44 THE SCIENTIST | the-scientist.com
© ISTOCK.COM, VUKOSLAVOVICsuch as diabetes. Research also indicates that these clocks may
influence muscle strength and structure, and may even regulate
neurological processes such as sleep.
“Clock systems are a sort of core, primordial part of our
genome that instruct and prepare cells for the work of using
nutrients, moving around, breathing, and [other] fundamental
processes,” says Joseph Bass, a clinical endocrinologist at North-
western University. “This is a story that’s evolving across a lot of
different experimental systems—and muscle is now a new experi-
mental system on the block.”Managing metabolism
The study of circadian rhythms, the daily cycles that regu-
late tissue and cell function, was once focused primarily on
the suprachiasmatic nucleus, the “master clock” in the brain.
Beginning in the late 1990s, scientists began uncoveringperipheral clocks—timekeepers located throughout the body—
and in 2007, Esser, Takahashi, and their colleagues confirmed
their presence in muscles.
Using microarrays to examine the transcriptomes in mouse
tissue, the researchers found a number of genes expressed in
a rhythmic fashion in muscle.^1 These included the clock genes
Bmal1 and Per2, as well as genes involved in a variety of functions,
such as transcription and metabolism.^2
By the time Schiaffino pivoted the course of his research to focus
on circadian biology, Esser and her colleagues had published these
results. “We were lucky that some pioneering groups had started
to do circadian transcriptomics on skeletal muscle,” says Kenneth
Dyar, a postdoc at the Institute for Diabetes and Obesity of Helm-
holtz Zentrum München in Germany who joined Schiaffino’s lab as
a graduate student in 2006. “So we had a short list of probable circa-
dian clock–dependent genes because they were cycling over 24 hours.”
Schiaffino and his colleagues decided to knock out Bmal1, a
core clock gene, from the muscles of mice. Upon doing so, they
discovered that the tissue’s ability to take up glucose in response
to insulin was impaired. Further analyses revealed that this was
due to decreased levels of proteins such as GLUT4, an insulin-
dependent glucose transporter, and TBC1D1, a factor involved in
the movement of GLUT4 to the plasma membrane of cells. The
researchers also found reduced activity of pyruvate dehydroge-
nase, an enzyme involved in metabolizing glucose in muscles.^3
These findings implied that “the intrinsic muscle clock is
an important controller of glucose metabolism,” Schiaffino
says. This makes sense, he adds, because a muscle can become
a “sponge for glucose” when insulin is released in a healthy ani-I think there has evolved a fairly
clear picture that the clock
is segregating... aspects of
metabolism to fit with the rest
and activity cycles of the day.
—Karyn Esser, University of Florida