January 16, 2013
Aerobic Capacity Of Selectively Bred Rats Being Observed
Alan McStravick for redOrbit.com — Your Universe Online
Last month, at the Wellcome Trust´s conference on ℠Rat Genomics and Models´, several different and interesting ongoing studies were presented to all in attendance. One study in particular, out of the University of Michigan (U of M), sought to explain how selectively bred rat models were able to yield both high and low capacity runners (HCR and LCR) and just what the implications, genetically, these models might have for a better understanding of our own human propensity to exercise or practice a sedentary lifestyle and how our intrinsic aerobic capacity influences disease susceptibility.
Prior to the study even being conducted, two researchers, Dr. Steve Britton and Dr. Lauren Koch of the University of Toledo, had established two different lines of rat to study both the functional and genetic basis of aerobic activity and related metabolic traits in 1998. The two lines were selectively bred for both high and low inborn aerobic running capacities, respectively, from a starting founder population of heterogeneous NIH stock. A rotational breeding scheme was implemented in order to minimize inbreeding and to maintain the rich genetic heterogeneity. In its current iteration, the study has analyzed rats to the 28th successive generation of selectively bred rats
Aerobic capacity in the study is measured by a treadmill run-to-exhaustion protocol, where the rats are placed on a treadmill that linearly increases in speed. The maximal running distance is collected for each animal, which serves as the measurement for their aerobic capacity. The HCR rats, at this point in the breeding process, have exhibited an aerobic ability that outpaces that of the LCR rats by a total of 8 fold. Where the HCR´s are able to run as far as 2,000 meters (or approximately 1.5 hours), the better of the LCR´s typically maxed out around 200 meters, reaching a point of exhaustion usually before the tenth minute of running. Additionally, the HCR´s tend to live longer lives, possess more lean body mass and lower body fat, enjoy better cardiovascular and respiratory capacity, overall, and are also far more resistant to substance addiction.
Dr. Jun Li of the U of M Department of Human Genetics, was the primary presenter for the study´s findings at the conference held in Cambridge, England. I had the opportunity, prior to their presentation, to sit down with fellow researcher and co-author on the study, Yu-yu Ren, a 3rd year PhD candidate. Ren took a few minutes to explain to me how the individual running trials were conducted and just what the researchers were hoping to determine as a result.
The purpose of their experiment was to measure the intrinsic running capacity of the rats. By introducing the rat to a treadmill it had never run on and by only taking three trial measurements, the researchers feel they were able to minimize the training effect. For their data, the researchers accepted the best running trial time and distance collected over the three individual runs. Ren claimed this was due, in no small part, to individual running trials being affected possibly by external environmental factors.
In our interview, Ren explained how each generation was measured in three individual trial runs that were conducted in one week´s time. Each rat was placed onto a treadmill on Monday, Wednesday and Friday. Previous generations were run each day for a week. However, due to the sheer number of rats that were being continually bred for the study, the study technicians were becoming unable to accommodate that quantity of subject trials.
Rats, for their trial runs, are placed in a 4-sided metal box that has a glass top for observation. The floor itself is a treadmill. The incline for the treadmill is placed at 10 degrees and the initial speed is set at 10 meters per hour. Once the running begins, the treadmill speed is increased by 1 meter per hour every 2 minutes until the rat reaches a point of exhaustion and can continue no more. Of course, as Ren stated, rats aren´t especially well known for their attention spans. This lack of focus, combined with the fact the rats had never been trained to run a treadmill, meant the researchers had to have an incentive for the rat to continue their exercise regimen. The incentive for this study is in the form of a pad, located on the back of the box, which administers a low-charge electric shock when the rat comes in contact with it. The researchers found this jolt was an effective means of helping the rats to maintain their focus on their current task at hand.
Once the rats reach exhaustion, where they simply cannot or will not run anymore, they continue to make contact with the shock pad. This observation comes much earlier in the LCR, in which some rats simply resign themselves to the shock. Of course, Ren assured me that the technicians administering the trials are trained to recognize the point of exhaustion, thus bringing the treadmill and trial to a halt. The subject rat is then removed and their overall distance for that trial is recorded.
According to Ren, “The high runners become better runners and are able to run for a longer period of time with each successive generation. The low runners pretty much stayed the same. Because they were being bred from the lowest of the low, with the caveat that the breeders have a non-zero running time, we encountered a man-made or synthetic plateau with the low runners. We found that the overall phenotype for the low-capacity runners did not decline significantly.”
As discussed above, the rats that had the higher aerobic capacity, and thus could run longer and further, had potentially improved outcomes in health over the spans of their lives. “Health risks are heritable,” states Ren. “Our hypothesis, essentially, is from the start of this experiment based on observations from the 1970´s, where it was noted people with better aerobic capacities, people that can run better, can have a higher capacity to do exercise, are generally healthier.” He continued, “Alternately, the people that are sedentary are generally not as healthy and are plagued by more disease risk, especially late in life. The assumption we are making is that if you are a better athlete, prone to engaging in exercise activities, then you are going to be healthier and that will then carry over to your offspring, as well.”
I found this explanation to be both a simple and a highly intuitive idea. Eat healthy and exercise more and you will live longer. So when I asked Ren if this couldn´t somehow be a toss-up between nature versus nurture, he had this to say. “Nurture would be a training effect. That is definitely more of a behavioral aspect. In fact, it might hold true with our study if the high running rats had the opportunity to teach their offspring to run more or if we actually let them run on the treadmills all their life up to the point of the trials. But we have only let them run the treadmill at the times we conducted the three individual trials.”
However, Ren did mention that one of the collaborators on the study is actually studying the training effect by exposing both the high- and low-capacity running rats to running opportunities to see if there is an improvement in the outcomes of either of the lines. That study, according to Ren, could specifically present an answer to my nature versus nurture query.
Still, other future study is intended to focus on whether or not there might be a psychological component to the HCR´s and their longer running times. By this, he means, perhaps they simply like to run more than the LCR´s do.
And yet another aspect the team will have to review might actually yield a concession of sorts on their previous assertions, though doubtful. It will be necessary for the team to explore the possibility that their results might have less to do with aerobic and athletic ability of the rats and whether or not the LCR´s might not have a higher resistance to the sensation of electric shock while, conversely, perhaps the HCR´s just can´t stand it.
Each generation is placed on the treadmill for their three trials for this study. Upon completion, the rats are bred in a very specific breeding cycle that the researchers at U of M have established. Once done with the trials and breeding, many members of the preceding generation of rats are sent to other laboratories around the globe for longevity studies. However, those not fortunate to make the cut for additional study are, once their young have been successfully weaned, sacrificed. But their contribution to science is not over just yet. Both their organs and other DNA samples are harvested for future genetic and metabolic research.
Prior to concluding my interview with Ren, I had to ask just how and why he found himself in this particular field of research. “I´m an athlete and I like studies that have to do with metabolic syndromes, especially because I can find a relationship to mitochondria,” he stated. “This is one of my biggest interests. One day, I hope to sequence the mitochondria genome in these rats because that has a huge factor in bioenergetics. So, this is all about ATP/ADP and my hypothesis is that the HCR rats are better able to utilize their food and caloric intake for energy and are better able to convert ADP to ATP.”
Looking back at this conference and this presentation in particular, through the prism of the New Year and the resolutions everyone is trying so hard to maintain, I am forced to ponder an interesting thought. As I see others on the jogging trails and at the gym, dropping in numbers day by day, is their inability to maintain their focus behavioral or genetic? Are some people just predisposed to living a healthier lifestyle? And can we talk to the gym manager about putting a shock pad at the back of my treadmill, please?