Disrupted circadian core-clock oscillations in Type 2 Diabetes are linked to altered rhythmic mitochondrial metabolism

Abstract

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 ARNTL, CLOCK, CRY1 and NR1D1 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. Mitochondrial associated genes were enriched for differential circadian amplitudes in T2D, and positively correlated with insulin sensitivity. ChIP-sequencing identified CLOCK and BMAL1 binding to circadian mitochondrial genes associated with insulin sensitivity, implicating regulation by the core clock. 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.

The skeletal muscle circadian clock regulates titin splicing through RBM20

“…Since skeletal muscle Bmal1 knockout and physiological disruption of circadian rhythms reduced Rbm20 expression, we asked whether Rbm20 is a direct transcriptional target of the core clock factors in skeletal muscle. Our first approach was to interrogate our skeletal muscle ChIP-seq data sets for BMAL1 and CLOCK as these proteins comprise the positive limb of the skeletal muscle circadian clock ( Gabriel et al, 2021 ). We also looked into our skeletal muscle ChIP-seq data set for MYOD1 as we have previously shown with Tcap that the clock factors can function synergistically with MYOD1 to transcriptionally regulate gene expression ( Hodge et al, 2019 ; Cao et al, 2010 ).…”

“…MYOD1, BMAL1, and CLOCK ChIP-seq data (accession numbers GSE122082 and GSE143334) recently published by our lab were searched for binding peaks in Rbm20 using UCSC Genome Browser ( Gabriel et al, 2021 ; Hodge et al, 2019 ; Cao et al, 2010 ). Following identification of overlapping peaks, putative regulatory regions identified by the ENCODE Registry of cis -Regulatory Elements were scanned for canonical E-box sequences 5′-CANNTG-3′ ( Moore et al, 2020 ).…”

The Skeletal Muscle Circadian Clock Regulates Titin Splicing Through RBM20

“…Since skeletal muscle Bmal1 knockout and physiological disruption of circadian rhythms reduced Rbm20 expression, we asked if Rbm20 is a direct transcriptional target of the core clock factors in skeletal muscle. Our first approach was to interrogate our skeletal muscle ChIP-Seq data sets for BMAL1, and CLOCK as these proteins comprise the positive limb of the skeletal muscle circadian clock (24). We also looked into our skeletal muscle ChIP-Seq data set for MYOD1 as we have previously shown with Tcap , that the clock factors can function synergistically with MYOD1 to transcriptionally regulate gene expression (25, 26).…”

“…Targeted ChIP-PCR in Adult Skeletal Muscle from C57Bl/6J Mice MYOD1, BMAL1, and CLOCK ChIP-seq data (Accession numbers GSE122082 and GSE143334) recently published by our lab were searched for binding peaks in Rbm20 using UCSC Genome Browser (23)(24)(25). Following identification of overlapping peaks, putative regulatory regions identified by the ENCODE Registry of cis-Regulatory Elements were scanned for canonical E-box sequences 5'-CANNTG-3' (26).…”

Circadian rhythm disruption is associated with skeletal muscle dysfunction within the blind Mexican Cavefish

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Circadian control of physiology and metabolism is pervasive throughout nature, with circadian disruption contributing to premature aging, neurodegenerative disease, and type 2 diabetes (Musiek et al 2016; Panda, 2016). It has become increasingly clear that peripheral tissues, such as skeletal muscle, possess cell-autonomous clocks crucial for metabolic homeostasis (Gabriel et al 2021). In fact, disruption of the skeletal muscle circadian rhythm results in insulin resistance, sarcomere disorganization, and muscle weakness in both vertebrates and non-vertebratesindicating that maintenance of a functional muscle circadian rhythm provides an adaptive advantage.

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