LAUSR

The circadian clock is an intrinsic timing mechanism which regulates most physiological processes within the body. Disruption of circadian rhythms has been identified as a risk factor for several chronic diseases with altered redox control. We investigated the hypothesis that NRF2, a master regulator of antioxidant defence, is a clock-controlled gene in skeletal muscle, which can modulate the circadian clock function. Using genetic, pharmacological and real-time imaging approaches, we identified a feedback mechanism between the circadian clock machinery and the NRF2/KEAP1 antioxidant pathway. Pharmacological manipulation of NRF2 exerted robust effects on both the amplitude and periodicity of circadian clock oscillations. Moreover, single muscle fibre isolation has confirmed cell-autonomous changes in core clock gene expression in fibres from Nrf2 KO mice. Interestingly, similar effects on clock gene expression were also evident in muscle fibres isolated from old wild-type mice. Loss of Nrf2, or ageing led to diminished clock gene cycles but activated rhythmic gene cycles of genes involved in inflammation and stress resistance. All together, these findings implicate NRF2 as an important therapeutic target which may be utilised in future to reset or re-align disrupted circadian rhythms seen in several chronic diseases associated with muscle wasting including COPD and sarcopenia.