2015 ISAKOS Biennial Congress ePoster #302

Oral Administration of Losartan Significantly Improves Muscle Healing After Compartment Syndrome-Like Muscle Injury in Rat

Makoto Kobayashi, MD, PhD, Nagoya, Aichi JAPAN
Yohei Kawakami, MD, PhD, Pittsburgh, PA UNITED STATES
Takanobu Otsuka, MD, PhD, Prof., Nagoya, Aichi JAPAN
Freddie H. Fu, MD, Pittsburgh, PA UNITED STATES
Johnny Huard, PhD, Houston, TX UNITED STATES

Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA

FDA Status Cleared

Summary: Oral administration of losartan significantly reduced the fibrosis formation and promoted muscle regeneration after compartment syndrome injury. Losartan will be the candidate for the development of safe biological treatments to accelerate muscle healing after compartment syndrome injury.

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Abstract:

Introduction

Compartment syndrome (CS) is a serious complication arising from a variety of extremity injuries which results from extreme swelling within the muscle fascicles. The current standard of care for treating CS is fasciotomy, which relieves the intracompartmental pressure of CS but inflicts further tissue damage. Potential new techniques for treating CS include: angiogenic therapy, antifibrosis treatments, and stem cell therapy, all of which could enhance tissue regeneration and functional muscle recovery. Since our group has shown that the oral administration of losartan after a muscle injury can improve the healing of skeletal muscle by reducing fibrosis, we investigated the potential beneficial effect that losartan could impart when used to treat a rat model of CS.

Material & Methods:
A compartment syndrome (CS) like injury was created in both hind limbs of rats as. All injured rats were randomly assigned to one of two groups ((1) losartan group, (2) No treatment group). Normal uninjured rats were also used as a normal control group ((3) Normal group). The losartan group received commercially available losartan at a dose of 10 mg/kg/day starting on day 3 after injury and continued until the end point. Rats underwent physiological testing at two or four weeks. After that, the rats were euthanized and their tibialis anterior (TA) muscles were analyzed histologically.

Results

At 4 weeks post-injury, the losartan group showed significantly greater muscle torque when compared with the No treatment group. Histological evaluation revealed that the losartan group had a significantly higher percentage of regenerating myofibers at 2 weeks when compared with the No treatment group. Also, the losartan group had significantly less fibrosis at 4 weeks compared with the No treatment group.After immuno-staining, the losartan group showed a significantly greater Smad7 expression at 1 week when compared with the No treatment group. In contrast, the losartan group showed a significantly less pSmad2/3 expression at 1 week when compared with the No treatment group. The losartan group also showed a significantly greater MyoD expression when compared with No treatment group.

Discussion

Although losartan has an effect through the blockade of TGF-ß1 signaling and improves muscle healing after muscle injury, the mechanism has not been completely elucidated. In the present study, we evaluated the oral administration of losartan for treating a CS-like injury model. We observed significantly better functional recovery in losartan group. As for the mechanism, we observed a greater amount of muscle regeneration and suppression of fibrosis in the losartan group compared to the untreated group. We also observed a significantly greater expression of Smad7 in the losartan group, which is known to be a negative modulator of TGF-ß1 signaling; moreover, we observed a reduction in the expression of pSmad2/3. These results suggest that losartan blocks the TGF-ß1-Smad pathway by blocking the phosphorylation of Smad2/3 via the over expression of Smad7. Interestingly, the losartan group also significantly enhanced MyoD expression. MyoD is a protein with a key role in regulating muscle differentiation and may be one of the mechanisms by which losartan promotes myogenesis