Written by: Padmini Pillai
Original Article: Cumnock et al. Current Biology 2018
The Gist of It:
We all know the symptoms we feel when we have a cold or the flu: not wanting to get out of bed, decreased appetite, and that pesky fever. These symptoms are known as “sickness behavior”. What you may not know is that sickness behavior is caused by your immune system responding to the pathogen, not by the infection itself. In fact, your symptoms are independent of the amount of virus, bacteria, or parasite present, and how quickly they go away depends on how well your body can tolerate infection. We generally treat disease by boosting resistance, our ability to kill invading pathogens, through the use of antibiotics or vaccines. In contrast, we know very little about boosting disease tolerance, the capacity to maintain health and minimize damage during infection. Imagine if we could carry on as normal while fighting an infection! To figure out how to boost disease tolerance, we need to understand how changes in our bodies during infection make us “feel sick.”
One example of an infectious disease that makes us “feel sick” is malaria. Malaria affects hundreds of millions of people each year and is characterized by sickness behaviors including lethargy and loss of appetite. This mosquito-borne disease is typically caused by the parasite Plasmodium falciparum, which enters and reproduces in red blood cells (RBCs), the cells responsible for carrying oxygen throughout the body. After the parasite has reproduced in the RBC, it causes the cell to pop so it can escape and move on to a new one, killing the RBC in its wake.
A research team at Stanford sought to determine how malaria impacts metabolism and disease tolerance. To do this, they measured behavioral and physiological changes in mice with malaria. Just as in human malarial infection, parasites were found in the blood, RBC counts dropped (in other words, the mice become anemic), and mice exhibited sickness behavior, including decreased appetite (or anorexia). During anorexia, your body produces energy by burning fat stores through a process that requires oxygen. But malaria causes anemia by killing RBCs, limiting the number of cells to carry the oxygen needed to burn the fat. Therefore, the researchers hypothesized that a shift to a form of energy production that doesn’t require oxygen would lend an advantage to handling the infection. Glycolysis, which turns sugar (glucose) into energy, doesn’t require oxygen and even triggers the production of RBCs.
The researchers tested this hypothesis by giving mice with malaria either 2-deoxyglucose (2-DG), which blocks glycolysis, or glucose, which sparks glycolysis. Infected mice that were given 2-DG had high parasite levels, severe anemia, and weight loss, leading to death. In contrast, glucose-treated mice had much better survival, but did not have lower parasite levels. In other words, glucose promoted disease tolerance without affecting resistance to the pathogen. This work further supports the established idea that nutrition and metabolism can affect the outcome of disease.
Disclaimer: Depending on the type of infection, consuming food can have beneficial or detrimental effects on fighting an infection. Although glucose induces tolerance in this scenario, fasting has been shown to boost tolerance during other infections.
The Nitty Gritty:
Mice were infected with P. chabaudi, and the parasite density and mouse body temperature, food and water intake, activity, respiratory quotient (RQ), energy expenditure, and RBC count were monitored over time. Compared to controls, infected mice exhibited hypothermia, weight loss, anorexia, and RBC loss. Significant decreases in activity correlated with ketosis and fat burn, based on RQvalues. Infection-induced anemia led to a 90% reduction in oxygen availability. Infected mice treated with 5 mg of 2-DG exhibited decreased body temperature, weight, and RBC counts between days 11-14 and typically succumbed to disease by day 15. Conversely, infected mice treated with 20 mg of glucose had body temperatures closer to normal and improved survival. Overall, no difference in parasite density was observed between the different treatment groups.
Written By: Kathleen Cunningham
Original Article: Pires & Early eLIFE 2018.
The Gist of It
Strokes are serious events resulting from reduced or blocked blood flow in the brain. During a stroke, the reduced blood flow causes neurons in the brain to die from lack of oxygen. In the United States, stroke is the fifth leading cause of death and the number one cause of disability (National Stroke Association). Although great strides have been made in surgical intervention and treatment to help survival during a stroke, much is still unknown about what interventions we can do to prevent or reduce neuron death. Researchers from Reno School of Medicine investigated one mechanism by looking at calcium channels on the lining of blood vessels. Channels are like a tunnel in your cell membrane that allows the passage of specific types of ions and small molecules. In this case, the researchers took arteries from the brain of mice and showed that the calcium channels in the mouse arteries opened with low oxygen conditions (like during a stroke!), allowing more calcium to flow into the cell. The channels opened due to the production of a specific type of molecule called a free radical during stroke-like conditions. This inflow of calcium stimulated a signaling pathway in the cell that allows the arteries to dilate and increased the blood flow. When the researchers induced a stroke in mice that lacked the calcium channel on the blood vessel lining, the blood vessels dilated less and more neurons died from lack of oxygen. Excitingly, the researchers could treat with drugs that opened the channel in normal mice while they were having a stroke– and those mice had less neuron death.
Researchers could one day target calcium channels to decrease the damage from stroke!
