Category Archives: Physiology

Physiology

Martha Merrow

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University of Groningen, the Netherlands

A chronobiologist makes sense of circadian dysfunction in illness.

When my grandfather was dying of cancer, he found himself up most nights with my grandmother, who was succumbing to Alzheimer’s disease. A nasty side effect of some neurodegenerative diseases is the loss of a regular sleep–wake cycle. Our circadian biological clock is manifest in every one of our cells, which show daily rhythms in gene expression; cellular clocks synchronise to become organ clocks, and these determine the whole organism clock.

When Jennifer Morton at the University of Cambridge, UK, and her colleagues investigated the timing of gene expression in tissues from mouse models of Huntington’s disease, they found daily ups and downs — at least in some genes — that were similar to those in healthy animals (E. Maywood et al. J. Neurosci. 30, 10199–10204; 2010). But the mice slept and woke at random even when exposed to regular light–dark cycles. Interestingly, the researchers found that rhythmic behaviour could be restored to Huntington’s mice through another stimulus — feeding the animals at a specific time of day.

I am intrigued by this work because it highlights the relevance of chronobiology to neurodegenerative disease. The authors show that in Huntington’s, the disease disrupts behavioural manifestation of the clock; in a bizarre feedback, the progression of the disease may be exacerbated by clock dysfunction through disruption in expression of a subset of clock-controlled genes.

This work also reminds me that non-photic clock stimuli are powerful tools and can be used to set the clock when light cannot. These alternatives will be important as we try to keep the clock synchronized in our increasingly unnatural modern environment — and as we try to improve the health and quality of life for both grandmothers and grandfathers

Frances Ashcroft

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University of Oxford, UK

A physiologist discusses matters close to the heart.

This time last year my father was suffering from congestive heart failure. He became increasingly frail, slowing down like an unwound clockspring until, in February, his heart simply stopped.

As a physiologist, I had some idea of his condition, but I did not then realize how close it was to my own research area.

In 1983, ATP-sensitive potassium (K-ATP) channels were found in the heart. These channels are gated pores that control potassium fluxes across the cell membrane. However, their precise role in the heart was unclear.

One year later, I discovered that these channels are central to the mechanism by which glucose stimulates insulin secretion from the pancreas. Unravelling the role of K-ATP channels in diabetes, and the way in which channel structure influences function, has been an all-consuming passion for me ever since.

To my surprise, it now turns out that these channels also play a role in heart failure. Heart failure is usually caused by narrowing of the arteries, which increases the pressure against which the heart has to pump, making it work harder. Eventually, it fails.

Recently, Andre Terzic of the Mayo Clinic in Rochester, Minnesota, and his group showed that K-ATP channels confer protection against heart failure (S. Yamada et al. J. Physiol. Lond. published online doi:10.1113/jphysiol.2006.119511; 2006). In normal mice, cardiac K-ATP channels open in response to an increased pressure load, reducing stress on the heart. Mice lacking K-ATP channels rapidly develop heart failure and die.

In the pancreas, K-ATP-channel activity is finely balanced: too much causes diabetes and too little hyperinsulinism. But in the heart, as this paper shows, opening is almost always beneficial.