Beneficial effects of a HIF-2α inhibitor on satellite cell function and muscle regeneration in Duchenne muscular dystrophy mouse models


Topic:

Muscle Regeneration in Disease (includes satellite cells)

Poster Number: 108

Author(s):

Denise Fahey, Albino G. Schifino, Amelia Yin, MS, Jarrod A. Call, PhD, Hang Yin, PhD

Institutions:

1. University of Georgia, 2. University of Georgia, 3. University of Georgia, 4. University of Georgia, 5. University of Georgia

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder that effects 1 in 3,000 males. This progressive disease causes continual muscle damage due to dystrophin deficiency. In later stages of DMD, damaged muscles appear to be inefficiently repaired, leading to fibrosis and functional impairment. Muscle stem cells, or satellite cells, are responsible for muscle repair and regeneration in the adult stage. When severe muscle damage occurs, satellite cells become activated to proliferate and eventually fuse to repair damaged myofibers. We hypothesized that tissue hypoxia in DMD muscle stabilizes hypoxia-inducible factor 2 alpha (HIF-2α) in satellite cells, impairing satellite cell function in regeneration and contributes to disease progression. PT-2385 is a compound inhibitor of HIF-2α that has already been proven safe in clinical trials in cancer indications. Thus, we sought to test the efficacy of PT-2385 in improving satellite cell function and muscle regeneration using DMD mouse models. Our preliminary results suggest that treating mdx-/- utrn-/+ mice with PT-2385 enhances satellite cell function, translating to improved muscle strength. Male mdx-/- utrn-/+ mice were intraperitoneally injected with PT-2385. Compared to control mice, the tibialis anterior muscle in PT-2385 treated mice had an increase in Pax7+ satellite cells and myofibers with centralized nuclei. Additionally, PT-2385 treatment also increased myofiber cross-sectional area. These enhancements are associated with improvements in maximal isometric force generation. Collectively, our preliminary results suggest that PT-2385 has advantageous effects in DMD mouse models and warrant further studies in its optimal treatment regime and mechanism of action.