Disrupted Circadian Oscillations in Type 2 Diabetes are Linked to Altered Rhythmic Mitochondrial Metabolism in Skeletal Muscle [RNA-seq]

Circadian rhythms are generated by an auto-regulatory feedback loop composed of transcriptional activators and repressors. Disruption of circadian rhythms contributes to Type 2 diabetes (T2D) pathogenesis. We elucidated whether altered circadian rhythmicity of clock genes is associated with metabolic dysfunction in T2D. Transcriptional cycling of core clock genes BMAL1, CLOCK, and PER3 was altered in skeletal muscle from individuals with T2D and this was coupled with reduced number and amplitude of cycling genes and disturbed circadian oxygen consumption. Inner-mitochondria associated genes were enriched for rhythmic peaks in NGT, but not T2D, and positively correlated with insulin sensitivity. ChIP-sequencing identified CLOCK and BMAL1 binding to inner-mitochondrial genes associated with insulin sensitivity, implicating regulation by the core clock. Inner-mitochondria disruption altered core-clock gene expression and free-radical production, phenomena that were restored by resveratrol treatment. We identify bi-directional communication between mitochondrial function and rhythmic gene expression, processes which are disturbed in diabetes. Skeletal muscle biopsies were obtained from men with either T2D or normal glucose tolerance (NGT). Primary myotubes cultures were prepared, synchronized and harvested every 6 hours over 42 hours and the transcriptome was analyzed by RNA-sequencing.