The Nitty Gritty
Pires and Earley from the University of Nevada in this study used ex vivo arteries from mice expressing the fluorescent calcium indicator Gcamp6 in the arterial endothelium to investigate the role of TRPA1 calcium channels in response to hypoxia. First, the researchers measured TRPA1 Gcamp sparklets of calcium activity in response to the peroxidated lipid 4-HNE, which has previously been shown to activate the TRPA1 channel during hypoxic conditions. 4-HNE increased the frequency and the number of sparklet sites in the endothelium, which were ablated in the presence of a TRPA1 channel antagonist. The researchers then carefully held other conditions constant while exposing the arteries to hypoxic conditions, which caused the formation of endogenous 4-HNE and activated TRPA1-mediated calcium influx. The generation of 4-HNE required the production of intracellular reactive oxygen species (ROS) and was blocked by intracellular superoxide dismutase (SOD) or by the mitochondrial-targetted antioxident mitoTEMPO. Vasodilation of the pial arteries and of penetrating arterioles in response to hypoxia was blocked by treatment by a TRPA1 inhibitor or in arteries from TRPA1 ecKO mice compared to wildtype littermates. The researchers finally demonstrated that the dilation of arteries and arterioles in response to TRPA1 channel activity was protective against ischemic strokes induced in mice using a middle cerebral artery occlusion (MCAO) model. Wildtype TRPA1 mice had considerably less ischemic damage after MCAO stroke than ecKO littermates. Further, wildtype C57/bl6 micce were more resistant to damage from ischemic stroke when treated with the TRPA1-activating compound cinnamaldehyde. The authors identify this pathway as an adaptive response to lower oxygen levels and that TRPA1 activation may be neuroprotective during ischemic stroke.
Written by: Ken Estrellas
Original Article: Kjeld et al. 2018
The Gist of It
Have you ever wondered why divers are able to hold their breath for so long? A recent study from the University of Copenhagen may provide some answers to that question. Researchers analyzed muscle samples from 8 free divers “ranked among (the) national top 10” in Denmark and 8 judokas (judo athletes) of similar age, height, weight, body mass, and whole-body aerobic capacity. The mitochondria that which help power these muscles appeared very similar at first. Mitochondria from both divers and judoka were made of the same proteins in the same amounts, and the enzymes that help power these mitochondria also appeared to work at the same levels. However, further tests revealed that the divers’ mitochondria consumed lower levels of oxygen compared to those of the judoka – almost as if the divers’ mitochondria were holding their breath for longer as well. The results of this research, while interesting for divers, could potentially have farther-reaching implications in helping scientists understand how the human body can react to conditions with low oxygen – whether it’s an underwater diver, an astronaut in space, or a person with a respiratory disease – and help come up with ways for the body to adapt.
Just like the divers don’t need to breathe as much oxygen, their mitochondria don’t use as much oxygen either!
The Nitty Gritty
In this study, Kjeld et al. report on the differential characterization of muscle mitochondria from 8 healthy, male, non-smoking elite breath hold divers (BHD) compared to 8 judokas with similar ages (age 42 ± 8 years), body morphometry measures (height, weight, body mass), and whole-body aerobic capacity (VO2max as measured by an incremental cycling test). After initial measurements were taken, biopsies were extracted from the vastus lateralis muscle and split; muscle fiber bundles were extracted to determine mitochondrial respiratory capacity and oxygen consumption, and whole segments of muscle were processed to determine mitochondrial enzyme activity (including maximal citrate synthase (CS) and 3-hydroxyacyl CoA dehydrogenase (HAD) activity as measured by spectrophotometric assays) and protein concentrations (respiratory complex I-V subunits and myoglobin as measured by Western blot). Protein concentrations of OXPHOS subunits I-V, myoglobin, GLUT4, HKII, PDH-E1α did not significantly differ between BHD muscle mitochondria and judoka mitochondria; observed activities of CS and HAD were also similar. However, BHD muscle mitochondria did demonstrate statistically significant differences in Complex I leak capacity and maximal Complex I+II leak capacity compared to controls. Increased levels of H2O2 emission (normalized to O2 consumption) during leak respiration were also observed in BHD muscle mitochondria compared to judoka, but these differences were not statistically significant. The authors of this study claim that these observations demonstrate “an actual human adaptation to hypoxia” among BHD, with potential implications in studying human reactions and adaptations to hypoxia in various environmental conditions as well as disease.
Original Research Article: Thomas Kjeld, Nis Stride, Anders Gudiksen, Egon Godthaab Hansen, Henrik Christian Arendrup, Peter Frederik Horstmann, Bo Zerahn, Lars Thorbjørn Jensen, Nikolai Nordsborg, Jacob Bejder, Jens Frey Halling. “Oxygen conserving mitochondrial adaptations in the skeletal muscles of breath hold divers.” PLOS One 2018 Sep 19;13(9):e020140.