Fibrosis is a pathogenic occurrence in many diseases. In the chronic disease muscular dystrophy, fibrosis is particularly devastating as it impedes; function, recovery and treatment delivery. Fibrosis impedes function because it is non-contractile but more importantly for diaphragm and cardiac tissue fibrosis slows relaxation, a key component of optimal muscle function and for cardiac tissue cannot transmit a contraction impulse. Recovery is hampered by fibrosis because muscle stem cells ? satellite cells ? are exquisitely sensitive to their niche and fibrosis destroys the niche. Fibrosis also decreases treatments which cannot progress to their sites of action due to excessive fibrosis. We have statistically significant preliminary data that 3 week treatment with the PAK1 activator FTY-720 drastically inhibits fibrosis in all three muscle tissues tested. We now plan to identify the best dose and treatment regime to inhibit murine muscular dystrophy. We will also investigate if the treatment alleviates other muscular dystrophy phenotypes; membrane permeability, aberrant calcium signaling, and excessive immune infiltration. Finally the mechanisms of action will be investigated. These results will greatly aid patients with muscular dystrophy as FTY-720 is already FDA approved for multiple sclerosis.
We have initiated treatment of a mouse model of severe muscular dystrophy with the FDA approved pharmaceutical; FTY720. Preliminary data indicates a significant decrease in fibrosis in diaphragm, cardiac and skeletal muscles and functional recovery of the diaphragm function. We will verify this data with additional animals and also investigate the beneficially altered signaling mechanisms.
| Heydemann, Ahlke (2017) Severe murine limb-girdle muscular dystrophy type 2C pathology is diminished by FTY720 treatment. Muscle Nerve 56:486-494 |
| Heydemann, Ahlke; González-Vega, Magdalis; Berhanu, Tirsit K et al. (2016) Hepatic Adaptations to a High Fat Diet in the MRL Mouse Strain are Associated with an Inefficient Oxidative Phosphorylation System. Jacobs J Diabetes Endocrinol 2: |
