Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle

Brendan Gabriel, Ali Altıntaş, Jonathon A. B. Smith, Laura Sardón Puig, Xiping Zhang, Astrid L. Basse, Rhianna C. Laker, Hui Gao, Zhengye Liu, Lucile Dollet, Jonas T. Treebak, Antonio Zorzano, Zhiguang Huo, Mikael Rydén, Johanna T. Lanner, Karyn A. Esser, Romain Barrès, Nicolas J. Pillon, Anna Krook, Juleen R. Zierath* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Circadian rhythms are generated by an autoregulatory feedback loop of transcriptional activators and repressors. Circadian rhythm disruption 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 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.
Original languageEnglish
Article numbereabi9654
Number of pages20
JournalScience Advances
Volume7
Issue number43
DOIs
Publication statusPublished - 20 Oct 2021

Fingerprint

Dive into the research topics of 'Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle'. Together they form a unique fingerprint.

Cite this