Characterizing fibro/adipogenic Progenitors (FAPs) in Duchenne’s Muscular Dystrophy (DMD) Mouse Model


Pre-Clinical Research

Poster Number: 246


Xuhui Liu, MD, UCSF, Mengyao Liu, California Northstate University, College of Medicine, Brian Feeley, MD, UCSF, Hubert Kim, MD/PhD, UCSF

Background: Duchenne’s Muscular Dystrophy (DMD) is a fatal genetic disease caused by the loss of functional dystrophin. DMD is characterized by progressive degeneration of cardiac and skeletal muscles. Muscle degeneration in DMD is accompanied with excessive accumulation fibrotic and adipose tissue in muscle, known as fibrosis and fatty infiltration. Fibro-adipogenic progenitors (FAPs) are muscle progenitor cells that are responsible for fibrosis and fatty infiltration in many muscle diseases. However, our understanding of FAPs in the myopathy of DMD remains limited, partially due to lacking of appropriate animal models.

Objectives: The objectives of this study are to 1) establish a novel FAP reporter DMD mouse model, thus to 2) investigate FAPs differentiation with development of muscle degeneration in DMD.

Results: A novel FAP reporter-DMD muscular dystrophic mouse model was generated by crossing PDGFRa-eGFP reporter mouse (JAX stock #007669) to D2-MDX mouse (JAX stock #013141) for 6 generations. Histology analysis showed significant myofiber damage and fibrosis in heart, diaphragm and tibialis anterior (TA) muscle as early as 3 months of age in FAP-reporter/D2-MDX mice. Flow cytometry showed percentage of FAPs in heart, diaphragm and TA muscle in DMD mice significantly increased compared to wildtype mice (5.4 % vs. 0.8 %, 18.8% vs. 1.0% and 7.3% vs. 1.1% respectively). Compared to wildtype mice, FAPs from DMD mice have significantly increased expression of fibrogenic and white fat adipogenic markers (including Col1a, ACTA2, perilipinA, adiponectin and CEB/P) and decreased expression brown/beige fat adipogenic markers (including UCP-1, PRDM16 and Dio2). FAPs in DMD muscle also have significantly decreased expression of beta3 adrenergic receptor (B3AR), a key receptor for FAP BAT differentiation.

Conclusions: In this study, we generated a novel FAP reporter DMD mouse model, in which profound muscle damage and fibrosis were observed. Since FAPs plays a central role in regulating muscle homeostasis, this novel mouse model may serve as a powerful tool in improving our understanding of cellular mechanisms of DMD myopathies.