Duchenne muscular dystrophy (DMD) is a progressive X-linked neuromuscular disease where patients develop severe muscle weakness, cardiomyopathy, and respiratory failure. Interestingly, many common pathological symptoms reported in DMD are under circadian regulation, including as sleep/activity disturbances and aberrant blood pressure nocturnal dipping. This suggests that DMD patients may have dysregulated circadian rhythms, yet this has not been directly studied. We hypothesize that loss of dystrophin results in substantial disruption of circadian rhythms, which may contribute to disease severity.
To investigate circadian behavior in DMD, we measured locomotor activity under 12L:12D conditions in 6-month old wild type (WT) and symptomatic DMD mdx male mice. Mdx mice exhibited a more variable period length, phase shift of activity onset, increased activity in subjective night and a less robust rhythmic behavior. Consistent with this, mdx muscle revealed BMAL1 transcription was up-regulated while PER and CRY transcription were severely down-regulated. Transcription of numerous clock-controlled genes (CCGs) were also dramatically reduced, such as Tcap, Ciart, Hk2 and Pfk. Additionally, we identified the novel microRNA, miR-484, to be upregulated in dystrophic muscle. CHIP-seq data reveal that BMAL:CLOCK transcription factors bind the miR-484 genetic region, suggesting miR-484 may be under influence of the circadian clock.
This work is the first to report disrupted circadian rhythms in dystrophic mouse model and potentially providing insight into a new role of dystrophin that could contribute to disease severity. Future work is aimed at further delineating the relationship of dystrophin and the circadian clock, and downstream mechanisms including miR-484.