Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle
Brendan M. Gabriel, Ali Altıntaş, Jonathon A. B. Smith, Laura Sardón Puig, Xiping Zhang, A. Basse, Rhianna C. Laker, Hui Gao, Zhengye Liu, Lucile Dollet, Jonas T. Treebak, António Zorzano, Zhiguang Huo, Mikael Rydén, Johanna T. Lanner, Karyn A. Esser, Romain Barrès, Nicolas J. Pillon, Anna Krook, Juleen R. Zierath
Abstract
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 normal glucose tolerance, but not T2D, and positively correlated with insulin sensitivity. Chromatin immunoprecipitation 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 bidirectional communication between mitochondrial function and rhythmic gene expression, processes that are disturbed in diabetes.