Targeting The Hif-1α Pathway To Eliminate Trauma-induced Muscle Fibrosis
David Cholok, BS, Shailesh Agarwal, MD, Shawn Loder, BS, John Li, MD, Joshua Peterson, BS, James Drake, BS, Hsiao Hsin Sung, DDS, Shuli Li, MD, Paul Cederna, MD, Benjamin Levi, MD.
University of Michigan, Ann Arbor, MI, USA.
PURPOSE: Muscle fibrosis is a pathologic condition characterized by abnormal collagen deposition causing loss of muscle excursion. Fibrosis develops in settings of trauma such as muscle crush or laceration and in muscle flaps or transfers which are prone to ischemic insult. Here we study the role of hypoxia-inducible factor-1 alpha (HIF-1α) as a mediator of muscle fibrosis to elucidate potential therapeutic targets.
METHODS: Mice with Cre-inducible expression of hyperactive BMP receptor (caACVR1fl/fl) underwent Ad.cre/cardiotoxin injection to generate intramuscular trauma and fibrosis. Mice were treated daily with vehicle control or the HIF-1α inhibitors rapamycin (10 mg/kg) or PX-478 (100 mg/kg) for 15 days and euthanized. Fibrosis was quantified using picrosirius staining, and pro-fibrotic mesenchymal cells were quantified using PDGFRα immunostaining.
RESULTS: Ad.cre/cardiotoxin injection caused reproducible intramuscular fibrosis on H&E and picrosirius after 15 days (A). Mice treated with HIF-1α inhibitors consistently produced less fibrosis at 15 days post-injection based on picrosirius (B). Immunostaining showed fewer PDGFRα(+) cells at the site of injury in treated mice when compared with untreated controls (C). These cells expressed Col1, but did not express cartilage or bone markers consistent with their role in fibrosis.
DISCUSSION: Our results suggest that HIF-1α inhibition represents a viable therapeutic strategy to reduce or eliminate intramuscular fibrosis. These therapeutics are readily available and may improve long-term function of muscle at risk for fibrosis.
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