Dystrophin as a novel regulator of the circadian clock in skeletal muscle and the brain

PROJECT SUMMARY/ABSTRACT
Duchenne muscular dystrophy (DMD) is a severe and progressive neuromuscular disease that affects 1:5000
live male births, making it the most common form of muscular dystrophy. DMD is caused by the disruption of the
DYSTROPHIN gene that results in the production of a non-functional or absent dystrophin protein. Lack of
dystrophin in muscle results in myofiber death and fibrosis that can result in fatal cardiac arrhythmia and/or
respiratory failure in end-stage DMD patients. Interestingly, many DMD patients report sleep disruption, nighttime
sleep/wake disruptions, nocturnal blood pressure dipping, and other symptoms independent of diaphragm
respiratory muscle weakness. These symptoms are strongly influenced by the circadian system, which suggests
that DMD patients exhibit dysregulated circadian rhythmicity of which root molecular cause has not been directly
identified. While the loss of dystrophin is the primary cause of DMD, it is evident that the circadian clock has the
ability to influence many of the same muscle health parameters, such as muscle function and metabolism, and
may represent a novel pathological factor influencing DMD patient outcomes. This proposal will investigate the
contribution of circadian rhythm disruption to DMD disease pathology and the mechanism of action to induce
disease-associated pathophysiologies through the use of a novel conditional dystrophin loss-of-function mouse
model. This proposal will evaluate the contribution of Dystrophin expression in the skeletal muscle and
suprachiasmatic nucleus (SCN)/brain towards the regulation of circadian rhythm, and define its role in muscular
health and disease pathogenesis.

Grant Number: 5R21NS140497-02
NIH Institute/Center: NIH
Principal Investigator: MATTHEW ALEXANDER