Reversing muscle loss

Muscle wasting, or cachexia, that is often associated with late-stage cancer is thought to be a key determinant of cancer-related deaths, but its mechanism remains poorly understood. Results from a study in mice with cancer now show that a molecule can fully reverse this muscle loss and prolong survival (Cell 142, 531–543; 2010).

H.Q. Han of Amgen Research in Thousand Oaks, CA and colleagues developed a 'decoy' receptor that blocks the ActRIIB signaling pathway, which is thought to be involved in muscle wasting. They administered this receptor, called sActRIIB, into mice with implanted colon cancer cells. This treatment rapidly and fully reversed muscle weight loss in these mice. The treated mice, however, continued to lose fat and their tumors kept growing. All of the mice that did not receive sActRIIB died within 40 days after implantation of cancer cells, while more than half of the mice that had received sActRIIB were still alive. Experiments in mice with other types of cancer showed that sActRIIB also completely reversed muscle loss in these cancer cachexia models.

There are currently few therapies available for cancer cachexia. Han and colleagues note that further studies are needed to better understand the role of the ActRIIB pathway in cancer cachexia in humans.

Resetting the circadian clock

A group of researchers has used an experimental drug to reset and restart the natural 24-hour biological clock of mice. These results suggest that it might be possible develop pharmaceutical treatments for conditions, such as jet lag and certain sleeping disorders, that are associated with altered circadian rhythms.

Most animals and plants have internal circadian clocks that consist of a complex system of molecules. Previous work has shown that mutations in the proteins casein kinase 1 (CK1) ɛ or δ can alter the circadian rhythm in mammals, but the specific roles of these proteins in setting the internal pacemaker remain unknown. Now, Andrew Loudon of the University of Manchester in the UK and colleagues have used inhibitors to selectively target CK1ɛ and CK1δ in mice (Proc. Natl. Acad. Sci. 107, 15240–15245; 2010).

The researchers found that both CK1ɛ and CK1δ are needed for proper circadian rhythm functioning. Inhibiting CK1δ (but not CK1ɛ) significantly lengthened circadian rhythms, suggesting that CK1δ is the primary circadian regulator. In mice with disrupted biological clocks, daily treatment with a drug that inhibited CK1δ reset and restarted the 24-hour activity cycles of these mice. In a press release, Loudon noted that it might also be possible to use similar drugs to treat some psychiatric diseases.

'Going under' and 'coming to' follow different paths

Despite their widespread use in surgical procedures, it is not clearly understood how anesthetics affect the central nervous system (CNS). It is generally believed that induction of anesthesia results from drug-induced modification of CNS function, whereas emergence from anesthesia is a passive process that occurs, inversely, as anesthetic is eliminated from the CNS. If this is true, then concentrations of anesthetic in the CNS should be the same at induction and at emergence. But this is not the case.

Max B. Kelz and his research group at the University of Pennsylvania School of Medicine (Philadelphia) carried out dose–response studies for two different anesthetic agents (halothane and isoflurane) in mice and in fruit flies. They found that anesthetic concentrations at emergence were significantly lower than concentrations at induction of anesthesia (PLoS ONE 5, e11903; 2010).

The results show that anesthetic induction and emergence are not exactly inverse processes, but that there is a lag in emergence from anesthesia. Once an animal (or group) transitioned from consciousness to anesthetic-induced unconsciousness, it resisted returning to the conscious state. Kelz's group called this resistance 'neural inertia'. This line of research may lead to a better understanding of disorders of sleep and consciousness, such as comas.