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role. A recent study by Bass and his colleagues at Northwest-
ern University revealed that muscle clocks interact with the
hypoxia-inducible factor (HIF) pathway, which responds to the
availability of oxygen.^13 When the muscles are rapidly depleted
of oxygen—during exercise, for example—HIF helps the body
transition from metabolizing glucose through mitochondrial
respiration, an aerobic process, to anaerobic glycolysis, which
takes place in the cytoplasm and produces lactic acid.
“The clock seems to be gating the capacity of the skeletal
muscle to activate HIF and HIF-dependent metabolism at dif-
ferent times of d a y,” says Clara Peek, a biochemist at North-
western University who took part in that work. “I think [this]
new molecular connection in mice possibly explains some of
the connections between metabolism and the clock in muscle.”
How the muscle clocks interact with other peripheral clocks
also remains an open question. The muscles do not act alone.
With metabolism, for example, researchers have found that
other peripheral timekeepers, such as those in the liver, pan-
creas, and adipose tissue, also play a part. Studies by Dibner’s
group^14 and others^15 have shown that the clocks cycling within
the pancreas’ islet cells are crucial for maintaining proper insu-
lin secretion. (See “Out of Sync,” The Scientist, 2013.)
“In animals with a central nervous system, clocks are orga-
nized—to the best of our approximation—in a hierarchical man-
ner,” says Bass. “A t the top of the pyramid is the so-called mas-ter clock, which is aligned with the light/dark cycle, and through
mechanisms that are still not fully known, it orchestrates the align-
ment of peripheral tissue clocks with the environmental cycle.”
And when it comes to uncovering the molecular path-
ways that keep time in muscles and control that clock’s effects
on the body, Esser says, researchers have only just begun.
“There’s a lot still to learn.” gReferences- B.H. Miller et al., “Circadian and CLOCK-controlled regulation of the mouse
transcriptome and cell proliferation,” PNAS, 104:3342–47, 2007. - J. J. McCarthy et al., “Identification of the circadian transcriptome in adult
mouse skeletal muscle,” Physiol Genomics, 31:86–95, 2007. - K.A. Dyar et al., “Muscle insulin sensitivity and glucose metabolism are
controlled by the intrinsic muscle clock,“ Mol Metab, 3:29–41, 2014. - B.A. Hodge et al, “The endogenous molecular clock orchestrates the
temporal separation of substrate metabolism in skeletal muscle,” Skeletal
Muscle, 5:17, 2015. - L. Perrin et al., “Transcriptomic analyses reveal rhythmic and CLOCK-driven
pathways in human skeletal muscle,” eLife, 7:e34114, 2018. - K.A. Dyar et al., “Transcriptional programming of lipid and amino acid
metabolism by the skeletal muscle circadian clock,” PLOS Biol, doi:10.1371/
journal.pbio.2005886, 2018. - F.W. Turek et al., “Obesity and metabolic syndrome in circadian clock mutant
mice,” Science, 308:1043–45, 2005. - B. Marcheva et al., “Disruption of the clock components CLOCK and BMAL1
leads to hypoinsulinaemia and diabetes,” Nature, 466:627:31, 2010. - C. Vetter et al., “Night shift work, genetic risk, and type 2 diabetes in the UK
Biobank,” Diabetes Care, 41:dc171933, 2018. - S. Fun et al., “Meta-analysis on shift work and risks of specific obesity types,”
Obes Rev, 19:28–40, 2018. - E.A. Schroder et al., “Intrinsic muscle clock is necessary for musculoskeletal
health,” J Physiol, 593:5387–404, 2015. - J.C. Ehlen et al., “Bmal1 function in skeletal muscle regulates sleep,” eLife,
6:e26557, 2017. - C.B. Peek et al., “Circadian clock interaction with HIF1α mediates oxygenic
metabolism and anaerobic glycolysis in skeletal muscle,” Cell Metab, 25:86–92, 2017. - C. Saini et al., “A functional circadian clock is required for proper insulin secretion
by human pancreatic islet cells,” Diabetes Obes Metab, 18:355–65, 2016. - M. Perelis et al., “Pancreatic cell enhancers regulate rhythmic transcription of
genes controlling insulin secretion,” Science, 350:aac4250, 2015.
If we succeed in showing that
the muscle clock is involved
in this passage from insulin-
sensitive to insulin-resistant
muscle, then we can imagine
ther apeutic directions, like
using clock modulators.
—Charna Dibner, University of Geneva