Aerobic exercise training improves muscle function in a murine model of FSHD


Non-Gene Targeting Therapies

Poster Number: 221


Adam Bittel, DPT, PhD, Daniel Bittel, PhD, Yi-Wen Chen, PhD


1. Children's Research Institute (CNMC), 2. Children's Research Institute (CNMC), 3. Children's Research Institute (CNMC)

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder caused by the aberrant expression of double homeobox protein 4 (DUX4), leading to muscle weakness, atrophy, and oxidative stress sensitivity. Exercise has been shown to improve skeletal muscle health and function in animals and humans. However, the role of exercise as a treatment for FSHD is poorly understood, including the molecular transducers of exercise adaptation.
Objective: To characterize the effects of aerobic exercise on grip strength, oxidative stress, and muscle architecture in a mouse model of FSHD (FLExDUX4) and wild type (Wt) mice.

Approach: Five-month old FLExDUX4 (16 M, 16 F) and Wt (7 M, 8 F) mice were randomly assigned to voluntary wheel running or no-wheel-running control for six weeks. Daily running distance was recorded using VitalView Software. Changes in grip strength were measured using an isometric force transducer. Muscle fibrosis was measured using Masson’s Trichrome staining. Accumulation of oxidized 2',7'-dichlorofluorescin-diacetate in single fibers of the extensor digitorum longus was used as a measure of oxidative stress.

Results: FLExDUX4 mice demonstrate significantly reduced grip strength (p<0.05), and elevated fibrosis (p<.001) relative to Wt mice at baseline. Both FLExDUX4 and Wt mice increased their running distance (p<.001) and total time (p<.001) running over the course of training, but FLExDUX4 males consistently ran a shorter distance per day than Wt male mice (p<0.05). Forelimb grip strength significantly increased (46±20%) in FLExDUX4 mice compared to control FLExDUX4 mice after training (p<0.05). Exercise tended to reduce fibrosis in FLExDUX4 mice compared to control FLExDUX4 mice (p=.09) and did not change skeletal muscle oxidative stress (p=.101).

Conclusion: FLExDUX4 mice demonstrate improved muscle performance and architecture following aerobic exercise training, which may be independent of changes in muscle oxidative stress.