mice treated with
NIM-811 showed increased gait speed and improved Tarlov scores compared to vehicle-treated mice. The ischemic limbs of female mice treated with
NIM-811 showed significantly lower levels of MCP-1,
IL-23,
IL-6, and IL-1α compared to limbs of vehicle-treated mice. Similarly, male mice treated with
NIM-811 showed significantly lower levels of MCP-1 and IL-1a. These findings are clinically relevant as MCP-1,
IL-23,
IL-6, and IL-1α are all pro-inflammatory factors that are thought to contribute directly to tissue damage after ischemic injury. Results from the in vitro and in vivo experiments suggest that
NIM-811 and possibly other mitochondrial permeability transition inhibitors may be effective for improving skeletal muscle salvage and survival after
ischemia-reperfusion injury.